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Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension
Abstract
Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients.
In 14 healthy subjects (47.1+/-4.8 years; blood pressure, 120.6+/-4.5/80.9+/-3.5 mm Hg) and 14 essential hypertensive patients (47.3+/-5.1 years; blood pressure, 153.9+/-7.1/102.3+/-4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg x 100 mL(-1) x min(-1)) or sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive patients but not in control subjects, vitamin C increased (P<0.01) the impaired vasodilation to acetylcholine, whereas the response to sodium nitroprusside was unaffected. Moreover, in another 14 hypertensive patients (47.1+/-5.2 years; blood pressure, 155.2+/-6.9/103.7+/-4.5 mm Hg), the facilitating effect of vitamin C on vasodilation to acetylcholine was reversed by N(G)-monomethyl-L-arginine (100 microg/100 mL forearm tissue per minute), a nitric oxide synthase inhibitor, suggesting that in essential hypertension superoxide anions impair endothelium-dependent vasodilation by nitric oxide breakdown. Finally, because in adjunctive 7 hypertensive patients (47.8+/-6.1 years; blood pressure, 155.3+/-6.8/103.5+/-4.3 mm Hg), indomethacin (50 microg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor, prevented the potentiating effect of vitamin C on vasodilation to acetylcholine, it is possible that in essential hypertension a main source of superoxide anions could be the cyclooxygenase pathway.
In essential hypertensive patients, impaired endothelial vasodilation can be improved by the antioxidant vitamin C, an effect that can be reversed by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. These findings support the hypothesis that nitric oxide inactivation by oxygen free radicals contributes to endothelial dysfunction in essential hypertension.
... Vitamin C is also thought to have indirect vasodilatory properties by buffering oxygen free radicals that normally inhibit nitric oxide, a potent endogenous vasodilator. Taddei et al. (7) demonstrated that vitamin C augments nitric oxide's ability to modulate systemic vascular tone, and its deficiency results in nitric oxide degradation and vasoconstriction. These studies support that vitamin C can help prevent inappropriate pulmonary vasoconstriction through its antioxidant affects in the pulmonary vasculature (7). ...
... Taddei et al. (7) demonstrated that vitamin C augments nitric oxide's ability to modulate systemic vascular tone, and its deficiency results in nitric oxide degradation and vasoconstriction. These studies support that vitamin C can help prevent inappropriate pulmonary vasoconstriction through its antioxidant affects in the pulmonary vasculature (7). ...
... Higher O 2 levels are associated with enhanced protein kinase C (PKC) activity and NOS uncoupling, as well as consequent loss of vasodilation [51]. ONOO-associated loss of vasodilation and subsequent endothelial dysfunction play a vital role in the development of hypertension and further contributes to hypertrophic remodeling [111]. In CKD patients, oxidative stress leads also to left ventricular hypertrophy (LVH). ...
... Higher O2 levels are associated with enhanced protein kinase C (PKC) activity and NOS uncoupling, as well as consequent loss of vasodilation [51]. ONOO-associated loss of vasodilation and subsequent endothelial dysfunction play a vital role in the development of hypertension and further contributes to hypertrophic remodeling [111]. In CKD patients, oxidative stress leads also to left ventricular hypertrophy (LVH). ...
Chronic kidney disease is highly prevalent worldwide. The decline of renal function is associated with inadequate removal of a variety of uremic toxins that exert detrimental effects on cells functioning, thus affecting the cardiovascular system. The occurrence of cardiovascular aberrations in CKD is related to the impact of traditional risk factors and non-traditional CKD-associated risk factors, including anemia; inflammation; oxidative stress; the presence of some uremic toxins; and factors related to the type, frequency of dialysis and the composition of dialysis fluid. Cardiovascular diseases are the most frequent cause for the deaths of patients with all stages of renal failure. The kidney is one of the vital sources of antioxidant enzymes, therefore, the impairment of this organ is associated with decreased levels of these enzymes as well as increased levels of pro-oxidants. Uremic toxins have been shown to play a vital role in the onset of oxidative stress. Hemodialysis itself also enhances oxidative stress. Elevated oxidative stress has been demonstrated to be strictly related to kidney and cardiac damage as it aggravates kidney dysfunction and induces cardiac hypertrophy. Antioxidant therapies may prove to be beneficial since they can decrease oxidative stress, reduce uremic cardiovascular toxicity and improve survival.
... Antioxidant treatment (e.g., vitamin C, E, α-lipoic acid, and Mito-Q10) has been reported to acutely restore or improve measures of endothelial function, vascular and myogenic tone, cardiac hypertrophy, and myocardial function in a variety of vascular derived conditions that are characterised by chronic low-grade oxidative stress including type 2 diabetes, chronic hypertension, atherosclerosis, cardiovascular disease, and ageing [165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181]. However, excess ROS can also lead to transient vascular dysfunction in healthy populations. ...
... For example, increased systemic oxidative stress and/or decreased antioxidant capacity following acute hyperlipidemia and hyperglycemia in healthy humans and rodents coincides with macro-and micro-vascular endothelial dysfunction [154,156,182], effects which can be largely prevented via acute co-infusion of vitamin C, N-acetylcysteine, and apocynin [154,156]. In the absence of an oxidative stress insult (e.g., nutrient overload) or chronically elevated levels of oxidative stress (e.g., oxidative stress associated disease), antioxidant treatment in healthy individuals rarely leads to improved vascular function [183], with the vast majority of evidence supporting little to no benefit [165,166,[168][169][170][171]173,174]. As such, acute antioxidant treatment for improving vascular function appears to be only effective under conditions of acute and/or chronic oxidative stress associated vascular pathophysiology. ...
Antioxidant supplements are commonly consumed by endurance athletes to minimize exercise-induced oxidative stress, with the intention of enhancing recovery and improving performance. There are numerous commercially available nutritional supplements that are targeted to athletes and health enthusiasts that allegedly possess antioxidant properties. However, most of these compounds are poorly investigated with respect to their in vivo redox activity and efficacy in humans. Therefore, this review will firstly provide a background to endurance exercise-related redox signalling and the subsequent adaptations in skeletal muscle and vascular function. The review will then discuss commonly available compounds with purported antioxidant effects for use by athletes. N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and α-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance. Finally, additional research should clarify the potential benefits of curcumin in improving muscle recovery post intensive exercise; and the potential hampering effects of astaxanthin, selenium and vitamin A on skeletal muscle adaptations to endurance training. Overall, we highlight the lack of supportive evidence for most antioxidant compounds to recommend to athletes.
... Ascorbic acid has also been reported to cause vasodilation. The vasodilatory effects of ascorbic acid were observed, in particular, in patients with non-insulin-dependent diabetes mellitus [92] and in essential hypertensive patients [93]. These properties of ascorbic acid may be useful in preventing CIN risk. ...
The use of conventional contrast media for diagnostic purposes (in particular, Gd-containing and iodinated agents) causes a large number of complications, the most common of which is contrast-induced nephropathy. It has been shown that after exposure to contrast agents, oxidative stress often occurs in patients, especially in people suffering from various diseases. Antioxidants in the human body can diminish the pathological consequences of the use of contrast media by suppressing oxidative stress. This review considers the research studies on the role of antioxidants in preventing the negative consequences of the use of contrast agents in diagnostics (mainly contrast-induced nephropathy) and the clinical trials of different antioxidant drugs against contrast-induced nephropathy. Composite antioxidant/contrast systems as theranostic agents are also considered.
... Fruits and vegetables are sources of vitamin C, whose effects on BP have been investigated both in clinical trials and in basic biochemistry experiments. Indeed, there is solid evidence from clinical studies that vitamin C treatment restores endothelial function in patients with coronary artery disease or coronary risk factors [65][66][67]. Of note, there are at least two meta-analyses [68,69] that conclude that provision of vitamin C (usually 500 mg/d) significantly reduce SBP and DBP and that this effect is more pronounced in hypertensive patients. ...
Purpose of Review
Accumulating data on the consumption of plant-based diets and their impact on blood pressure indicate a consensus that plant-based diets are linked to reduced blood pressure. The suggested mechanisms of action are manifold, and, in this systematic review, we provide a summary of the most recent findings on plant-based diets and their impact on blood pressure, along with an analysis of the molecules accountable for the observed effects.
Recent Findings
The overwhelming majority of intervention studies demonstrate that plant-based diets result in lower blood pressure readings when compared to diets that are based on animal products. The various mechanisms of action are being clarified.
Summary
The data discussed in this systematic review allow us to conclude that plant-based diets are associated with lower blood pressure and overall better health outcomes (namely, on the cardiovascular system) when compared to animal-based diets. The mechanisms of action are being actively investigated and involve many macro- and micronutrients plentiful in plants and the dishes prepared with them.
... As already discussed, effectiveness of antioxidants such as vitamin C may further depend on the relative level of glycaemic control of an individual within the type 2 diabetes population, with individuals with higher HbA1c responding more favourably than patients with lower HbA1c [115,156]. Other examples of antioxidant treatment leading to divergent effectiveness have been reported between healthy control populations and individuals with chronic obstructive pulmonary disease and essential hypertension [363][364][365]. One possible explanation for the divergent effects may be the presence of, or lack-there-of, oxidative stress-related pathology in the population investigated. ...
Growing evidence suggests that vitamin C supplementation may be an effective adjunct therapy in the management of people with diabetes. This paper critically reviews the current evidence on effects of vitamin C supplementation and its potential mechanisms in diabetes management. Evidence from meta-analyses of randomized controlled trials (RCTs) show favourable effects of vitamin C on glycaemic control and blood pressure that may be clinically meaningful, and mixed effects on blood lipids and endothelial function. However, evidence is mostly of low evidence certainty. Emerging evidence is promising for effects of vitamin C supplementation on some diabetes complications, particularly diabetic foot ulcers. However, there is a notable lack of robust and well-designed studies exploring effects of vitamin C as a single compound supplement on diabetes prevention and patient-important outcomes (i.e. prevention and amelioration of diabetes complications). RCTs are also required to investigate potential preventative or ameliorative effects of vitamin C on gestational diabetes outcomes. Oral vitamin C doses of 500-1000 mg per day are potentially effective, safe, and affordable for many individuals with diabetes. However, personalisation of supplementation regimens that consider factors such as vitamin C status, disease status, current glycaemic control, vitamin C intake, redox status, and genotype is important to optimize vitamin C's therapeutic effects safely. Finally, given a high prevalence of vitamin C deficiency in patients with complications, it is recommended that plasma vitamin C concentration be measured and monitored in the clinic setting.
... In addition, vitamin C neutralizes free radicals and protects the body against cellular damage, and it can provide a protective effect against cardiovascular diseases by regulating the production of free radicals via nitric oxide. 8,9 It has even been shown that the antipsychotic effect of haloperidol in-creases with ascorbic acid treatment in psychosis produced by hallucinogenic drugs. Although it is not known exactly how this effect occurs, it is thought that haloperidol and other dopamine receptor antagonists regulate their binding to the receptor and that ascorbic acid may have an effect on dopamine receptors. ...
Coronavirus infection (COVID-19) caused by the new coronavirus SARSCoV-2 is a global public health problem. Ascorbic acid (vitamin C) is low-cost, safe, antioxidant, anti-inflammatory, and immunomodulating, and has viral load-reducing effects when taken as a supplement. In addition, vitamin C neutralizes free radicals and protects the body against cellular damage, and it can provide a protective effect against cardiovascular diseases by regulating the production of free radicals via nitric oxide. This situation makes ascorbic acid a notable treatment candidate for preventing the worsening of COVID-19. In our case, we present a patient who had a brief psychotic episode following ingestion of high-dose vitamin C due to fear of getting infected with SARS-CoV-2. The psychotic episode may have developed due to increased levels of circulating vitamin C in the central nervous system, which may affect dopamine and GABA levels and changes in NMDA receptor function in the brain. We aim to draw attention to possible neurotoxicity and inflammation caused by free radicals on neuropsychiatric diseases. [ Psychiatr Ann . 2022;52(10):442–444.]
... Collagen polypeptide synthesis, posttranslational hydroxylations, and actions of the two hydroxylases are independently regulated by vitamin C [84]. Vitamin C also increases the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation [85], promoting adhesion [86], inhibiting apoptosis [87], scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow [88]. Since moderate and severe SARS-CoV2 infection produces high level of oxidative stress in many tissues, it therefore creates a higher demand for vitamin C since vitamin C insufficiency among healthy people in USA is 45% [49], it must be presumed that the vast majority of COVID-19 patients are depleted; however, for optimal collagen synthesis, oral might be enough. ...
Currently available anti-viral drugs may be useful in reducing the viral load but are not providing the necessary physiological effects to reduce the SARS-CoV-2 complications efficiently. Treatments that provide better clinical outcomes are urgently needed. Vitamin C (ascorbic acid, AA) is an essential nutrient with many biological roles that have been proven to play an important part in immune function; it serves as an antioxidant, an anti-viral, and exerts anti-thrombotic effects among many other physiological benefits. Research has proven that AA at pharmacological doses can be beneficial to patients with acute respiratory distress syndrome (ARDS) and other respiratory illnesses, including sepsis. In addition, High-Dose Intravenous Vitamin C (HDIVC) has proven to be effective in patients with different viral diseases, such as influenza, chikungunya, Zika, and dengue. Moreover, HDIVC has been demonstrated to be very safe. Regarding COVID-19, vitamin C can suppress the cytokine storm, reduce thrombotic complications, and diminish alveolar and vascular damage, among other benefits. Due to these reasons, the use of HDIVC should be seriously considered in complicated COVID-19 patients. In this article, we will emphasize vitamin C’s multiple roles in the most prominent pathophysiological processes presented by the COVID-19 disease.
... Peak arterial diameter will be compared to baseline diameter to calculate absolute change (mm) and percent change in diameter in response to the forearm hyperemic stimulus at baseline, after the 24-week training period, and at 4-and 12-weeks post-intervention. To determine tonic oxidative stress-mediated suppression of endothelial function, FMD BA will be repeated after intravenous infusion of supratherapeutic concentrations of the potent ROSscavenging antioxidant, Vitamin C, and isovolumic saline infusion, as described previously (57,58). A bolus of 0.06 g Vitamin C/kg fat-free mass dissolved in 100 mL of saline will be infused by IV at a rate of 5 mL/min for 20 min, followed immediately by a drip infusion of 0.02 g/kg fat-free mass dissolved in 30 mL saline infusion at a rate of 0.5 mL/min. ...
Background: Cardiovascular disease is a major global health concern and prevalence is high in adults with obstructive sleep apnea (OSA). Lowering blood pressure (BP) can greatly reduce cardiovascular disease risk and physical activity is routinely prescribed to achieve this goal. Unfortunately, many adults with OSA suffer from fatigue, daytime sleepiness, and exercise intolerance—due to poor sleep quality and nocturnal hypoxemia—and have difficulty initiating and maintaining an exercise program. High-resistance inspiratory muscle strength training (IMST) is a simple, time-efficient breathing exercise consistently reported to reduce BP in small, selective groups of both healthy and at-risk adults. Herein we present the study protocol for a randomized clinical trial to determine the long-term efficacy of IMST performed regularly for 24 weeks in middle-aged and older adults with OSA. The primary outcome is casual systolic BP. Secondary outcomes are 24-h systolic BP and circulating plasma norepinephrine concentration. Other outcomes include vascular endothelial function (endothelial-dependent and -independent dilation), aortic stiffness, casual and 24-h diastolic BP, and the influence of circulating factors on endothelial cell nitric oxide and reactive oxygen species production. Overall, this trial will establish efficacy of high-resistance IMST for lowering BP and improving cardiovascular health in middle-aged and older adults with OSA.
Methods: This is a single-site, double-blind, randomized clinical trial. A minimum of 92 and maximum of 122 male and female adults aged 50–80 years with OSA and above-normal BP will be enrolled. After completion of baseline assessments, subjects will be randomized in a 1:1 ratio to participate in either high-resistance or sham (low-resistance) control IMST, performed at home, 5 min/day, 5 days/week, for 24 weeks. Repeat assessments will be taken after the 24-week intervention, and after 4 and 12 weeks of free living.
Discussion: This study is designed to assess the effects of 24 weeks of IMST on BP and vascular function. The results will characterize the extent to which IMST can reduce BP when performed over longer periods (i.e., 6 months) than have been assessed previously. Additionally, this study will help to determine underlying mechanisms driving IMST-induced BP reductions that have been reported previously.
Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (Registration Number: NCT04932447; Date of registration June 21, 2021).
... From early studies, the use of Vit C has been proposed to counteract the oxidative stress produced by the cardiac I/R process in order to reduce the heart damage (Table 1), where it has been described that patients undergoing PCI suffer from a depletion of Vit C [59]. Several in-vitro experiments have shown the benefits of the ROS-scavenging capacity of Vit C [60], while its intra-arterial administration in high doses was found to suppress the in-vivo effects of superoxide anions on vascular endothelial dysfunction in subjects with essential hypertension [61,62]. A study showed that AMI patients undergoing thrombolysis had decreased SOD enzyme activity along with increased XO enzyme activity and malondialdehyde (MDA) levels after reperfusion, which was restored to normal or near-normal levels by oral administration of Vit C after reperfusion [63]. ...
Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients. Among these studies, results derived from the use of vitamin C (Vit C) have been inconclusive so far, likely due to suboptimal study designs, misinterpretations, and the erroneous conclusions of clinical trials. Nevertheless, recent clinical trials have shown that the intravenous infusion of Vit C prior to PCI-reduced cardiac injury biomarkers, as well as inflammatory biomarkers and ROS production. In addition, improvements of functional parameters, such as left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume, showed a trend but had an inconclusive association with Vit C. Therefore, it seems reasonable that these beneficial effects could be further enhanced by the association with other antioxidant agents. Indeed, the complexity and the multifactorial nature of the mechanism of injury occurring in AMI demands multitarget agents to reach an enhancement of the expected cardioprotection, a paradigm needing to be demonstrated. The present review provides data supporting the view that an intravenous infusion containing combined safe antioxidants could be a suitable strategy to reduce cardiac injury, thus improving the clinical outcome, life quality, and life expectancy of patients subjected to PCI following AMI.
... Tonic suppression of endothelial function with hookah use is supported by prior research showing that ascorbic acid has no effect on FMD in healthy non-smokers. 19 Similar findings on FMD changes after ascorbic acid have been reported in patients with cardiovascular disease conditions that may be associated with oxidative stress, including hypercholesterolemia, 38 hypertension, 39 insulin-dependent diabetes mellitus, 40 and aging. 19 Our findings are consistent with a previous study showing that ascorbic acid markedly improved endothelium-dependent responses in chronic cigarette smokers. ...
Background
Electronic hookah (e‐hookah) vaping has increased in popularity among youth, who endorse unsubstantiated claims that flavored aerosol is detoxified as it passes through water. However, e‐hookahs deliver nicotine by creating an aerosol of fine and ultrafine particles and other oxidants that may reduce the bioavailability of nitric oxide and impair endothelial function secondary to formation of oxygen‐derived free radicals.
Methods and Results
We examined the acute effects of e‐hookah vaping on endothelial function, and the extent to which increased oxidative stress contributes to the vaping‐induced vascular impairment. Twenty‐six healthy young adult habitual hookah smokers were invited to vape a 30‐minute e‐hookah session to evaluate the impact on endothelial function measured by brachial artery flow‐mediated dilation (FMD). To test for oxidative stress mediation, plasma total antioxidant capacity levels were measured and the effect of e‐hookah vaping on FMD was examined before and after intravenous infusion of the antioxidant ascorbic acid (n=11). Plasma nicotine and exhaled carbon monoxide levels were measured before and after the vaping session. Measurements were performed before and after sham‐vaping control experiments (n=10). E‐hookah vaping, which increased plasma nicotine (+4.93±0.92 ng/mL, P <0.001; mean±SE) with no changes in exhaled carbon monoxide (−0.15±0.17 ppm; P =0.479), increased mean arterial pressure (11±1 mm Hg, P <0.001) and acutely decreased FMD from 5.79±0.58% to 4.39±0.46% ( P <0.001). Ascorbic acid infusion, which increased plasma total antioxidant capacity 5‐fold, increased FMD at baseline (5.98±0.66% versus 9.46±0.87%, P <0.001), and prevented the acute FMD impairment by e‐hookah vaping (9.46±0.87% versus 8.74±0.84%, P =0.002). All parameters were unchanged during sham studies.
Conclusions
E‐hookah vaping has adverse effects on vascular function, likely mediated by oxidative stress, which overtime could accelerate development and progression of cardiovascular disease.
Registration
URL: https://ClinicalTrials.gov . Unique identifier: NCT03690427.
... Hypertensive patients also commonly suffer endothelial dysfunction (173)(174)(175) as a result of increased NO breakdown (176), although decreased synthesis caused by increased asymmetric dimethylarginine (ADMA) cannot be ruled out (177). The increased breakdown of NO in these circumstances is often a consequence of increased oxidative stress. ...
Cyclooxygenase (COX), which can be expressed as COX-1 or COX-2 in endothelial cells has the unique ability to regulate microvascular tone through balanced production of dilator/constrictor prostanoids. This study investigated the roles of these isoforms in microvascular endothelial dilator function and how these are affected by supplement-derived ecdysteroids. Acetylcholine or 20-hydroxyecdysone relaxation were recorded in Skeletal muscle (SKM) and mesenteric (ME) arteries from healthy sheep and omental (OM) and subcutaneous (SC) fat arteries from obese humans by wire myography in the absence and presence of inhibitors of nitric oxide synthase, cyclooxygenase (COX) isoforms 1 and 2 and endothelium-derived hyperpolarizing factors. Gene and protein expression analysis were also carried out to fully characterize the roles of COX in these arteries. Non-selective COX inhibition attenuated acetylcholine relaxation in SKM arteries but enhanced it in ME arteries. Selective inhibition of COX-1 in both SKM and ME arteries also attenuated acetylcholine relaxation. In contrast, selective inhibition of COX-2 enhanced acetylcholine relaxation in ME arteries and had no effect in SKM arteries. In OM arteries from obese patients, selective inhibition of COX-1 but not COX-2 significantly improved acetylcholine relaxation. The OM arteries also displayed enhanced responsiveness to thromboxane A2 mimetic (U46619) compared with SC arteries. 20-hydroxyecdysone caused relaxation which was attenuated by NOS inhibition compared with COX inhibition in SKM and ME arteries. COX roles in microvascular endothelial dilator function are isoform-specific and dependent on type and health of the vasculature. In healthy arteries, COX-1 promotes but COX-2 opposes vasodilation. In human obesity, COX-1 opposes while COX plays no part in OM endothelial dilator function. Although 20-hydroxyecdysone alters COX expression, its vasodilatory effect is more eNOS-dependent than COX-dependent.
... An increased production of reactive oxygen species and a heightened inflammatory status also contribute to VED in patients with hypertension 60 . oxidative stress causes NO inactivation 61 and might oxidize LDL particles thereby affecting their function, with resulting toxicity to endothelial cells and adhesion and migration of leukocytes to the arterial wall 62 . Meta-analytical evidence indicates that exercise improves endothelial function (typically assessed by flow-mediated dilatation of the brachial artery) and arterial stiffness (measured as pulse wave velocity and augmentation index), with a dose-response relationship between exercise intensity, at least in the case of aerobic exercise, and the benefits obtained 63,64 . ...
Hypertension affects approximately one third of the world’s adult population and is a major cause of premature death despite considerable advances in pharmacological treatments. Growing evidence supports the use of lifestyle interventions for the prevention and adjuvant treatment of hypertension. In this Review, we provide a summary of the epidemiological research supporting the preventive and antihypertensive effects of major lifestyle interventions (regular physical exercise, body weight management and healthy dietary patterns), as well as other less traditional recommendations such as stress management and the promotion of adequate sleep patterns coupled with circadian entrainment. We also discuss the physiological mechanisms underlying the beneficial effects of these lifestyle interventions on hypertension, which include not only the prevention of traditional risk factors (such as obesity and insulin resistance) and improvements in vascular health through an improved redox and inflammatory status, but also reduced sympathetic overactivation and non-traditional mechanisms such as increased secretion of myokines.
... mmLDL (Siow et al, 1998;Siow et al, 1999) and improves endotheliumdependent vasodilation (Taddei et al, 1998). The physiological concentration range of vitamin C in human plasma is 30-150pM (Frei et al, 1989), while a plasma concentration of 40-50pM has been associated with minimal risk of cardiovascular disease and cancer (Gey et al, 1994). ...
Oxidative stress has been implicated in the pathogenesis of various diseases including cancer, septic shock, stroke, hypertension and atherosclerosis. This manifests itself in oxidative modification of low-density lipoprotein (LDL) and the expression of specific proteins such as tissue factor (TF). It has been claimed that some of these effects can be reversed by dietary antioxidants and that at least some of these actions may be at gene level in vascular cells. The aim of the project was to study the effects of minimally oxidised low-density lipoprotein (mmLDL) and the bacterial endotoxin - lipopolysaccharide (LPS) on the expression of genes for TF and TF pathway inhibitor (TFPI) in a human monocytic cell line (THP-1) and the cell line ECV 304 (once thought to be of endothelial origin). The effect of antioxidant vitamins on the expression of these genes was elucidated. The action of the antioxidant vitamins on TF protein activity was also investigated. The principal antioxidants studied were ascorbate, α-tocopherol and lutein. The mode of action of the antioxidants was also studied through the involvement of selected nuclear transcription factors (NFkB, CREB, ELK-1 and HIF-1). In this study, Quantitative Competitive RT-PCR (QC RT-PCR) was successfully developed and applied for the determination of the changes in TF and TFPI expression. Some of the results were confirmed using Northern blot techniques. There was simultaneous expression of TF and TFPI mRNA in both THP-1 and ECV 304 cells after stimulation with a range of effectors. When an increase in TF expression was evident, a corresponding decrease in TFPI expression was noted in the case of LPS stimulation. The study confirmed that mmLDL and LPS are potent inducers of TF expression in THP-1 and ECV 304 cells. The treatment of cells with antioxidant vitamins significantly suppressed the induction of the TF gene and also induced the expression of TFPI mRNA. LPS and mmLDL also increased TF pro-coagulant activity on the surface of the cells and this activity was suppressed by antioxidants. Also, the antioxidants have effects on some of the nuclear transcription factors studied. The timing of the effects of antioxidants was given particular attention.
... Three systematic reviews with meta-analysis have summarized the benefit of VC for CABG and cardiac surgery patients [45][46][47][48]. The finding of improved endothelial function was documented in two reports focusing on the effect of high doses of VC on endothelial function [58,59]. ...
Percutaneous coronary intervention (PCI) is the preferred treatment for acute coronary syndrome (ACS) secondary to atherosclerotic coronary artery disease. This nonsurgical procedure is also used for selective patients with stable angina. Although the procedure is essential for restoring blood flow, reperfusion can increase oxidative stress as a side effect. We address whether intravenous infusion of vitamin C (VC) prior to PCI provides a benefit for cardioprotection. A total of eight randomized controlled trials (RCT) reported in the literature were selected from 371 publications through systematic literature searches in six electronic databases. The data of VC effect on cardiac injury biomarkers and cardiac function were extracted from these trials adding up to a total of 1185 patients. VC administration reduced cardiac injury as measured by troponin and CK-MB elevations, along with increased antioxidant reservoir, reduced reactive oxygen species (ROS) and decreased inflammatory markers. Improvement of the left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume (TLVV) showed a trend but inconclusive association with VC. Intravenous infusion of VC before PCI may serve as an effective method for cardioprotection against reperfusion injury.
... Due to the oxidation of Vc into H 2 O 2 , it has been proposed to use as a prodrug of H 2 O 2 for delivering to tumors [4,5]. Antioxidant activity of Vc quenches reactive oxygen species (ROS) by inhibiting ROS-mediated nitric oxide (NO) inactivation [6,7]. Ascorbic acid accumulates in ocular tissues in higher amount and protects the cornea and lens from photo-oxidative damage [8]. ...
Background
“Health is wealth” and to maintain it 7 essential nutrients are required. Among these, Vitamin is one that has great importance in very low concentration. As per the solubility, it divides into water-soluble and water-insoluble vitamins. This study concentrates on Vitamin C, a water-soluble vitamin which is essential for human growth due to its activity in the synthesis of carnitine, collagen, and neurotransmitter. It possesses antioxidant, antiatherogenic, and immunomodulatory functions, which may lead to the activity of Vitamin C in many diseases. But humans and some other non-human primates are unable to produce Vitamin C from glucose due to the absence of enzyme gulonolactone oxidase. As a result, humans are dependent on various dietary sources of Vc especially citrus fruit. But these dietary supplies also fail to achieve the required level in the body due to its poor bioavailability and storage.
Method
Vitamin C has already proven its activity in cancer therapy. It is also used as a prodrug of H2O2. But due to the poor bioavailability and storage of Vitamin C in the human body, mankind is unable to avail the benefits of Vitamin C. These problems lead to generating different and suitable nanoformulations to incorporate Vitamin C and its derivatives into it. Different research work shows several ways to develop nanoformulations. Amongst all liposomes, microsphere, nanocarriers are of great importance. For Vitamin C incorporation into the nanoformulation, nanocarriers become the most popular choice for researchers. There were several nanocarrier systems developed using Chitosan- Alginate, Silica-Coated-Au Nanoparticles, Chitosan, Mesoporous-silica NCs for suitable incorporation of Vitamin C into these. The performances were assured by performing different in vitro and in vivo tests which will be discussed here.
Result
As a result, Vitamin C is now in use for many purposes. It includes not only the above mentioned functions but also other functions too. Due to an antioxidant property, Vitamin C is able to quench reactive oxygen species (ROS) by inhibiting ROS-mediated Nitric Oxide (NO) inactivation. Vitamin C helps to elevate the level of absorption of iron within the cell from dietary iron sources. It also prevents the oxidation of drugs. To achieve all these functions, NCs or nanoformulation plays a great role.
Conclusion
It can be concluded that depending on the biocompatibility, loading capacity, protection of the loading molecule, efficiency of cellular uptake, controllable rate of release to achieve the desired effect, and many more factors, the choice of different Nanocarriers (NCs) will be done which ultimately help the human to use it for different purposes. This paper tries to gather some information in one place with respect to different experimental studies.
... The hypertensive-associated ED is a common state characterized by an imbalance between endothelium-derived vasodilators and vasoconstrictor factors and increased oxidative stress which has an important role in the decreased bioavailability of NO, and antioxidant capacity. In fact, an enhanced oxidative stress in patients with essential hypertension causes lower NO availability leading to ED (Taddei et al. 1998). Antioxidants such as vitamins C and E ameliorate endothelium-dependent relaxation of mesenteric artery rings in stroke-prone spontaneously hypertensive rats (SHRSP) by decreasing NADPH oxidase activation and by increasing superoxide dismutase (SOD) activity ). ...
Sodium-glucose cotransporter (SGLT)2 inhibitors have shown remarkable cardiovascular protective effects with reduced risk of cardiovascular mortality and hospitalization for heart failure in T2DM patients with a high cardiovascular risk and that this effect is independent of glucose control. The possibility that SGLT1 and 2 inhibitors protect the cardiovascular system by targeting the pivotal protective endothelial function remains unclear. The first in vitro study indicates that angiotensin II and circulating microparticles from patients with coronary artery disease via the activation of the local angiotensin system are potent inducers of SGLT1 and 2 expression to promote endothelial senescence and dysfunction. The second in vivo study indicates that the selective SGLT2 inhibitor empagliflozin protects the heart and the vascular system, and that the treatment is particularly effective to delay premature vascular senescence known to promote the development of cardiovascular diseases at arterial sites at risk of atherogenesis. Altogether, these studies suggest that inhibition of SGLT2 and/or SGLT1 might be an attractive therapeutic strategy to protect the endothelial function, and the subsequent development of cardiovascular diseases.
... VitC is a vitamin found in fresh fruits and vegetables and is an essential water-soluble antioxidant in the human body. [30] According to a review by Taddei et al [31] in 1998, VitC might improve endothelial-dependent vasodilation in patients with essential hypertension and reverse the nitric oxide synthase inhibitor NG-monomethyl-L-arginine 1. Other studies also attempted to explain the possible mechanism of VitC efficacy in the treatment of essential hypertension. ...
Background:
Vitamin C as a supplement to treat hypertension has been proposed. However, it remains controversial whether vitamin C can improve blood pressure in patients with primary hypertension.
Objectives:
To analyze the effect of vitamin C (VitC) supplementation on systolic (SBP) and diastolic (DBP) blood pressure in patients with essential hypertension.
Methods:
We searched the Chinese Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, WANFANG Data, Cochrane Library, National Library of Medicine's PubMed, EMBASE, and other databases until June 2019. Eight RCTs involving 614 participants were analyzed. SBP and DBP before and after VitC supplementation were compared between the intervention and control groups. The risk of bias of individual studies was assessed using the Cochrane Collaboration risk of bias tool. Two reviewers selected studies independently of each other. The Cochrane Collaboration Review Manager 5.3 was used to perform the meta-analysis.
Results:
There was a significant difference in the change of SBP (weighted mean difference [WMD] = -4.09; 95% confidence interval [CI] -5.56, -2.62; P < .001) and DBP (WMD = -2.30; 95% CI -4.27, -.331; P = .02) between the groups. Further, there was a significant difference in the SBP (WMD = -3.75, 95% CI -6.24, -1.26, P = .003) and DBP (WMD = -3.29, 95% CI -5.98, -.60, P = .02) for the subgroup with an age ≥60 years and that with ≥35 participants. In the subgroup analysis, result for SBP with a study duration ≥6 weeks was statistically significant different (WMD = -4.77; 95% CI -6.46, -3.08; P < .001). For an intervention dose of VitC ≥500 mg daily, SBP was statistically significant (WMD = -5.01; 95% CI -8.55, -1.48; P = .005).
Conclusion:
VitC supplementation resulted in a significant reduction of blood pressure in patients with essential hypertension.
... Vitamin E inhibits the expression of adhesion molecules [14], and, consequently, vascular structural changes associated with hypertension. Vitamins C and E prevent oxidation of proteins and lipids by scavenging free radicals and thereby protect against oxidative stress [15]. Vitamin E [16,17] may modulate the interactions between cytochrome b558, the membranebound part of nicotinamide adenine dinucleotide (P) H oxidase that is essential for both the activity and stability of the enzyme. ...
Objective: Both Vitamin C and Vitamin E supplementation were associated with reduction in blood pressure (BP) in observational studies, although, results of clinical trials are inconsistent. The objective of our study is to conduct a clinical trial to observe the effects of oral supplementation of Vitamin C and Vitamin E on BP. Methods: About 60 non-teaching staffs of our college with systolic BP more than 130 mmHg and diastolic BP more than 90 mmHg were taken as subjects and divided into two groups. Initial BP and BP after oral Vitamin C, 500 mg/day for a period of 12weeks to Group 1 and initial BP and BP after oral Vitamin E, 200 IU/day, for a period of 12 weeks to Group 2 were recorded. Results: Statistical analysis was done by paired t-test, analysis of variance (ANOVA), and least significant difference (LSD) tests. *p<0.05 was considered statistically significant. Systolic 2 and diastolic 2 – after 3 months of supplementation showed 0.161 and 0.161 which is not significant. ANOVA and LSD tests show no significant results. Conclusion: Long-term trials on the effects of Vitamin C and Vitamin E supplementation on BP and clinical events are needed.
In the microcirculatory system, endothelial cells mediate the dialogue between the bloodstream and the tissue. They play an essential role in the adaptive response to any stimuli. The large number of physiologic processes in which they are involved is defined as endothelial function and is dependent on nitric oxide bioavailability. In hypertension, several factors concur to increase the level of reactive oxygen species, reducing nitric oxide bioavailability. In this chapter, we will first describe the physiologic role of endothelial cells. Then, we will move to which are the major factors responsible for endothelial dysfunction in the patient with arterial hypertension. We will explore microvascular inflammation, cyclo-oxygenase 2, mineralocorticoid receptors and the role of the sphingolipid metabolisms. We will provide mechanistic insight on how these factors induce microvascular dysfunction and how this latter became the major propellent for a vicious cycle that leads to the progressive onset of heart failure. In this regard, we will focus on heart failure with a preserved ejection fraction, a metabolic phenotype of heart failure embodied in the cardiometabolic spectrum of disease to which arterial hypertension also belongs and on which the role of endothelial dysfunction is crucial.
Background
Severe pulmonary hypertension (PH) in childhood is rare and can manifest as a life-threatening episode. We present 2 children with restrictive dietary habits with severe pulmonary hypertension secondary to scurvy and iron deficiency anemia with treatment and outcome.
Case presentation
The first case is a 2-year-old boy who presented with vomiting, diarrhea, and fever. After rehydration, he had recurrent episodes of hypotension with intermittent abdominal pain. Fluid resuscitation and inotropic medication were given. Then he suddenly collapsed. After 4-min cardiopulmonary resuscitation, his hemodynamic was stabilized. Most of the medical workup was unremarkable except for PH from the echocardiogram with estimated systolic pulmonary artery pressure (PAP) at 67 mmHg. Transient PH was diagnosed, and milrinone was prescribed. Since he had restrictive dietary habits and sclerotic rim at epiphysis in chest films, his vitamin C level was tested and reported low-level result. The second case is a 6-year-old boy with acute dyspnea, a month of low-grade fever, mild cyanosis, and a swollen left knee. Echocardiogram indicated moderate TR with estimated systolic PAP at 56 mmHg (systolic blood pressure 90 mmHg). Milrinone was given. Right cardiac catheterization showed PAP 66/38 (mean 50) mmHg and PVRi 5.7 WU.m². Other medical conditions causing PH were excluded. With a history of improper dietary intake and clinical suspicion of scurvy, vitamin C was tested and reported undetectable level. Administration of vitamin C in both cases rapidly reversed pulmonary hypertension.
Conclusion
Pediatric PH related to vitamin C deficiency can manifest with a wide range of symptoms, varying from mild and nonspecific to severe life-threatening episodes characterized by pulmonary hypertensive crises. PH associated with scurvy is entirely reversible with appropriate investigation, diagnosis, and treatment. Our report highlights the importance of considering nutritional deficiencies as potential confounding factors in pediatric PH, emphasizing the need for comprehensive evaluation and management of these patients.
Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.
Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that results in precapillary pulmonary hypertension. PAH is caused by a group of clinical conditions involving multiple organ systems. Several cases have been reported in the literature demonstrating an association between vitamin C deficiency and PAH. Low endothelial nitric oxide levels in the pulmonary vasculature, combined with the inappropriate activation of hypoxia-inducible transcription factors, seen in patients with ascorbic acid deficiency, are believed to be the main contributors to the pathogenesis of pulmonary vasculopathy and the exaggerated pulmonary vasoconstrictive response seen in patients with scurvy-induced PAH. Vitamin C supplementation is considered the definitive treatment.
Background: Flemingia faginea Guill. & Perr. is a medicinal plant used for the endogenous treatment of hypertension. This study aimed to establish the phytochemical profile, antioxidant power, and vasodilation effects of aqueous decoction (FAD), ethyl acetate (EAF) and aqueous residual fractions (ARF) of the leafy stem of Flemingia faginea (F. faginea). Methods: The phytochemical study was performed using high-performance thin-layer chromatography technique and high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). Folin-Ciocalteu and aluminum trichloride colorimetric methods were used, respectively, to quantify total polyphenols and flavonoids. The antioxidant properties of the extracts were determined using 2,29-azinobis-3-ethylbenzothiazoline-6-sulfonic (ABTS•), 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and ferric ion reduction (FRAP) methods. The vasodilatory effects of F. faginea extracts were performed using the DMT 620M myograph technique for an ex vivo study. Results: The phytochemical study revealed the presence of flavonoids, tannins, coumarins, sterols, and triterpenes, alkaloids, and saponins in the extracts studied. HPLC MS analysis identified as the main phenolic compounds, gallic acid-glucoside (16.56 ± 0.06 mg/g), myricetin rhamnoside (15.39 ± 0.04 mg/g), myricetin rutinoside (9.32 ± 0.00 mg/g), quercetin rutinoside (9.05 ± 0.00 mg/g), caffeoyl-glucoside (6.07 ± 0.02 mg/g) and 5-Caffeoylquinic acid (4.52 ± 0.00 mg/g). The present data also showed higher contents of phenolic compounds and flavonoids in fractions of ARF (280.49 ± 0.08 mgGAE/g) and EAF (33.31 ± 0.33 mgQE/g) fractions respectively. Furthermore, the ARF fraction had the best iron ion reduction capacity (16.96 ± 0.01µgAAE/100 mg), while, the EAF (ABTS: IC50=67.33 ± 0.04 µg/mL; DPPH: IC50=4.69 ± 0.20 µg/mL) was the best free radical scavenger. In endothelium-intact rings, study extracts showed a vasodilation effect in a concentration-dependent manner with half-maximum effective concentration (EC50) of 0.24 ± 0.03 mg/mL, 0.85 ± 0.07 mg/mL and 0.05±0.01 mg/mL respectively for FAD, ARF and EAF. In endothelium-denuded vessels, these values were 0.26 ± 0.09 mg/mL, 0.57 ± 0.05 mg/mL, and 0.85 ± 0.01 mg/mL for EAF, FAD, and ARF, respectively. The maximum effects were of 99.94 ± 0.15%, 86.89 ± 5.58%, and 62.69 ± 5.14% (endothelium-intact) and of 100 ± 0.06%, 96.55 ± 4.68%, and 74.16 ± 4.06% (endothelium-denuded), respectively, for EAF, FAD, and ARF with a significant difference between them. Conclusion: This study reports that the decoction and fractions of F. faginea are rich in various chemical compounds and possess antioxidant and vasodilatory properties. These preliminary data provide a scientific basis which contributed to justify that plant used in traditional medicine.
The diabetic state confers an increased propensity to accelerated atherogenesis. In addition to the established risk factors, there is evidence for increased oxidative stress in diabetes. Increased oxidative stress is manifested by increased lipid peroxidation, increased F 2 -isoprostanes, increased nitrotyrosine, and increased DNA damage. Also, in diabetics, there is increased superoxide release. With regard to diabetes, antioxidants such as α-tocopherol, α-lipoate, and ascorbic acid supplementation have been shown to be beneficial. Most importantly, α-tocopherol therapy, especially at high doses, clearly shows a benefit with regard to low-density lipoprotein oxidation, isoprostanes, and monocyte superoxide release. Thus, it appears that, in diabetes, antioxidant therapy could alleviate the increased attendant oxidative stress and emerge as an additional therapeutic modality.
As a major cause of morbidity and mortality globally, hypertension remains a serious threat to global public health. Despite the availability of many antihypertensive medications, several hypertensive individuals are resistant to standard treatments, and are unable to control their blood pressure. Regulation of the renin-angiotensin-aldosterone system (RAAS) controlling blood pressure, activation of the immune system triggering inflammation and production of reactive oxygen species, leading to oxidative stress and redox-sensitive signaling, have been implicated in the pathogenesis of hypertension. Thus, besides standard antihypertensive medications, which lower arterial pressure, antioxidant medications were tested to improve antihypertensive treatment. We review and discuss the role of oxidative stress in the pathophysiology of hypertension and the potential use of antioxidants in the management of hypertension and its associated organ damage.
A sedentary lifestyle has evoked a high risk of cardiovascular (CV) disease, diabetes, and obesity, all of them with high morbimortality rates and with a common denominator, hypertension. Numerous pharmacological drugs have been used for the treatment of hypertension. However, the side effects associated with the use of existing pharmacological therapies have triggered a demand for plant-based medications. In this connection, the aim of this review was to provide an in-depth analysis of the use of plant-derived bioactives for the effective management of hypertension. Phytoconstituents from leaves, bark, stem, roots, seeds, and fruits of medicinal plants grown in our different regions of the globe have been highly searched. Among them, polyphenols (e.g., flavonoids as quercetin, anthocyanins as cyanidin, tannins as ellagic acid, stilbenes as resveratrol, lignans as honokiol and others as hydroxytyrosol or curcumin), organosulfur compounds (e.g. s-allyl cysteine and allicin), fatty acids (e.g. α-lipoic acid, DHA and oleic acid), alkaloids (e.g. berberine or tetrandrine) and some terpenes have been intensively investigated for the management of hypertension, with effective ability being stated in controlling high blood pressure and related health problems both in vivo and in vitro studies. Some of the activities presented by these bioactive compounds are reducing oxidative stress, renin-angiotensin system control, SIRT1 activation, regulating platelet aggregation and COX activity, anti-atherogenic effects, anti-inflammatory properties, vasorelaxation and other results that translate into the prevention or control of hypertension. The knowledge of these bioactive compounds is important in developing countries where traditional medicine is the majority, but it can also give rise to new approaches in hypertension therapy.
Regulation of skeletal muscle blood flow is a complex process, which involves an integration of multiple mechanisms and a number of vasoactive compounds. Skeletal muscle blood flow may be affected by changes in microvascular structure or function which occur in pathological conditions such as hypertension with subsequent increase in vascular resistance. Exercise training may elicit beneficial effects on skeletal muscle blood flow by inducing favorable microvascular remodeling, capillary angiogenesis, and modulating vasomotor reactivity of small arteries and arterioles. In particular, activation of angiogenic process, with increase in capillary network, seems to have the major influence in ameliorating local blood flow in several tissues including skeletal muscle. Furthermore, phenotypic expression of skeletal muscle fiber type also has powerful influences on vascular structure and function in skeletal muscle, which may influence training-induced vascular adaptations in skeletal muscle. Recently, new approaches in exercise training have highlighted the key role of miRNAs in the modulation of hypertension.KeywordsMicrocirculationPhysical exerciseHypertensionCapillaries small resistance arteries
The purpose of this study was to examine the relationship between lifestyle habits and brachial-ankle pulse wave velocity (baPWV), which is an index of arteriosclerosis, among men college students. A lifestyle questionnaire survey was conducted on healthy men college students, and the brachial-ankle pulse wave velocity (baPWV) was measured. The result of grouping by the cutoff value of baPWV and comparing lifestyles,the high baPWV group showed a significantly lower value than the low baPWV group in terms of dietary regularity. Next, after stratifying blood pressure, a logistic regression analysis based on normal blood pressure was performed on the relationship with baPWV,and as a result, a significant relationship was found between normal high and high blood pressure. These findings suggest that baPWV was higher in those who had a meal time shift or skipping meals, and that even college students with normal blood pressure tend to had higher baPWV as their blood pressure increases. Previous studies have reported a relationship between eating behavior and arteriosclerosis, and early measures may be required to prevent arteriosclerosis.
Background
In preclinical models, the pannexin-1 channel has been shown to be involved in blood pressure regulation through an effect on peripheral vascular resistance. Pannexin-1 releases ATP, which can activate constrictive purinergic receptors on the smooth muscle cells. Pannexin-1 opening is proposed to be mediated by α-adrenergic receptors to potentiate sympathetic constriction. This positions pannexin-1 as a putative pharmacological target in blood pressure regulation in humans. The aim was to provide the first translational evidence for a role of pannexin-1 in essential hypertension in humans by use of an advanced invasive mechanistic approach.
Methods
Middle-aged stage-1 hypertensive (n=13; 135.7±6.4 over 83.7±3.7 mm Hg) and normotensive men (n=12; 117.3±5.7 over 72.2±3.5 mm Hg) were included. Blood pressure and leg vascular resistance were determined during femoral arterial infusion of tyramine (α-adrenergic receptor stimulation), sodium nitroprusside, and acetylcholine. Measurements were made during control conditions and with pannexin-1 blockade (3000 mg probenecid). Expression of purinergic- and α-adrenergic receptors in skeletal muscle biopsies was determined by Western blot.
Results
The changes in leg vascular resistance in response to tyramine (+289% versus +222%), sodium nitroprusside (−82% versus −78%) and acetylcholine (−40% versus −44%) infusion were not different between the 2 groups ( P >0.05) and pannexin-1 blockade did not alter these variables ( P >0.05). Expression of pannexin-1 and of purinergic- and α-adrenergic receptors was not different between the 2 groups ( P >0.05).
Conclusions
Contrary to our hypothesis, the data demonstrate that pannexin-1 does not contribute to the elevated blood pressure in essential hypertension, a finding, which also opposes that reported in preclinical models.
Longer life span and increased prevalence of chronic, non-communicable, inflammatory diseases fuel cardiovascular mortality. The microcirculation is central in the crosstalk between ageing, inflammation, cardiovascular and metabolic diseases. Microvascular dysfunction, characterized by alteration in the microvascular endothelial function and wall structure, is described in an increasing number of chronic, age-associated diseases, suggesting it might be a marker of ageing superior to chronological age. The aim of this review is to thoroughly explore the connections between microvascular dysfunction, ageing and metabolic disorders by detailing the major role played by inflammation and oxidative stress in their evolution. Older age, hypertension, nutrient abundance and hyperglycaemia concur in the induction of a persistent low-grade inflammatory response, defined as meta-inflammation or inflammageing. This increases the local generation of reactive oxygen species that further impairs endothelial function and amplifies the local inflammatory response. Mitochondrial dysfunction is a hallmark of many age-related diseases. The alterations of mitochondrial function promote irreversible modification in microvascular structure. The interest in the hypothesis of chronic inflammation at the centre of the ageing process lies in its therapeutic implications. Inhibition of specific inflammatory pathways has been shown to lower the risk of many age-related diseases, including cardiovascular disease. However, the whole architecture of the inflammatory response underpinning the ageing process and its impact on the burden of age-related diseases remain to be fully elucidated. Additional studies are needed to unravel the connection between these biological pathways and to address their therapeutic power in terms of cardiovascular prevention.
High altitude‐induced hypoxaemia is often associated with peripheral vascular dysfunction. However, the basic mechanism(s) underlying high‐altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high altitude. Ten young healthy lowlanders were tested at sea level (344 m) and following 4–6 days at high altitude (4300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain‐gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP) and a co‐infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high altitude than at sea level (P = 0.048). There was no difference in the response to SNP at high altitude (P = 0.860). At sea level, the co‐infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxaemia (R² = 0.60, P = 0.008 and R² = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high altitude are in part attributable to oxidative stress, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high‐altitude sojourns, with important implications for understanding the aetiology of high altitude‐related vascular dysfunction. image
Key points
Vascular dysfunction has been demonstrated in lowlanders at high altitude (>4000 m). However, the extent of impairment and the delineation of contributing mechanisms have remained unclear.
Using the gold‐standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4–6 days after rapid ascent to 4300 m.
The total forearm blood flow response to acetylcholine at high altitude was decreased by ∼30%. Co‐infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxaemia.
These data extend our basic understanding of vascular (mal)adaptation to high‐altitude sojourns, with important implications for understanding the aetiology of high altitude‐related changes in endothelial‐mediated vasodilatory function.
Insufficient nightly sleep (<7 hour/night) has been linked to the cause of hypertension and is a prevalent, often ignored, comorbidity. We tested the hypotheses that chronic nightly insufficient sleep is associated with lower nitric oxide-mediated endothelium-dependent vasodilation and endothelial tPA (tissue-type plasminogen activator) release in hypertensive adults; and that the insufficient sleep-related reduction in endothelial vasodilator and fibrinolytic function is due to increased oxidative stress. Fifty hypertensive adults were studied: 20 with normal nightly sleep duration (14M/6F; age: 59±2 year; blood pressure: 138/83±1/1 mm Hg; sleep: 7.6±0.1 hour/night) and 30 with short nightly sleep duration (21M/9F; 56±1 year; 138/84±2/1 mm Hg; 5.8±0.1 hour/night). Forearm blood flow (plethysmography) was determined in response to intraarterial infusion of: acetylcholine in the absence and presence of N G -monomethyl-L-arginine and the antioxidant vitamin C; bradykinin in the absence and presence of vitamin C; and sodium nitroprusside. Endothelial release of tPA was determined in response to bradykinin without and with vitamin C. Vasodilation to acetylcholine was significantly lower (≈20%) in the short versus normal sleep adults. N G -monomethyl-L-arginine reduced (≈25%; P <0.05) acetylcholine vasodilation in the normal but not short sleepers. Vitamin C increased (≈35%; P <0.05) acetylcholine vasodilation in short sleepers only. Endothelial tPA release to bradykinin was significantly lower (≈25%) in the short versus normal sleep duration adults. Co-infusion of vitamin C induced greater tPA release in short sleepers. In hypertensive adults, insufficient sleep is associated with reduced nitric oxide–mediated endothelium-dependent vasodilation and endothelial tPA release. These sleep-related abnormalities in endothelial function are due, in part, to oxidative stress.
Objective: Aging is associated with some changes in the liver function including increased collagen deposition and decreased mitochondrial function. This study aims to evaluate the effect of resistance exercise and vitamin C intake on the expression of Peroxisome Proliferator-Activated Receptor-Γ Coactivator-1α (PGC-1α) and Mitofusin 1 (MFn1) genes and collagen deposition in older rats.
Methods: This is an experimental study conducted on 25 male Wistar rats aged 24 weeks and weighted 280-320 g. They were randomly divided into five groups of young control, older exercise, older vitamin C, older exercise + vitamin C, and older control. In the supplementation groups, rats were given liposomal vitamin C (100 mg/kg per body weight) by gavage daily. One-way ANOVA was used to examine the difference between the groups and Tukey’s post hoc test was used to determine the location of group differences. For all analyses, the significance level was set at 0.05.
Results: Aging significantly reduced the expression of PGC-1α and MFn1 and increased collagen deposition in the liver tissue of rats (P=0.001). In the older exercise + vitamin C group, a significant increase in PGC-1α expression was observed compared to the older control group (P=0.001), but there was no significant changes in MFn1 expression. A significant decrease in collagen deposition was reported in the older exercise, older vitamin C, and older exercise + vitamin C groups compared to the older control group (P=0.001).
Conclusion: Resistance exercise combined with vitamin C intake reduces collagen deposition in liver tissue and increases PGC-1α expression in older rats.
Lack of long-term patency has hindered the clinical use of small-diameter prosthetic vascular grafts with the majority of these failures due to the development of neointimal hyperplasia. Previous studies by our laboratory revealed that small-diameter expanded polytetrafluoroethylene (ePTFE) grafts coated with antioxidant elastomers are a promising localized therapy to inhibit neointimal hyperplasia. This work is focused on the development of poly(diol-co-citrate-co-ascorbate) (POCA) elastomers with tunable properties for coating ePTFE vascular grafts. A bioactive POCA elastomer (@20 : 20 : 8, [citrate] : [diol] : [ascorbate]) coating was applied on a 1.5 mm diameter ePTFE vascular graft as the most promising therapeutic candidate for reducing neointimal hyperplasia. Surface ascorbate density on the POCA elastomer was increased to 67.5 ± 7.3 ng mg-1 cm-2. The mechanical, antioxidant, biodegradable, and biocompatible properties of POCA demonstrated desirable performance for in vivo use, inhibiting human aortic smooth muscle cell proliferation, while supporting human aortic endothelial cells. POCA elastomer coating number was adjusted by a modified spin-coating method to prepare small-diameter ePTFE vascular grafts similar to natural vessels. A significant reduction in neointimal hyperplasia was observed after implanting POCA-coated ePTFE vascular grafts in a guinea pig aortic interposition bypass graft model. POCA elastomer thus offers a new avenue that shows promise for use in vascular engineering to improve long-term patency rates by coating small-diameter ePTFE vascular grafts.
Background:
Breast cancer (BC) survivors are at increased risk of cardiovascular disease. We evaluated whether chemotherapy induces early or late vascular dysfunction in vivo.
Methods:
Early-stage BC patients (n=33) underwent measurements of forearm blood flow (FBF), 24-hour blood pressure, aortic pulse wave velocity (PWV) and inflammatory markers before (T0), 14 days after (T1) and 12 months after (T2) chemotherapy. FBF was assessed during intra-arterial infusion of acetylcholine (ACh), ACh during simultaneous nitric oxide synthase inhibition with L-NG -monomethyl arginine (L-NMMA), and during infusion of sodium nitroprusside (SNP). Controls matched by age and menopausal status were examined for baseline comparison.
Results:
At T0, absolute FBF in the BC patients did not differ from controls. At T1, ACh-induced absolute FBF was higher compared to T0. ACh-induced FBF decreased significantly at T2, evaluated as area under the dose-response curve (AUC), and when corrected for FBF in the contra-lateral arm, (FBF ratio at T0:4.05[2.54;5.74], and T2:2.77[2.41;3.50]), without difference evident during L-NMMA-infusion. FBF during SNP-infusion remained unchanged. PWV and BP remained unchanged. Asymmetric dimethylarginine (T0:0.68 μmol/L±0.17,T1:0.75 μmol/L±0.16) and the inflammation-related biomarkers Cd163 (T0:1.86 mg/L[1.68;2.05],T1:2.04 mg/L[1.76;2.4]) and Cd206 (T0:0.22 mg/L[0.19;0.26],T1: 0.27 mg/L[0.23;0.30]) all increased significantly at T1, but returned to baseline values at T2. L-arginine was significantly increased at both T1 (78.5 μmol/L[68.9;86.6]) and T2 (76.8 (μmol/L)[66.9;90.6]), compared to T0 (59.6 μmol/L[53.7;68.0]).
Conclusion:
Chemotherapy for BC seems associated with early amplification of endothelium-dependent vasodilation and inflammation. One year after chemotherapy, microvascular dysfunction persists in terms of reduced NO-dependent vasodilation without alterations in BP or arterial stiffness.
Using Nanoplatforms as a hauler for photosensitizers is a bespoke paradigm to improve its bioavailability and to boost the PDT efficacy. Herein, the photodynamic cytotoxicity of methylene blue (MB) loaded on hydroxyapatite nanoparticles (HA-NPs) was tested against human osteosarcoma-derived cells (Saos-2 cell line). HA-NPs and HA-NPs loaded with MB (HA-NPs-MB) were prepared by a chemical precipitation method and characterized by TEM, Zeta potential, FTIR, and XRD. TEM images revealed that HA-NPs have a rod shape with a diameter of 14–17 nm and length around 46–64 nm. FTIR and Zeta potential confirmed the adsorption of cationic MB on HA-NPs. XRD pattern was identical to the standard XRD pattern of HA-NPs. Incubation of Saos-2 cells (24 h) with HA-NPs-MB then irradiation of cells (5 min) with a diode laser (808 nm), causes a higher decrement of cell viability (determined by MTT assay) than that caused by free MB. The LC50 was 57.53 µg/mL and 86.99 µg/mL for HA-NPs-MB and free MB, respectively. Thus, the nanoformulation of MB greatly reduced the dose of MB required for effective PDT. This study also investigated the mode of cell death after incubation of cells with free MB or HA-NPs-MB composite then exposure to laser radiation. The results revealed that the majority of cells died by apoptosis while a minor fraction of cells died by necrosis, especially in the case of HA-NPs-MB. Levels of caspase-3 and death receptor-4 (DR-4) were more elevated in the case of HA-NPs-MB than free MB. The effect of the prepared nanocomposite and free MB on Raw murine macrophage (RAW 264.7) viability was also examined using the MTT assay. The results indicated that HA-NPs-MB in the presence of laser has a great cytotoxic effect on macrophage cells compared to other treatments. This may present an advantage through decreasing macrophage that promotes tumor growth. In conclusion, HA-NPs-MB nanocomposite surmounts free MB and HA-NPs in destroying macrophage cells and Saos-2 cells through apoptosis in the presence of laser irradiation. This study introduces a thorough and new insight on osteosarcoma (cancer cell line Saos-2) PDT using HA-NPs-MB exploiting the biosafety of HA-NPs.
The menopausal transition is associated with increased prevalence of hypertension, and in time postmenopausal women (PMW) will exhibit a cardiovascular disease risk-score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive PMW have blunted nitric-oxide (NO)-mediated leg vasodilator responsiveness, and whether this is reversible by high-intensity training (HIT) is unknown. To address these questions, we examined the leg vascular conductance (LVC) in response to femoral-infusion of acetylcholine (ACh) and sodium nitroprusside (SNP), and skeletal muscle markers of oxidative stress and NO bioavailability before and after HIT in PMW (12.9±6.0 (mean±SD) years since last menstrual cycle). We hypothesized that ACh- and SNP-induced LVC responsiveness was reduced in hypertensive compared to normotensive PMW and that 10 weeks of HIT would reverse the blunted LVC response and decrease blood pressure (BP).Nine hypertensive (HYP; clinical systolic/diastolic BP 149±11/91±83 mmHg) and 8 normotensive (NORM; 122±13/75±8 mmHg) PMW completed 10 weeks of bi-weekly small-sided floorball training (4-5x3-5 min interspersed by 1-3 min rest periods). Before training, the SNP-induced change in LVC was lower (P<0.05) in HYP compared with NORM. With training, the ACh- and SNP-induced change in LVC at maximal infusion rates i.e. 100 and 6 μg∙min-1∙kg leg mass-1, respectively, improved (P<0.05) in HYP only. Further, training decreased (P<0.05) clinical systolic/diastolic BP (-15±11/-9±7 mmHg) in HYP, and systolic BP (-10±9 mmHg) in NORM. Thus, the SNP-mediated LVC responsiveness was blunted in hypertensive PMW, and reversed by a period of HIT that was associated with a marked decrease in clinical BP.
Endothelial dysfunction which characterizes human essential hypertension is largely dependent on an impaired endothelial nitric oxide (NO) availability and an increased production of endothelium-derived contracting factors (EDCFs), including endothelin (ET)-1, and reactive oxygen species (ROS). Acute intra-arterial administration of indomethacin, a nonselective cyclooxygenase (COX) inhibitor, and ascorbic acid, an antioxidant, normalized the blunted endothelial dysfunction by restoring NO availability at the level of peripheral microcirculation, thus demonstrating that COX-derived EDCFs are involved in generating ROS. Recent studies put in evidence new lights on the mechanisms involved in endothelial dysfunction in human hypertension. Functional and immunohistochemical experiments with selective COX inhibitors identified the isoform COX-2 as the main source of intravascular ROS generation in isolated small vessels from essential hypertensive patients. In addition, important vascular protective properties by human ghrelin have been demonstrated, in terms that its systemic reduction is involved in the pathophysiology of endothelial dysfunction, while a normalization of its levels may restore vascular homeostasis.
In 1980, Furchgott and Zawadzki demonstrated the release of an endothelium-derived relaxing factor in isolated rabbit aorta with exposure to acetylcholine (ACh) (1). This factor has subsequently been identified as nitric oxide (NO·) (2) or a closely related redox form of NO· (3). It is now known that NO· is synthesized enzymatically from L-arginine and O2 by a family of FAD- and FMN-containing enzymes, the nitric oxide synthases (NOSs), that require NADPH and tetrahydrobiopterin (BH4) as cofactors (4). As a class of enzymes, the NOSs appear ubiquitous and have been identified in a number of mammalian cell types and tissues including endothelium (5), epithelium (6), neurons skeletal muscle (8), ventricular myocardium (9), and cytokine-stimulated inflammatory cells (10,11).
Cardiovascular disease remains the leading cause of death in patients with renal failure. In common with other risk factor groups associated with accelerated atherogenesis such as diabetes mellitus and hyperlipidaemia, atherosclerosis is preceded by vascular dysfunction in renal failure. This thesis investigates the mechanisms of vascular dysfunction in renal failure, with particular reference to reduced bioactivity of the nitric oxide (NO) pathway. I have used in vivo techniques to study the activity of the NO pathway in both conduit and resistance arteries. To assess the effect of circulating uraemic toxins on endothelial function, flow-mediated vasodilatation (FMD) of the brachial artery was measured before and after dialysis. I demonstrated that haemodialysis resulted in rapid clearance of uraemic toxins from plasma and transiently increased FMD; in contrast, automated peritoneal dialysis treatment did not reduce levels of uraemic toxins or improve FMD. These data suggest that acute reduction of circulating inhibitors of endothelial function is associated with improved endothelial function in conduit vessels. To explore this further, the role of competitive inhibition of NO synthase by L-arginine analogues was investigated by administering the natural substrate, L-arginine. Despite normalising the ratio of plasma arginine/NO synthase inhibitors, there was no improvement in either conduit or resistance artery endothelial function. These findings imply that in renal failure, impaired endothelium-dependent vasodilatation is not solely due to competitive inhibition of NOS. I examined whether reactive oxygen species may contribute to impaired endothelial function in uraemia. The acute administration of the anti-oxidant, vitamin C, reduced biochemical markers of oxidant stress and improved endothelial function of resistance, but not conduit arteries. In conclusion, the mechanisms responsible for endothelial dysfunction in uraemia remain obscure. I have shown, however, that endothelial function can be corrected by both acute haemodialysis and by an acute increase in plasma anti-oxidant capacity. The observed beneficial effect of haemodialysis on vascular function may explain reports of improved cardiovascular outcome in patients who routinely undergo long hour or daily haemodialysis treatments. It remains to be seen whether other interventions, such as statin therapy, which are known to improve endothelial function can confer similar outcome benefit in this high risk patient group.
A 42 year-old patient presented with circulatory failure and lactic acidosis. Clinical features, later coupled with biological tests, led to the diagnosis of wet beriberi syndrome and scurvy. Echocardiography showed a pattern of thiamine deficiency with high cardiac output and low vascular resistance. The patient's condition and biological parameters immediately improved after treatment injections of thiamine. Wet BeriBeri is often overlooked in western countries and is a diagnosis that must be considered based on history, clinical and echocardiographical findings.
In a chronic model of smoking-induced cardiovascular disease, we define underlying mechanisms of smoking-induced vascular endothelial dysfunction (VED). Smoking exposure triggered VED and hypertension and led to vascular macrophage infiltration with concomitant increase in superoxide and NADPH oxidase levels as early as 16 wk of exposure. This oxidative stress was accompanied by tetrahydrobiopterin depletion, resulting in endothelial nitric oxide synthase uncoupling with further superoxide generation triggering a vicious cycle of oxidative stress and VED.
Significance:
Hypertension has major health consequences, which is associated with endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) produced nitric oxide (NO) signaling in the vasculature plays an important role in maintaining vascular homeostasis. Considering the importance of NO system, this review is aimed to provide a brief overview of the biochemistry of members of NO signaling including GTPCH1, BH4, and eNOS.
Critical issues:
Under conditions of tetrahydrobiopterin (BH4) depletion, eNOS generated superoxide trigger pathological events. Abnormalities in NO availability and BH4 deficiency lead to disturbed redox regulation causing pathological events. This disturbed signaling influences the development of systemic hypertension as well as pulmonary hypertension. Recent Advances: Being NO signaling activators and regulators of eNOS signaling, BH4 treatment is getting widespread attention either as potential therapeutic agents or as preventive agents. Recent clinical trials also support that BH4 treatment could be considered as a promising therapeutics in hypertension.
Future directions:
Considering the importance of BH4 and NO to improve the translational significance, it is essential to continue research on this field to manipulate BH4 to increase the efficacy for treating hypertension. Thus, this review also examines the current state of knowledge on the effects of eNOS activators on preclinical models and humans to utilize this information for the potential therapy.
Innovation:
We have dealt with the effectiveness of the BH4 treatment by providing the clinical evidence in hypertension and we discuss how to avoid potential limitations of BH4 therapy.
Background
Increased arterial stiffness and vascular endothelial dysfunction are important nontraditional cardiovascular risk factors evident in patients with CKD. Vascular oxidative stress and inflammation may contribute to vascular dysfunction in CKD, but direct evidence is lacking.
Methods
We assessed carotid-femoral pulse-wave velocity (arterial stiffness) and brachial artery flow-mediated dilation (vascular endothelial function) in participants with moderate-to-severe CKD (eGFR 15–59 ml/min per 1.73 m ² ) and in healthy controls. Change in brachial artery flow-mediated dilation after an acute infusion of ascorbic acid to inhibit vascular oxidative stress (versus saline) was also measured. Protein expression of vascular endothelial cells collected from a peripheral vein and ELISAs to assess circulating markers were also performed.
Results
A total of 64 participants with CKD (mean±SD, 65±8 years) and 17 healthy controls (60±5 years) were included. Carotid-femoral pulse-wave velocity was greater in participants with CKD compared with healthy controls (1071±336 versus 732±128 cm/s; P <0.001). Brachial artery flow-mediated dilation was lower in participants with CKD compared with healthy controls (3.5%±2.8% versus 5.5%±3.2%; P =0.02). Circulating inflammation markers (C-reactive protein and IL-6) were elevated in the CKD group ( P ≤0.02). Endothelial cell protein expression of NADPH (intensity versus human umbilical vein endothelial cell control, 1.48±0.28 versus 1.25±0.31; P =0.05) was greater in participants with CKD. However, ascorbic acid significantly improved brachial artery flow-mediated dilation in control participants (saline, 5.5±3.2; ascorbic acid, 6.8±3.6); as compared with participants with CKD (saline, 3.5±2.8; ascorbic acid, 3.6±3.2) (group×condition interaction P =0.04), suggesting vascular oxidative stress could not be overcome with ascorbic acid in participants with CKD.
Conclusions
Vascular oxidative stress is present in CKD, which cannot be overcome with acute infusion of ascorbic acid.
Essential hypertension is associated with impairments in vascular function and sympathetic nerve hyperactivity; however, the extent to which the lower limbs are affected remains unclear. We examined the leg vascular responsiveness to infusion of acetylcholine (ACh), sodium nitroprusside (SNP) and phenylephrine (PEP) in ten hypertensive men (HYP: age 59.5±9.7 (mean±SD) years, clinical and night-time blood pressure: 142±10/86±10 and 141±11/83±6 mmHg, respectively, BMI: 29.2±4.0 kg∙m ⁻² ) and 8 age-matched normotensive counterparts (NORM: age 57.9±10.8 years, clinical and night-time blood pressure: 128±9/78±7 and 116±3/69±3 mmHg, respectively, BMI: 26.3±3.1 kg∙m ⁻² ). The vascular responsiveness was evaluated before and after 6 weeks of 10-20-30 training, consisting of 3x 5x10-s sprint followed by 30 and 20 s of low- to moderate-intensity cycling, respectively, interspersed by 3 min of rest. Before training, the vascular responsiveness to infusion of SNP was lower (P<0.05) in HYP compared to NORM, with no difference in the responsiveness to infusion of ACh and PEP. The vascular responsiveness to infusion of SNP and ACh improved (P<0.05) with training in HYP, with no change in NORM. With training, intra-arterial systolic blood pressure decreased (P<0.05) by 9 mmHg in both HYP and NORM whereas diastolic blood pressure decreased (5 mmHg; P<0.05) in HYP only. We provide here the first line of evidence in humans that smooth muscle cell vasodilator responsiveness is blunted in the lower limbs of hypertensive men. This impairment can be reversed by 10-20-30 training, which is an effective intervention to improve the responsiveness of smooth muscle cells in men with essential hypertension.
Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress.
We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients.
The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58).
Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.
Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension.
To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography.
The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03).
Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.
We studied the vasomotion of epicardial coronary arteries during exercise and tested the hypotheses that abnormal vasoconstriction is related to the presence of atherosclerosis and may be related to endothelial dilator dysfunction. During cardiac catheterization quantitative coronary angiography was performed in 21 patients during supine bicycle exercise. 21 of 28 smooth, angiographically normal vessel segments dilated (14.0 +/- 1.8%) during exercise; four smooth segments did not change whereas only three constricted. In contrast, 15 of 16 vessel segments with irregularities constricted in response to exercise (17.0 +/- 0.1%) with only one segment dilating. All 10 stenotic segments constricted to exercise (23 +/- 4%). Six patients also received intracoronary acetylcholine before exercise to test endothelium-dependent dilator function. In five of six patients all nine vessel segments showed the same directional response to acetylcholine and exercise. Three irregular and two stenotic segments constricted with acetylcholine (51 +/- 21%) and exercise (9.0 +/- 0.6%). In contrast, four smooth segments dilated to acetylcholine (19 +/- 6%) and exercise (9 +/- 1%). Both exercise and acetylcholine generally dilated smooth but constricted irregular and stenosed coronary segments. It appears likely that atherosclerosis plays an important role in the abnormal vasomotion of diseased coronary arteries during exercise and the pattern of abnormality suggests impairment of vasodilator function.
We have shown recently that the temporal order of antioxidant consumption in human blood plasma exposed to a constant flux of aqueous peroxyl radicals is ascorbate = protein thiols greater than bilirubin greater than urate greater than alpha-tocopherol and that detectable lipid peroxidation starts only after ascorbate has been consumed completely. In this paper, we show that it is indeed ascorbate that completely protects plasma lipids against detectable peroxidative damage induced by aqueous peroxyl radicals and that ascorbate is the only plasma antioxidant that can do so. Plasma devoid of ascorbate, but no other endogenous antioxidant, is extremely vulnerable to oxidant stress and susceptible to peroxidative damage to lipids. The plasma proteins' thiols, although they become oxidized immediately upon exposure to aqueous peroxyl radicals, are inefficient radical scavengers and appear to be consumed mainly by autoxidation. Our data demonstrate that ascorbate is the most effective aqueous-phase antioxidant in human blood plasma and suggest that in humans ascorbate is a physiological antioxidant of major importance for protection against diseases and degenerative processes caused by oxidant stress.
Interest in the antioxidant vitamin E as a possible protective nutrient against coronary disease has intensified with the recognition that oxidized low-density lipoprotein may be involved in atherogenesis.
In 1980, 87,245 female nurses 34 to 59 years of age who were free of diagnosed cardiovascular disease and cancer completed dietary questionnaires that assessed their consumption of a wide range of nutrients, including vitamin E. During follow-up of up to eight years (679,485 person-years) that was 97 percent complete, we documented 552 cases of major coronary disease (437 nonfatal myocardial infarctions and 115 deaths due to coronary disease).
As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 (95 percent confidence interval, 0.50 to 0.87) after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, including other antioxidants, had little effect on the results. Most of the variability in intake and reduction in risk was attributable to vitamin E consumed as supplements. Women who took vitamin E supplements for short periods had little apparent benefit, but those who took them for more than two years had a relative risk of major coronary disease of 0.59 (95 percent confidence interval, 0.38 to 0.91) after adjustment for age, smoking status, risk factors for coronary disease, and use of other antioxidant nutrients (including multi-vitamins).
Although these prospective data do not prove a cause-and-effect relation, they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of these trials.
OBJECTIVE: To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) Study. DESIGN: Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments - ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin - in the prevention of myocardial infarction, stroke or cardiovascular death. SETTING: Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America. PATIENTS: Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months. INTERVENTIONS: A 2×2 factorial design with ramipril and vitamin E with follow-up for up to four years. CONCLUSIONS: HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.
The calcium ionophore A23187 causes endothelium-dependent contractions in canine basilar arteries. Removal of the endothelium, or treatment with indomethacin or superoxide dismutase (SOD), prevented the endothelium-dependent excitatory effect of the calcium ionophore. Catalase and deferoxamine were without effect. Superoxide anion generated by xanthine plus xanthine oxidase in the presence of catalase caused contractions of the vascular smooth muscle, which were abolished by SOD or heat inactivation of xanthine oxidase. The A23187-induced production of prostaglandins F(2α) and E2 and thromboxane B2 was abolished by the removal of endothelium and by treatment with indomethacin but was not affected by the presence of SOD plus catalase. These observations are consistent with the hypothesis that superoxide anion, rather than prostaglandins generated by hydroperoxidase activity of cyclooxygenase, is an endothelium-derived contracting factor in canine cerebral arteries.
Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue1 and for the inhibition of platelet aggregation2 and platelet adhesion3 attributed to endothelium-derived relaxing factor4. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay5, chemiluminescence1 or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
Objective: There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients. Design: The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls. Methods: Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography. Results: In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 [mu]mol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups. Conclusions: The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.
Ascorbate has been demonstrated to be an effective antioxidant. It can act both directly, by reaction with aqueous peroxyl radicals, and indirectly, by restoring the antioxidant properties of fat-soluble vitamin E. The overall consequence of these antioxidant activities is the beneficial control of lipid peroxidation of cellular membranes including those surrounding as well as within intracellular organelles. Intracellular free radical attack on non-lipid nuclear material may also be diminished.In addition to reviewing the chemical basis of the antioxidant function of vitamin C, this report will focus on the importance of vitamin C as an antioxidant component of plasma as well as the extracellular fluids surrounding the lung, lens and retina. The protection by vitamin C of phagocytic cells involved in the defense against pathogen invasion will also be discussed.This review presents evidence which supports the importance of vitamin C as a component of the overall antioxidant protective mechanisms found in cells and tissues. The data are consistent and form a strong consensus for investigating the importance of the antioxidant function of vitamin C in the maintenance of human health.
Endothelium-derived relaxing factor (EDRF) is a labile humoral agent which mediates the action of some vasodilators. Nitrovasodilators, which may act by releasing nitric oxide (NO), mimic the effect of EDRF and it has recently been suggested by Furchgott that EDRF may be NO. We have examined this suggestion by studying the release of EDRF and NO from endothelial cells in culture. No was determined as the chemiluminescent product of its reaction with ozone. The biological activity of EDRF and of NO was measured by bioassay. The relaxation of the bioassay tissues induced by EDRF was indistinguishable from that induced by NO. Both substances were equally unstable. Bradykinin caused concentration-dependent release of NO from the cells in amounts sufficient to account for the biological activity of EDRF. The relaxations induced by EDRF and NO were inhibited by haemoglobin and enhanced by superoxide dismutase to a similar degree. Thus NO released from endothelial cells is indistinguishable from EDRF in terms of biological activity, stability, and susceptibility to an inhibitor and to a potentiator. We suggest that EDRF and NO are identical.
The cell employs several lines of defense against the toxic products of oxygen reduction. The first is systemic protection against high oxygen tensions at the cellular level. The second is the intracellular localization of the enzymes appropriate to the decomposition of the toxic intermediates at or near the site where they are generated, together with steep gradients of the reactive species themselves. A third line of defense is provided by radical scavengers such as α-tocopherol and β-carotene, which also have the advantage of being appropriately distributed in the membranes where lipid peroxidation might occur. A fourth level of protection is provided by glutathione peroxidase, which reacts directly with lipid peroxides. Finally, recent understanding of the beneficial action of H(2)O(2) in phagocytosis and in ethanol oxidation suggests caution in condemning any metabolite as useless until its functions in toto are thoroughly understood.
SMOOTH muscle tone seems to be primarily regulated by the concentration of free calcium in cytoplasm1,2. Several agents that cause smooth muscle contraction increase the tissue content of cyclic GMP with no significant change or only small reduction of the cyclic AMP concentration3-7. It has been suggested5-7 that cyclic GMP may be casually involved in the contractile response of smooth muscle and that this nucleotide may act as a comediator with calcium to promote contraction. Several observations, however, are not consistent with this assumption. Although increases both in tissue tonus1,2 and in the cyclic GMP level8-10 induced by hormones and neurotransmitters are generally dependent on the presence of extracellular calcium and seem to be secondary to increased influx of calcium into the cytoplasm, the correlation between these two calcium-dependent events is poor in various tissues10-16. On the basis of such observations, we have suggested that cyclic GMP may act as a negative feedback inhibitor of hormonally stimulated calcium influx into cytoplasm8,10,11. We have studied the effects of various agents on cyclic nucleotide levels in the ductus deferens of the rat, and report here that many smooth muscle relaxants, including sodium nitroprusside (SNP), increase cyclic GMP levels in the ductus deferens.
The reactive superoxide radical, O2-, formerly of concern only to radiation chemists and radiobiologists, is now understood
to be a normal product of the biological reduction of molecular oxygen. An unusual family of enzymes, the superoxide dismutases,
protect against the deleterious actions of this radical by catalyzing its dismutation to hydrogen peroxide plus oxygen.
There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients.
The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls.
Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography.
In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 mumol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups.
The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.
The concept of oxidant-antioxidant balance seems to be emerging in the free radical field. The remarkable ubiquity of superoxide dismutase (SOD) among aerobic organisms is accompanied by an equally remarkable constancy of activity. A number of lines of evidence suggest that the steady state free radical concentration in a healthy cell must be very low, but not zero. This chapter briefly reviews and updates the essentials of superoxide and the superoxide dismutases, placing most of the emphasis on the more recent developments. It is clear that after two decades of intensive investigation into the biological roles of superoxide and the superoxide dismutases, we are far from a complete understanding. SOD has proven to be an invaluable tool in these investigations, and the tool is being honed to provide greater discrimination by delineation and alteration of its pharmacokinetic proper ties. This knowledge may also contribute to the eventual success of SOD as a human therapeutic agent.
Although active oxygen species play important roles in the pathogenesis of various diseases, the molecular mechanism for oxygen toxicity in vascular diseases remains to be elucidated. Since endothelium-derived relaxing factor (EDRF) is inactivated by superoxide radicals in vitro, oxidative stress in and around vascular endothelial cells may affect the circulatory status of animals. To study the role of superoxide radicals and related enzymes, such as superoxide dismutase (SOD), in vascular diseases, we have developed a fusion protein (HB-SOD) consisting of human Cu/Zn-type SOD and a C-terminal basic peptide with high affinity for heparan sulfate on endothelial cells. When injected intravenously, HB-SOD bound to vascular endothelial cells, underwent transcellular transport, and localized within vascular walls by a heparin-inhibitable mechanism. The blood pressure of spontaneously hypertensive rats (SHR) but not normal animals was decreased significantly by HB-SOD. Heparin inhibited the depressor effect of HB-SOD. In contrast, native SOD had no effect on blood pressure of either SHR or normal rats. Neither H2O2-inactivated HB-SOD nor the C-terminal heparin-binding peptide showed such a depressor effect, suggesting that the catalytic function of HB-SOD is responsible for its depressor action. To know the source of superoxide radicals, we determined xanthine oxidase activity in the aorta and uric acid levels in the plasma. Although no appreciable difference in xanthine oxidase activity was found between the two animal groups, uric acid levels were significantly higher in SHR than in normal rats. Oxypurinol, a potent inhibitor of xanthine oxidase, also decreased the blood pressure of SHR but not of normal rats. These findings indicate that superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension of SHR.
Endothelium-derived relaxing factor (EDRF) is rapidly inactivated by radicals. Endothelial cells possess several antioxidant defense mechanisms. It is not clear which intrinsic antioxidant defense systems are important to preserve the release of biologically active EDRF. We impaired antioxidant defense in normal vascular tissue by inhibiting catalase activity with 3-amino-1,2,4-triazole (AT), superoxide dismutase with diethyldithiocarbamate (DETC), and by reducing glutathione content via inhibiting glutathione synthesis with L-buthionine-(S,R)-sulfoximine (BSO). Pretreatment of rabbit aorta in vitro with DETC markedly reduced endothelium-dependent relaxation in response to acetylcholine and calcium ionophore A23187 and, to a lesser extent, reduced endothelium-independent relaxation in response to nitroprusside. Pretreatment of cultured bovine aortic endothelial cells (BAEC) with DETC did not alter release of nitrogen oxides (measured by chemiluminescence), but, the effluent of pretreated cells showed marked depression in vasodilator activity (measured by bioassay). Pretreatment of rabbit aorta in vitro with AT did not alter endothelium-dependent and -independent relaxations. Pretreatment of BAEC with BSO did not alter the release of nitrogen oxides or the vasodilator activity. These results suggest that endothelial superoxide dismutase activity, but not catalase or glutathione, is necessary for the release of biologically active EDRF. An imbalance of the intrinsic superoxide dismutase and the production of superoxide anions may therefore predispose to impaired endothelium-dependent relaxations and alter vascular reactivity.
Endothelial cells may produce and release vasoconstrictor substances in response to a number of agents and physical stimuli. In this brief review, current understanding of the mechanisms of endothelium-dependent contractions will be discussed. Cyclooxygenase products of arachidonic acid metabolism including thromboxane A2, prostaglandin H2, superoxide anions, vasoconstrictor peptide endothelin-1, and unidentified factor released from endothelium by hypoxia may mediate these contractions. The physiological role of endothelium-dependent contractions in regulation of the cardiovascular system is unknown. Existing evidence supports the concept that contracting factors may become important regulators of vascular tone under pathological conditions. We speculated about the possible importance of endothelium-dependent contractions for venous graft function, development of vasospasm, increased vascular resistance in hypertension, and vascular complications in diabetes.
In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.
Endothelium-dependent contractions to acetylcholine and endothelium-independent contractions to oxygen-derived free radicals in the aorta of the spontaneously hypertensive rat (SHR) are mediated by an unidentified product of the cyclooxygenase pathway of arachidonic acid metabolism. To determine the role of thromboxane A2 (TXA2) or prostaglandin H2 (PGH2) in these contractions, rings of the thoracic aorta of SHR were suspended in organ chambers for measurement of isometric force. Acetylcholine caused endothelium-dependent contractions in quiescent rings from SHR aortas. Oxygen-derived free radicals generated with xanthine plus xanthine oxidase caused contractions in rings without endothelium. Dazoxiben (thromboxane synthetase inhibitor) did not affect contractions evoked by acetylcholine. AH 23,848, SQ 29,548, or R 68,070 (TXA2/PGH2 receptor antagonists) inhibited contractions to U 46,619 (a TXA2/PGH2 receptor agonist), acetylcholine, and oxygen-derived free radicals. Acetylcholine stimulated the release of prostacyclin from Wistar-Kyoto (WKY) rat and SHR aortas but not the release of other prostaglandins (PGE2, PGF2 alpha, TXA2). Oxygen-derived free radicals did not stimulate the release of prostaglandins from either SHR or WKY rat aortas. These results demonstrate that stimulation of TXA2/PGH2 receptors probably by PGH2 might be involved in endothelium-dependent contractions. Oxygen-derived free radicals, which might be an endothelium-derived contracting factor or factors, ultimately cause contraction by stimulation of TXA2/PGH2 receptors.
The present experiment was performed to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The rings of the thoracic aorta were obtained from age-matched SHR and WKY rats, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the aortic rings from SHR were significantly weaker than those from WKY rats. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase inhibitor (indomethacin) or thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) in aortic rings from both SHR and WKY rats. A thromboxane A2 synthetase inhibitor (OKY-046) did not affect the acetylcholine-induced relaxation in the aortic rings from SHR or WKY rats. In the organ bath solution, after acetylcholine stimulation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations increased but not prostaglandin F2 alpha and thromboxane B2 concentrations. Exogenous prostaglandin H2, a stable analogue of thromboxane A2, and prostaglandin F2 alpha induced contractions of the SHR rings at a lower concentration than prostaglandin E2, prostaglandin D2, and prostaglandin I2. These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin synthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endothelium-derived contracting factor is produced and released by acetylcholine stimulation not only in the aorta of SHR but also in those of WKY rats and suggest that prostaglandin H2, a precursor of the released prostaglandins, is a strong candidate for endothelium-derived contracting factor produced by acetylcholine stimulation.
In isolated blood vessels, acetylcholine releases endothelium-derived relaxing factor (EDRF). In vivo, the vasodilator action of acetylcholine may be mediated by EDRF, but prostacyclin or prejunctional inhibition of adrenergic neurotransmission may also be involved. Therefore, we investigated whether acetylcholine releases EDRF in humans in vivo and, if so, whether the response altered in essential hypertension. Acetylcholine was infused into the brachial artery, and forearm blood flow measured by venous occlusion plethysmography. In control subjects, acetylcholine (0.02-16 micrograms/min/100 ml tissue) increased flow from 2.4 +/- 5.0 to 20.6 +/- 5.2 ml/min/100 ml tissue (n = 14; p less than 0.05) and decreased forearm vascular resistance from 42.0 +/- 4.1 to 6.0 +/- 1.4 units (p less than 0.03), a response comparable to that of sodium nitroprusside (0.6 micrograms/min ml tissue). Acetylsalicylic acid (500 mg i.v.) given to block vascular prostacyclin production did not alter the response (n = 14). alpha-Adrenoceptor blockade by phentolamine (12 micrograms/min/100 ml tissue) did not prevent the increase in flow evoked by acetylcholine. In hypertensive patients, the decrease in forearm vascular resistance induced by acetylcholine but not evoked by sodium nitroprusside was reduced as compared with controls (14.5 +/- 3.1 and 6.1 +/- 1.6 units, respectively; n = 8; p less than 0.05). Thus, the vascular effects of acetylcholine in the human forearm circulation are independent of prostaglandins and adrenergic neurotransmission and therefore are most likely to be mediated by EDRF; the acetylcholine-induced release of EDRF is blunted in patients with essential hypertension.
The calcium ionophore A23187 causes endothelium-dependent contractions in canine basilar arteries. Removal of the endothelium, or treatment with indomethacin or superoxide dismutase (SOD), prevented the endothelium-dependent excitatory effect of the calcium ionophore. Catalase and deferoxamine were without effect. Superoxide anion generated by xanthine plus xanthine oxidase in the presence of catalase caused contractions of the vascular smooth muscle, which were abolished by SOD or heat inactivation of xanthine oxidase. The A23187-induced production of prostaglandins F2 alpha and E2 and thromboxane B2 was abolished by the removal of endothelium and by treatment with indomethacin but was not affected by the presence of SOD plus catalase. These observations are consistent with the hypothesis that superoxide anion, rather than prostaglandins generated by hydroperoxidase activity of cyclooxygenase, is an endothelium-derived contracting factor in canine cerebral arteries.
NG monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived nitric oxide (NO), was infused into the brachial arteries of healthy volunteers to study the role of NO in the control of forearm blood flow. L-NMMA caused a 50% fall in basal blood flow and attenuated the dilator response to infused acetylcholine but not that to glyceryl trinitrate. These results indicate that the dilator action of endothelium-derived NO contributes to the control of basal and stimulated regional blood flow in man. Impairment of production of NO might account for the abnormalities in vascular reactivity that characterise a wide variety of disease states.
Cross-cultural studies suggest that low plasma antioxidant levels contribute to the high incidence of coronary heart disease (CHD) in Scotland. One hundred twenty-five cases of angina without reported history were identified by a postal WHO chest pain questionnaire from a systemic population sample of 6000 Edinburgh men (35-54 years). Classical CHD risk factors (lipids, blood pressure, smoking, and relative weight), plasma vitamins, and a new independent CHD risk factor, adipose tissue linoleate, were measured in angina (n = 125) and healthy controls (n = 430). Cigarette smoking was common in angina (46% vs. 29%, p less than 0.01), and adipose tissue linoleate was lower (8.77 +/- 0.18% vs. 9.81 +/- 0.14% (p less than 0.01). Classical CHD risk factors were not different. Vitamin E/cholesterol molar ratio (micron/mM) was lower in angina than in controls: 1.58 +/- 0.03 vs. 1.66 +/- 0.02 (p less than 0.01). Plasma vitamin C was also lower in angina than in controls: 23.6 +/- 1.7 vs. 30.5 +/- 1.1 microM (p less than 0.001). The relative risk of angina for those in the lowest versus those in the highest quintile of the vitamin E/cholesterol ratio distribution was 2.2:1, irrespective of other risk factors (p less than 0.009). Adipose tissue linoleate removed the association between vitamin E and angina. The relative risk of angina for those in the lowest versus those in the highest quintile of plasma vitamin C was 2.6:1 (p less than 0.01), and the increased risk was also independent of classical risk factors, but closely related to a smoking habit. Low plasma vitamin E or adipose linoleate predisposes to angina, and smoking may increase the risk of angina by lowering plasma vitamin C levels in Scottish men.
To study the mechanism of decreased endothelium-dependent relaxations in spontaneously hypertensive rats (SHR), rings of thoracic aorta with and without endothelium were taken from age-matched male SHR and normotensive Wistar-Kyoto rats (WKY) and suspended for isometric tension recording. Acetylcholine caused endothelium-dependent contractions in quiescent rings from SHR but not in those from WKY. These contractions were inhibited by atropine but not by hexamethonium and were prevented by inhibitors of phospholipase A2 or cyclooxygenase but not by inhibitors of prostacyclin synthetase, thromboxane synthetase, or leukotriene synthetase. Prostaglandin D2, E1, E2, and F2 alpha caused concentration-dependent contractions in rings without endothelium from both SHR and WKY; the responses to the highest concentration (10(-5) M) of the individual prostaglandins were comparable in both strains. Endothelium-dependent relaxations evoked by high but not by low concentrations of acetylcholine were significantly depressed in SHR as compared with those in WKY (p less than 0.05). Indomethacin normalized endothelium-dependent relaxations in SHR. Thus, acetylcholine can activate muscarinic receptors that evoke endothelium-dependent contractions in the aorta of SHR but not in that of WKY. The contraction probably is mediated by a cyclooxygenase product(s) other than prostacyclin or thromboxane A2. The reduced endothelium-dependent relaxations to acetylcholine in the SHR probably are not due to a decreased release of endothelium-derived relaxing factor(s) but to the simultaneous release of endothelium-derived contracting substance(s).
The role of l ‐arginine in the basal and stimulated generation of nitric oxide (NO) for endothelium‐dependent relaxation was studied by use of N G ‐monomethyl l ‐arginine ( l ‐NMMA), a specific inhibitor of this pathway.
l ‐Arginine (10–100 μ m ), but not d ‐arginine (100 μ m ), induced small but significant endothelium‐dependent relaxations of rings of rabbit aorta. In contrast, l ‐NMMA (1–300 μ m ) produced small, endothelium‐dependent contractions, while its enantiomer N G ‐monomethyl‐ d ‐arginine (d‐NMMA; 100 μ) had no effect.
l ‐NMMA (1–300 μ m ) inhibited endothelium‐dependent relaxations induced by acetylcholine (ACh), the calcium ionophore A23187, substance P or l ‐arginine without affecting the endothelium‐independent relaxations induced by glyceryl trinitrate or sodium nitroprusside.
The inhibition of endothelium‐dependent relaxation by l ‐NMMA (30 μ m ) was reversed by l ‐arginine (3–300 μ m ) but not by d ‐arginine (300 μ m ) or a number of close analogues (100 μ m ).
The release of NO induced by ACh from perfused segments of rabbit aorta was also inhibited by l ‐NMMA (3–300 μ m ), but not by d ‐NMMA (100 μ m ) and this effect of l ‐NMMA was reversed by l ‐arginine (3–300 μ m ).
These results support the proposal that l ‐arginine is the physiological precursor for the basal and stimulated generation of NO for endothelium‐dependent relaxation.
Endothelium-derived vascular relaxing factor (EDRF) is a humoral agent that is released by vascular endothelium and mediates vasodilator responses induced by various substances including acetylcholine and bradykinin. EDRF is very unstable, with a half-life of between 6 and 50 s, and is clearly distinguishable from prostacyclin. The chemical structure of EDRF is unknown but it has been suggested that it is either a hydroperoxy- or free radical-derivative of arachidonic acid or an unstable aldehyde, ketone or lactone. We have examined the role of superoxide anion (O-2) in the inactivation of EDRF released from vascular endothelial cells cultured on microcarrier beads and bioassayed using a cascade of superfused aortic smooth muscle strips. With this system, we have now demonstrated that EDRF is protected from breakdown by superoxide dismutase (SOD) and Cu2+, but not by catalase, and is inactivated by Fe2+. These findings indicate that O-2 contributes significantly to the instability of EDRF.
Experiments were designed to determine the effects of oxygen-derived free radicals on the production and biological activity of endothelium-derived relaxing factor or factors released by acetylcholine. Rings of canine coronary arteries without endothelium (bioassay rings) were superfused with solution passing through a canine femoral artery with endothelium. Superoxide dismutase caused maximal relaxation of the bioassay ring when infused upstream, but not downstream, of the femoral artery; this effect of superoxide dismutase was inhibited by catalase. Infusion of acetylcholine relaxed the bioassay rings because it released a labile relaxing factor (or factors) from the endothelium. When infused below the femoral artery, superoxide dismutase and, to a lesser extent, catalase augmented the relaxations to acetylcholine. Superoxide dismutase, but not catalase, doubled the half-life of the endothelium-derived relaxing factor(s). This protective effect of the enzyme was augmented fivefold by lowering the oxygen content of the perfusate from 95 to 10%. These data demonstrate that: superoxide anions inactivate the relaxing factor(s) released by acetylcholine from endothelial cells and hyperoxia favors the inactivation of endothelium-derived relaxing factor(s).
A circulating Na+, K+-ATPase inhibitor may cause arterial hypertension in patients with suppressed plasma renin activity, either directly or by sensitizing peripheral vessels to alpha-adrenergic stimulation. This hypothesis was tested by evaluating forearm arteriolar (plethysmographic technique) response to exogenous alpha-adrenergic stimulation by a 2-minute intra-arterial infusion of norepinephrine (0.1 microgram/dl tissue per minute) and to Na+, K+-ATPase inhibition by sequential 20-minute intra-arterial infusions of ouabain (0.36 and 0.72 microgram/dl tissue per minute). Two groups of hypertensive subjects with suppressed plasma renin activity, either essential or secondary to aldosterone excess, were compared with age-matched and sex-matched hypertensive subjects with normal plasma renin activity (n = 7 per group). No significant differences in forearm vascular response to norepinephrine were found among the three groups. Ouabain caused a highly significant, dose-related increment in forearm vascular resistance that was not accompanied by changes in the contralateral limb or systemic blood pressure. No significant interindividual differences in vascular responsiveness to ouabain were found. The individual increments in forearm vascular resistance during ouabain administration were unrelated to basal values or to plasma aldosterone, norepinephrine, or potassium concentrations. These data are not consistent with the hypothesis that suppressed basal Na+, K+-ATPase activity is primarily a characteristic of hypertensive patients with unresponsive plasma renin activity. Overall, these results cast doubts on the possibility of linking the development of human low renin hypertension to an endogenous Na+, K+-ATPase inhibitor.
Endothelial thromboxane A2 (TXA2) in maintaining the resting tone and producing the contractile response to acetylcholine (ACh) and arachidonic acid was studied in canine cerebral artery. The spontaneous release of TXB2 from cerebral artery was about tenfold higher than that of coronary, mesenteric and saphenous arteries. The resting tone, the release of TXB2 and the contraction produced by arachidonic acid were decreased by the presence of cyclooxygenase inhibitor, TXA2 synthetase inhibitor, TXA2 antagonist and rubbing of the luminal side of preparations. The contraction produced by ACh was inhibited by the presence of the above inhibitors and rubbing of the preparations without decreasing the release of TXB2. These results suggest that the resting tone of canine cerebral artery and the contractile response to arachidonic acid are related to activation of TXA2 synthesis in the endothelium.
The appearance of superoxide anion radical in cerebral extracellular space during and after acute hypertension induced by intravenous norepinephrine was investigated in anesthetized cats equipped with cranial windows. Superoxide was detected by demonstrating the presence of superoxide dismutase-inhibitable reduction of nitroblue tetrazolium. The superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 4.1 +/- 1.61 nM/min per cm2 during hypertension and 4.55 +/- 0.62 nM/min per cm2 one hour after hypertension had subsided. During norepinephrine administration in the absence of hypertension, the superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 0.44 +/- 0.17 nM/min per cm2. The reduction of nitroblue tetrazolium during hypertension was also inhibited by prior treatment of the brain surface with phenylglyoxal at pH 10, to induce irreversible inhibition of the anion channel. The results show that acute hypertension is associated with the generation of superoxide which enters the extracellular space of the brain via the anion channel. Following hypertension, the sustained vasodilation caused by acute hypertension was inhibited significantly by topical application of superoxide dismutase and catalase, showing that it was due in part to superoxide and other radicals derived from it. The vasodilator response of cerebral arterioles to topical acetylcholine was converted to vasoconstriction following acute hypertension, and restored to vasodilation following topical application of superoxide dismutase and catalase. The results show that superoxide and other radicals generated after acute hypertension interfere with acetylcholine-induced endothelium-dependent vasodilation, probably because they destroy the endothelium-derived relaxant factor.
The existence of endothelium-derived vascular relaxant factor (EDRF) was postulated by Furchgott and colleagues when they observed that acetylcholine paradoxically relaxed preconstricted aortic strip preparations by an endothelium-dependent mechanism. This phenomenon has since been demonstrated in different blood vessels and mammalian species and it can be elicited by several other agents. EDRF has been thought to be a humoral agent, a lipoxygenase derivative and possibly a free radical. In the study reported here, by using aortic preparations from the rabbit, alone and in cascade experiments with isolated perfused coronary preparations, we demonstrate definitively that EDRF is a humoral agent. It is released from unstimulated aortic preparations containing endothelium, its release can be stimulated for prolonged periods by acetylcholine, and it is not a lipoxygenase derivative or free radical but an unstable compound with a carbonyl group at or near its active site.
Patients with essential hypertension have abnormal endothelium-dependent vasodilation related to decreased nitric oxide activity. The specific mechanism responsible for this abnormality is unknown. Recent studies in hypertensive animals have suggested an augmented destruction of nitric oxide by superoxide anions. Therefore, in the present study we aimed to investigate whether this mechanism is responsible for the abnormal vasodilator function of hypertensive patients. To this end, we studied the vascular responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct smooth muscle dilator) before and after combined administration of copper-zinc superoxide dismutase (a scavenger of superoxide anions with poor intracellular penetrance; 6000 U/min) in 20 healthy control subjects (11 men and 9 women; aged 50 +/- 6 years) and 20 hypertensive patients (13 men and 7 women; aged 51 +/- 9 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with control subjects (maximal flow: 8.2 +/- 4 versus 12.7 +/- 3 mL/min per 100 mL; P < .02); however, no difference was observed in the response to sodium nitroprusside (8.1 +/- 4 versus 9.5 +/- 3 mL/min per 100 mL). In healthy control subjects superoxide dismutase infusion did not modify the vasodilator response to acetylcholine (maximal flow: 12.7 +/- 3 before versus 12.1 +/- 3 after superoxide dismutase). Similarly, in hypertensive patients superoxide dismutase infusion did not alter the response to acetylcholine (maximal flow: 8.2 +/- 4 versus 7.7 +/- 4).(ABSTRACT TRUNCATED AT 250 WORDS)
We undertook these studies to determine whether a deficient nitric oxide production in genetically hypertensive rats could result from its being scavenged by an excess production of superoxide. In one study we used a porphyrinic microsensor to measure nitric oxide concentrations released by cultured endothelial cells from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). SHRSP cells released only about one third the concentration of nitric oxide as did WKY cells. Treatment of cells with superoxide dismutase increased nitric oxide release, demonstrating that normally nitric oxide is scavenged by endogenous superoxide. The increase in nitric oxide release in response to superoxide dismutase treatment was more than twice as great from SHRSP as from WKY cells, demonstrating the greater amount of superoxide in the hypertensive rats. A direct measure of superoxide with the use of lucigenin demonstrated the presence of 68.1 +/- 7.1 and 27.4 +/- 3.5 nmol/L of this anion in SHRSP and WKY endothelial cells, respectively. The presence of superoxide in the rat aorta was also estimated by quantification of its effect on carbachol relaxation. This relaxation was diminished when endogenous superoxide dismutase was blocked by diethyldithiocarbamic acid. This blockade reduced the relaxation by 51.2 +/- 5.2% in SHRSP aortas and by only 22.0 +/- 8.2% (P = .015) in WKY aortas. Data from these diverse systems are in agreement that superoxide production is excessive in SHRSP tissues. This excess superoxide, by scavenging endothelial nitric oxide, could contribute to the increased vascular smooth muscle contraction and hence to the elevated total peripheral resistance of these rats.
The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypertensive patients is related to a specific defect of the muscarinic receptor or to a broader abnormality of the vascular endothelium.
Patients with essential hypertension have abnormal endothelium-dependent vasodilator response to acetylcholine. However, whether this results from an isolated dysfunction of the endothelial cell muscarinic receptor is unknown.
The responses of the forearm vasculature to acetylcholine and substance P (endothelium-dependent agents acting on different receptors) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in eight hypertensive patients (six men, two women; mean age [+/- SD] 50 +/- 12 years) and eight normal control subjects (four men, four women; mean age 49 +/- 9 years). To determine the nitric oxide contribution to substance P-induced vasodilation, the vascular responses to substance P were also measured after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain gauge plethysmography.
The response to acetylcholine was significantly blunted in hypertensive patients (highest blood flow [mean +/- SD] 8.4 +/- 4 vs. 13.8 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). Similarly, the vasodilator effect of substance P was significantly reduced in hypertensive patients (highest blood flow [mean +/- SD] 8.8 +/- 4 vs. 13.9 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). A significant correlation was found between the maximal blood flow with acetylcholine and that with substance P (r = 0.68, p < 0.004). The vasodilator response to sodium nitroprusside was similar in patients and control subjects. The nitric oxide contribution to substance P-induced vasodilation was reduced in hypertensive patients, such that the responses to substance P measured during infusion of NG-monomethyl-L-arginine were not significantly different between the two groups.
These findings indicate that the endothelial abnormality of patients with essential hypertension is not restricted to the muscarinic cell receptor.
The present study was designed to directly test the vasodilation action of insulin and its relation to endothelium-dependent mechanisms.
In 18 normotensive subjects and 27 patients with untreated mild to moderate essential hypertension, we studied the effect of intrabrachial insulin on the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (at doses of 0.15, 0.45, 1.5, 4.5, and 15 micrograms.min-1.dL-1), an endothelium-dependent vasodilator, or sodium nitroprusside (at doses of 1, 2, and 4 micrograms.min-1.dL-1), and endothelium-independent vasodilator. Local hyperinsulinemia (deep venous plasma insulin, 48 +/- 6 and 51 +/- 5 microU/mL in control subjects and hypertensive patients, respectively) did not affect basal forearm blood flow and stimulated forearm glucose extraction (control subjects, 3 +/- 1% to 11 +/- 2%, P < .001; hypertensive patients, 3 +/- 1% to 6 +/- 1%, P < .001; P < .01 for the between-group difference). In both normotensive and hypertensive subjects, insulin significantly potentiated acetylcholine-induced vasodilation, whereas it did not alter the vasodilatory response to sodium nitroprusside. NG-monomethyl-L-arginine, an inhibitor of endothelial nitric oxide synthesis, blunted insulin-induced facilitation of acetylcholine vasodilation in normotensive but not in hypertensive subjects. In contrast, in hypertensive patients but not in normotensive control subjects, the potentiation of the vascular response to acetylcholine induced by local hyperinsulinemia was abolished by intrabrachial ouabain, an inhibitor of Na(+)-K+ pump.
In healthy humans and essential hypertensive patients alike, local physiological hyperinsulinemia per se does not increase forearm blood flow but potentiates the vasodilation induced by acetylcholine regardless of metabolic insulin resistance. This effect is endothelium-dependent because it is not seen with nitroprusside and is related to the L-arginine-nitric oxide pathway in normotensive subjects and to smooth muscle cell hyperpolarization in essential hypertensive patients.
Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown.
We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal.
Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group.
The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.
Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality.
The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48 +/- 9 years old [mean +/- SD]) and 12 control subjects (6 men, 6 women; aged 48 +/- 7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of NG-monomethyl-L-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5 +/- 2 versus 16.6 +/- 8 mL.min-1.100 mL-1 in control subjects [mean +/- SD]; P < .005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7 +/- 2 versus 15.8 +/- 6 mL.min-1.100 mL-1 in control subjects; P < .005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (r = .89). No significant differences were found between the two groups for vascular response to sodium nitroprusside. NG-monomethyl-L-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8 +/- 6 to 10.1 +/- 2 mL.min-1.100 mL-1, P < .003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7 +/- 2 and 8.5 +/- 3 before and during infusion of NG-monomethyl-L-arginine, respectively; P = NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups.
Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.
Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients.
Within the normotensive or hypertensive group (n = 53 and n = 57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 micrograms/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly (P < .01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive (r = -.86, P < .001) and hypertensive (r = -.85, P < .001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r = -.37; hypertensive patients, r = -.36) compared with acetylcholine.
The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.
We designed experiments to characterize the role of superoxide anions in the mediation of endothelium-dependent contractions in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2-6% CO2 (37 degrees C, pH 7.4). Radioimmunoassay was used to determine the levels of cyclic GMP and cyclic AMP. Calcium ionophore A23187 (10(-9) to 10(-6) mol/L) caused concentration-dependent contractions. The removal of endothelium abolished the effect of A23187. Contractions to A23187 were reversed into relaxations in the presence of superoxide dismutase (150 U/mL) or the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 (10(-6) mol/L). NG-nitro-L-arginine methyl ester (3 x 10(-4) mol/L) augmented contractions to A23187. In rings with endothelium, A23187 (3 x 10(-7) mol/L) significantly increased levels of both cyclic AMP and cyclic GMP. Indomethacin (10(-5) mol/L) inhibited stimulatory effects of A23187 on cyclic AMP production. In contrast, indomethacin augmented A23187-induced production of cyclic GMP. Selective augmentation of cyclic GMP production by indomethacin appears to be due to protection of nitric oxide or a closely related molecule released following translocation of calcium into endothelial cells. Our findings suggest that (1) an increased concentration of calcium in endothelial cells may activate both cyclooxygenase and the L-arginine/nitric oxide pathway, (2) arachidonic acid metabolism via cyclooxygenase is a source of superoxide anions, and (3) superoxide anions may be responsible for impairment of balance between relaxing and contracting factors leading to contraction of underlying smooth muscle cells.
1. Small arteries were isolated from either rat mesentery or human subcutaneous fat, and mounted in a myograph for the measurement of isometric force.
2. Superoxide dismutase, either in the presence or absence of catalase, relaxed noradrenaline-induced tone. This effect was abolished by removal of the endothelium or incubation with an inhibitor of NO synthase, N-ω-nitro-L-arginine methyl ester. Catalase alone had a negligible effect on noradrenaline-induced tone.
3. Captopril, an angiotensin-converting enzyme inhibitor and putative free-radical scavenger, did not relax pre-contracted isolated vessels. N-Acetylcysteine caused an endothelium-independent relaxation of rat vessels. Similar effects were observed in human vessels.
4. Acetylcholine induced a concentration-dependent relaxation of isolated resistance arteries, which was inhibited by removal of the endothelium or N-ω-nitro-L-arginine methyl ester, but unaffected by indomethacin. Preincubation with captopril, N-acetylcysteine or catalase alone did not alter the acetylcholine concentration-response relationship, but superoxide dismutase in combination with catalase enhanced responses to acetylcholine, causing a six-fold increase in potency.
5. Superoxide dismutase causes endothelium-dependent relaxation of resistance arteries and potentiates responses to acetylcholine. This action is probably due to the ability of the enzyme to scavenge superoxide anions which inhibit endothelium-dependent relaxation.
6. N-Acetylcysteine causes an endothelium-independent relaxation of resistance arteries which is probably unrelated to the putative ability of this compound to scavenge superoxide radicals and may reflect a direct action on vascular smooth muscle.
The oxidative modification of low-density lipoproteins increases their incorporation into the arterial intima, an essential step in atherogenesis. Although dietary antioxidants, such as vitamin C, carotene, and vitamin E, have been hypothesized to prevent coronary heart disease, prospective epidemiologic data are sparse.
In 1986, 39,910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C, carotene, and vitamin E in addition to other nutrients. During four years of follow-up, we documented 667 cases of coronary disease.
After controlling for age and several coronary risk factors, we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E, the multivariate relative risk was 0.64 (95 percent confidence interval, 0.49 to 0.83) as compared with those consuming less than 7.5 IU per day. As compared with men who did not take vitamin E supplements, men who took at least 100 IU per day for at least two years had a multivariate relative risk of coronary disease of 0.63 (95 percent confidence interval, 0.47 to 0.84). Carotene intake was not associated with a lower risk of coronary disease among those who had never smoked, but it was inversely associated with the risk among current smokers (relative risk, 0.30; 95 percent confidence interval, 0.11 to 0.82) and former smokers (relative risk, 0.60; 95 percent confidence interval, 0.38 to 0.94). In contrast, a high intake of vitamin C was not associated with a lower risk of coronary disease.
These data do not prove a causal relation, but they provide evidence of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men. Public policy recommendations with regard to the use of vitamin E supplements should await the results of additional studies.