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Effect of ANG-(1-7) on ANG II-induced vasoconstriction in the presence of A-779 (10 −5 M) (n=12) (a) or endothelium removal (n=13) (b). In graph A, ANG-(1-7) basal effect curve was added for visual comparison. Values are presented as means ± SE. P<0,05: * vs. ANG-(1-7)
Source publication
Purpose:
The renin-angiotensin system plays a key role in cardiovascular pathophysiology and one of its members, angiotensin-(1-7) (ANG-(1-7)), is now recognized as a peptide with the ability to counter-regulate angiotensin II (ANGII) effects. We sought to investigate ANG-(1-7) actions in human vessels, particularly its effect on ANGII-induced vas...
Contexts in source publication
Context 1
... with A-779 or endothelial removal did not signif- icantly change ANG-(1-7) effect on ANG II-induced vaso- constriction. In the A-779 treatment protocol, we observed a maximum increase in active tension of 15.4±2.3 % (ANG II/ PE max ) in ANG-(1-7) treated rings and an increase of 49.4± 3.6 % (ANG II/PE max ) in the vehicle treated rings (Fig. 3a, P<0.01). Regarding EC50, no difference was observed ...
Context 2
... (27) RAS renin-angiotensin system; ARAII Angiotensin II receptor 1 antago- nist; ACEi angiotensin converting enzyme inhibitor between ANG-(1-7) and vehicle-treated vessels (EC 50 , 5.22± 1.98 vs. 2.95±0.83·10 −8 M), respectively). Similarly, endo- thelium removal did not affect ANG-(1-7) effect on ANG II response, with an increase of 28.2±5.8 % (ANG II/PE max ) in the active tension in ANG-(1-7) treated rings and of 71.7±3.3 % (ANG II/PE max ) in the vehicle treated rings (Fig. 3b, P<0.01). EC 50 was also not different between ANG-(1-7) and control rings (EC 50 , 3.55±1.78 vs. 1.86±0.94·10 −8 M, ...
Citations
... In the current study, we found that direct effects of Ang II on endothelial function was not sex-dependent. Although such findings may seem somewhat surprising, there are studies in humans and preclinical models where the effects of Ang II were sex-independent, and other studies where Ang II caused greater vascular responses in women than in men (Gandhi et al., 1998;Mendonca et al., 2014;Schneider et al., 2010). Thus, a single pattern is not applicable across all studies. ...
The renin-angiotensin system (RAS) contributes to vascular disease with multiple cardiovascular risk factors including hypertension. As a major effector within the RAS, angiotensin II (Ang II) activates diverse signaling mechanisms that affect vascular biology. Despite the impact of such vascular pathophysiology, our understanding of the effects of Ang II in relation to the function of endothelial cells is incomplete. Because genetic background and biological sex can be determinants of vascular disease, we performed studies examining the direct effects of Ang II using carotid arteries from male and female mice on two genetic backgrounds, C57BL/6J and FVB/NJ. Although FVB/NJ mice are much less susceptible to atherosclerosis than C57BL/6J, the effects of Ang II on endothelial cells in FVB/NJ are poorly defined. Overnight incubation of isolated arteries with Ang II (10 nmol/L), impaired endothelial function in both strains and sexes by approximately one-half (p < 0.05). To examine the potential mechanistic contribution of Rho kinase (ROCK), we treated arteries with SLX-2119, an inhibitor with high selectivity for ROCK2. In both male and female mice of both strains, SLX-2119 largely restored endothelial function to normal, compared to vessels treated with vehicle. Thus, Ang II-induced endothelial dysfunction was observed in both FVB/NJ and C57BL/6J mice. This effect was sex-independent. In all groups, effects of Ang II were reversed by inhibition of ROCK2 with SLX-2119. These studies provide the first evidence that ROCK2 may be a key contributor to Ang II-induced endothelial dysfunction in both sexes and in mouse strains that differ in relation to other major aspects of vascular disease.
... The vasodilatory effects of Ang-(1-7) were observe in arterioles of the adipose and atrial tissue of patients with or without clinical diagnosis of coronary artery diseases. [30] Intra-brachial infusion of the Ang-(1-7) increased forearm blood flow in healthy and hypertensive subjects [31], reduces Ang II-induced vasoconstriction in mammary arteries of healthy subjects [32]. Ang-(1-7) stimulated the production of endothelium-derived nitric oxide, prostaglandins, and relaxation factors in endothelial cells in animal models [33]. ...
Background
The ECA2/Ang-(1–7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPβ-CD-Ang-(1–7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPβ-CD-Ang-(1–7) on the performance of mountain bike (MTB) practitioners.
Methods
Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPβ-CD-Ang-(1–7) (1.75 mg) and HPβCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPβ-CD-Ang-(1–7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO2), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer.
Results
There were no significant differences in terms of HR or BP at rest and maximum effort between the HPβ-CD-Ang-(1–7) and placebo groups. The VO2max showed significant differences (p = 0.04). It was higher in the Ang-(1–7)condition (66.15 mlO2.kg− 1.min− 1) compared to the placebo (60.72 mlO2.kg− 1.min− 1). This was also observed for TET (Ang-(1–7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1–7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1–7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate.
Conclusions
These results suggest that HPβ-CD-Ang-(1–7) improves the physical performance of MTB recreational athletes and could be a promising supplement.
Trial registration
RBR-2 × 56pw8, registered January 15th, 2021. The study was prospectively registered.
... The vasodilatory effects of Ang-(1-7) were observe in arterioles of the adipose and atrial tissue of patients with or without clinical diagnosis of coronary artery diseases. [30] Intra-brachial infusion of the Ang-(1-7) increased forearm blood ow in healthy and hypertensive subjects [31], reduces Ang II-induced vasoconstriction in mammary arteries of healthy subjects [32]. Ang-(1-7) stimulated the production of endothelium-derived nitric oxide, prostaglandins, and relaxation factors in endothelial cells in animal models [33]. ...
Background: The ECA2/Ang-(1-7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPβ-CD-Ang-(1-7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPβ-CD-Ang-(1-7) on the performance of mountain bike (MTB) practitioners.
Methods: Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPβ-CD-Ang-(1-7) (1.75 mg) and HPβCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPβ-CD-Ang-(1-7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO2), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer.
Results: There were no significant differences in terms of HR or BP at rest and maximum effort between the HPβ-CD-Ang-(1-7) and placebo groups. The VO2max showed significant differences (p = 0.04). It was higher in the Ang-(1-7)condition (66.15 mlO2.kg⁻¹.min⁻¹) compared to the placebo (60.72 mlO2.kg⁻¹.min⁻¹). This was also observed for TET (Ang-(1-7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1-7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1-7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate.
Conclusion: These results suggest that HPβ-CD-Ang-(1-7) improves the physical performance of MTB recreational athletes and could be a promising supplement.
Trial registration: RBR-2x56pw8, registered January 15th, 2021.
... Ang-(1-7) significantly reduces Ang II-induced vasoconstriction in mammary arteries from healthy subjects and splanchnic vessels from cirrhotic subjects. [55][56][57] Ang-(1-7) also vasodilates adipose and atrial arterioles from patients without coronary artery disease, with effects attenuated in patients with coronary artery disease. 58 This suggests protective effects of Ang-(1-7) in human coronary and peripheral microvasculature, similar to preclinical observations. ...
Despite decades of research and numerous treatment approaches, hypertension and cardiovascular disease remain leading global public health problems. A major contributor to regulation of blood pressure, and the development of hypertension, is the renin-angiotensin system. Of particular concern, uncontrolled activation of angiotensin II contributes to hypertension and associated cardiovascular risk, with antihypertensive therapies currently available to block the formation and deleterious actions of this hormone. More recently, angiotensin-(1-7) has emerged as a biologically active intermediate of the vasodilatory arm of the renin-angiotensin system. This hormone antagonizes angiotensin II actions as well as offers antihypertensive, antihypertrophic, antiatherogenic, antiarrhythmogenic, antifibrotic and antithrombotic properties. Angiotensin-(1-7) elicits beneficial cardiovascular actions through mas G protein-coupled receptors, which are found in numerous tissues pivotal to control of blood pressure including the brain, heart, kidneys, and vasculature. Despite accumulating evidence for favorable effects of angiotensin-(1-7) in animal models, there is a paucity of clinical studies and pharmacokinetic limitations, thus limiting the development of therapeutic agents to better understand cardiovascular actions of this vasodilatory peptide hormone in humans. This review highlights current knowledge on the role of angiotensin-(1-7) in cardiovascular control, with an emphasis on significant animal, human, and therapeutic research efforts.
... Secondly, SW increased the blood pressure in the WKY rats and exacerbated the blood pressure in the SHR. This is mainly attributed to the increase in the levels of ANG-II in the serum caused by metabolic disorders, as well as increased expression of AGTR and decreased expression of eNOS in the carotid artery, ultimately resulting in increased blood pressure [60][61][62] . In addition, metabolic disorders trigger an elevation in the levels of IL-6, resulting in an increase in the inflammatory response of the blood vessel [63,64] . ...
... In the present study, the decrease in compliance was primarily associated with the increase in the content of collagen fiber in the vessel wall [67][68][69] , and the imbalance in the ratio of eNOS to AGTR expression in the vessel wall. [60][61][62] However, with respect to the blood flow velocity, the effects of SW on the carotid arteries of the two types of rats were not identical. In the WKY rats, SW reduced the diameter of the carotid artery and increased the blood flow velocity. ...
Objective
The objective was to investigate the effects of shift-work (SW) on the carotid arteries.
Methods
This study used two inverted photoperiods (inverted light:dark [ILD]16:8 and ILD12:12) to create the SW model. We recorded the rhythm and performed serological tests, carotid ultrasound, magnetic resonance imaging, and carotid biopsy.
Results
SW induced elevated blood pressure and increased angiotensin-II, apolipoprotein E, blood glucose, and triglycerides. SW increased the carotid intima-media thickness. SW led to the development of carotid arterial thrombosis, reduced cerebral blood flow, and increased the number of collagen fibers, expression of angiotensin receptor and low-density lipoprotein receptor in the carotid arteries. SW decreased 3-hydroxy-3-methylglutaryl-CoA reductase and nitric oxide. SW induced the atherosclerotic plaque in the aorta. Multiple results of SHR were worse than WKY rats.
Conclusion
SW can induce metabolic disorders and elevated blood pressure. SW can cause intima-media thickening of the carotid artery and aorta atherosclerosis. SW may result in carotid arterial thrombosis and affect cerebral blood flow. Hypertension can aggravate the adverse effects of SW.
... RAS is an important mechanism in the development and progression of atherosclerosis and hypertension. After the combination of PRR and ligand, a large amount of Ang II can cause vasoconstriction, while RAS can also lead to an inflammatory reaction (31,32). ox-LDL, an LDL peroxidation product with strong cytotoxicity, causes an increase in oxidative stress, while it can also induce the maturation of macrophages, thereby releasing inflammatory factors, such as IL-6 and TGF, and exerting pro-inflammatory effects (33,34). ...
The incidence of depression has previously been correlated to hypertension. The aim of the present study was to explore the mechanisms of depression and hypertension by examining the expression and interaction of renin/prorenin receptor (PRR) and heme oxygenase 1 (HO-1) in vascular endothelial cells. A case-control study was conducted, and general data and serum factors were compared between hypertension patients complicated with depression and patients with hypertension alone. Logistic regression analysis was used to detect risk factors associated with hypertension complicated with depression. In addition, human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) and/or PRR gene silencing, and a Cell Counting Kit-8 (CCK-8) assay was performed to test their proliferation. The concentrations of inflammatory factors and oxidative stress factor were also detected using enzyme-linked immunosorbent assay and chemical colorimetry. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were applied to detect protein and mRNA expression levels, respectively. The results revealed that HO-1 and renin precursor (Rep) were independent factors that affected hypertension complicated with depression. Serum HO-1 levels in patients with hypertension complicated with depression were significantly lower than that in hypertensive patients without depression, while Rep levels in patients with hypertension complicated with depression were significantly higher than that in hypertensive patients without depression. In HUVECs, ox-LDL reduced the cell proliferation in a dose-dependent manner, upregulated the expression of PRR gene and downregulated the expression of HO-1 gene. It was also observed that silencing of the PRR gene promoted the expression of the HO-1 gene. Furthermore, ox-LDL upregulated the inflammatory response and oxidative stress levels, while PRR gene silencing inhibited the ox-LDL-induced inflammatory factor and oxidative stress levels in HUVECs. Thus, regulating the expression levels of HO-1 and PRR to inhibit the oxidative stress and pro-inflammatory effect of ox-LDL may provide new insight for the treatment of hypertension patients with depression.
... IMA rings used in the present study were obtained from patients who underwent coronary bypass grafting (CABG) surgery due to various cardiovascular diseases as shown in Table-1.The SNP-induced endothelium-independent relaxation protocol was used as the relaxation protocol by taking the possibility of vascular endothelium being damaged during the operation into consideration.The most commonly used vessels as graft for coronary arteries are IMA and saphenous vein. The use of these vessels as grafts instead of the heart-feeding blood vessels makes the contractile activity in these vessels quite important and therefore this topic has become an important research area (23). ...
Aim: Apelin has important effects on the circulatory system and heart. The main aim of this study was to investigate the effects of apelin-13 on the contraction induced by norepinephrine (NE), and the endothelium-independent relaxation induced by sodium nitroprusside (SNP) in human internal mammary artery (IMA) obtained from patients undergoing coronary artery bypass grafting (CABG) surgery. Material and Methods: IMA rings, obtained from patients undergoing CABG surgery, were suspended in isolated tissue baths containing Krebs-Henseleit solution, which were continuously gassed with 95% O2 and 5% CO2 at 37°C. Results: The IMA rings were pre-contracted with increasing concentrations of norepinephrine (NE 10-9-10-4 mol/l) and the endothelium-independent relaxation responses to sodium nitroprusside (SNP) were studied. Apelin-13 (10 μM) caused a dose-dependent relaxation in NE pre-contracted IMA rings. Apelin also facilitated the endothelium-independent relaxation induced by SNP. Conclusion: According to the results, apelin facilitated the endothelium-independent relaxation and inhibited the contractile activity of IMA. These results suggest that apelin may be a physiological agent against the deterioration of vascular elasticity caused by endothelial damage especially in atherosclerotic cardiac patients and hypertensive patients.
... The same authors (560) demonstrated that the effect of ANG-(1-7) infusion on renal blood flow was also reduced in stenotic kidneys. Mendonça et al. (359) have recently demonstrated that ANG-(1-7) significantly attenuates ANG IIinduced vasoconstriction in human mammary arteries from patients submitted to coronary revascularization, probably through direct effects on smooth muscle cells, since this action was not abolished by A-779, PD123177, or endothelium removal. ...
The renin-angio-tensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the deca-peptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
... In this study evidence is presented for the first time demonstrating that Ang II mediated vasoconstriction is negatively influenced by Ang-(1-7) in isolated human cirrhotic arteries. Similar findings have been reported for studies performed in isolated mammary arteries from patients undergoing coronary artery bypass grafting where an identical concentration of Ang-(1-7) was used (10 −5 M) [34,35]. The abrogating effect of Ang-(1-7) on Ang II induced tone was independent of MasR since it was not attenuated by A779 and this was also the case for human mammary arteries [35]. ...
... Similar findings have been reported for studies performed in isolated mammary arteries from patients undergoing coronary artery bypass grafting where an identical concentration of Ang-(1-7) was used (10 −5 M) [34,35]. The abrogating effect of Ang-(1-7) on Ang II induced tone was independent of MasR since it was not attenuated by A779 and this was also the case for human mammary arteries [35]. It has been reported that MasR is not the sole site of action for Ang-(1-7) with animal studies demonstrating Ang-(1-7) vasodilatory responses to be attenuated either in the presence of AT1R blockade [36,37] or alternatively a selective Ang-(1-7) antagonist, D-pro 7 -Ang-(1-7) [37][38][39]. ...
... However, in subsequent studies of vessels from two cirrhotic patients we found that attenuation of the Ang II response by Ang-(1-7) was not inhibited by D-pro 7 -Ang-(1-7) (data not shown) adding support to the argument that this attenuation response may be the direct result of an Ang-(1-7)-AT1R interaction. The concept of an Ang-(1-7)-AT1R interaction in human vessels has been raised in the past both in vivo [40] and in vitro [34,35] where Ang-(1-7) attenuated Ang II contractile responses but had no effect on adrenergic contractility. This supports the present findings that although the omental vessels express MasR, Ang-(1-7) failed to affect the adrenergic response, reiterating the concept of Ang-(1-7)-AT1R interaction in these vessels. ...
... Although that finding is somewhat surprising, there are studies in humans and animal models where effects of Ang II were sex independent and also cases where Ang II caused greater vascular responses in women than in men. [30][31][32] Thus, when the broader literature is considered, the lack of sexdependent effects of Ang II in this study is perhaps less of a surprise. ...
Pharmacological activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) protects the vasculature. Much less is known on the cell-specific impact of PPAR-γ when driven by endogenous ligands. Recently, we found that endothelial PPAR-γ protects against angiotensin II-induced endothelial dysfunction. Here, we explored that concept further examining whether effects were sex dependent along with underlying mechanisms. We studied mice expressing a human dominant-negative mutation in PPAR-γ driven by the endothelial-specific vascular cadherin promoter (E-V290M), using nontransgenic littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from nontransgenic and E-V290M mice. Incubation of isolated arteries with angiotensin II (1 nmol/L) overnight had no effect in nontransgenic, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice (P<0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-κB (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-γ may influence the angiotensin 1-7 arm of the renin-angiotensin system. In the basilar artery, dilation to angiotensin 1-7 was selectively reduced in E-V290M mice by >50% (P<0.05), an effect reversed by Y-27632. Thus, effects of angiotensin II are augmented by interference with endothelial PPAR-γ through sex-independent mechanisms, involving oxidant-inflammatory signaling and Rho kinase (ROCK2). The study also provides the first evidence that endothelial PPAR-γ interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-γ have implications for pathophysiology and therapeutic approaches for vascular disease.
