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2 Mechanism of action of angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockade. Angiotensinogen is converted to angiotensin I by renin secreted from juxtaglomerular apparatus in the kidney. Angiotensin I is further converted to angiotensin II by ACEIs, which are released in the lungs and also responsible for breakdown of bradykinin, a potent vasodilator . Angiotensin II acts on AT1 receptor in the kidney, which is blocked by ARBs. The role of AT2 receptor in adults remains poorly understood. Note that the production of bradykinin is enhanced by ACE inhibitors (not by ARBs) which is largely responsible for major side effects of these drugs (e.g., dry cough, angioedema)
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Vasodilators, as their name imply, treat hypertension by causing the smooth muscle walls of blood vessels to relax, thus dilating the vessel. The systemic peripheral vascular resistance (afterload) is reduced by dilating on the arterial side of the Vasodilators work by reducing preload, afterload, or both preload and afterload. Preload reduction re...
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Heart is a vital blood pumping organ of human body. Cholesterol buildup, smoking, obesity and high blood pressure causes heart malfunctioning leading to heart diseases. Coronary artery disease (CAD), cardiac arrhythmia, myocardial infarction, congenital heart diseases, cardiomyopathy are some among many cardiovascular diseases. Several drugs are clinically available to treat these cardiac disorders, for example, antiplatelet drugs have been useful in ischemic stroke, CAD and peripheral arterial disease. Moreover, aspirin is commonly used in myocardial infarction, while atorvastatin, a drug used to lower cholesterol, deters with cytochrome P450-mediated metabolism of clopidogrel that results in the resistance against clopidogrel (antithrombotic drug). Atropine is used in cardiac dysrhythmia and heart block while adenosine has depressant effects on atropine. The antibiotic, benzathine penicillin G, is an important antibiotic for the treatment of group A streptococcal infections associated with rheumatic heart disease. Furthermore, beta blockers, thiazides, ACE inhibitors, diuretics are also used for several other heart disorders. Resistance has been reported against some of the drugs, such as some antiplatelet drugs and antithrombotic agents. Resistance towards aspirin is influenced by several factors such as clinical, biological and genetic aspects. COX1-A1 mutation and glycoprotein IIIa (GPIIIa) gene polymorphism is linked to aspirin resistance and could possibly be involved in it. However, drug resistance against atorvastatin, atropine and benzathine penicillin G is still unknown.
Benzoyltryptamine analogues act as neuroprotective and spasmolytic agents on smooth muscles. In this study, we investigated the ability of N-salicyloyltryptamine (STP) to produce vasorelaxation and determined its underlying mechanisms of action. Isolated rat mesenteric arteries with and without functional endothelium were studied in an isometric contraction system in the presence or absence of pharmacological inhibitors. Amperometric experiments were used to measure the nitric oxide (NO) levels in CD31+ cells using flow cytometry. GH3 cells were used to measure Ca2+ currents using the whole cell patch clamp technique. STP caused endothelium-dependent and -independent relaxation in mesenteric rings. The endothelial-dependent relaxations in response to STP were markedly reduced by L-NAME (endothelial NO synthase-eNOS-inhibitor), jHydroxocobalamin (NO scavenger, 30 µM) and ODQ (soluble Guanylyl Cyclase-sGC-inhibitor, 10 µM), but were not affected by the inhibition of the formation of vasoactive prostanoids. These results were reinforced by the increased NO levels observed in the amperometric experiments with freshly dispersed CD31+ cells. The endothelium-independent effect appeared to involve the inhibition of voltage-gated Ca2+ channels, due to the inhibition of the concentration-response Ca2+ curves in depolarizing solution, the increased relaxation in rings that were pre-incubated with high extracellular KCl (80 mM), and the inhibition of macroscopic Ca2+ currents. The present findings show that the activation of the NO/sGC/cGMP pathway and the inhibition of gated-voltage Ca2+ channels are the mechanisms underlying the effect of STP on mesenteric arteries.
Alagille syndrome (ALGS) is a genetic disorder associated with multisystem dysfunction involving the hepatic, cardiovascular, and neurologic systems. Tetralogy of Fallot (TOF), a congenital cardiac anomaly, is commonly found in these patients. Patients with ALGS may also have an increased risk of cerebrovascular abnormalities and bleeding. Ruptured cerebral aneurysm and subarachnoid hemorrhage (SAH) may be developed, increasing the incidence of morbidity and mortality. Advances in neuroimaging and neurosurgery have allowed early identification and treatment of such vascular abnormalities, improving patients’ outcomes and reducing life-threatening complications such as intracranial bleeding. Authors describe the perioperative management of a patient with ALGS and TOF who was admitted to the emergency department due a ruptured intracranial aneurysm with concomitant SAH. Surgical treatment included diagnostic cerebral arteriography with coil embolization of a left posterior communicating artery aneurysm, and placement of right external ventricular drain (EVD). The combination of neuroprotective anesthetic techniques, fast emergence from anesthesia, and maintenance of intraoperative hemodynamic stability led to a successful perioperative management. A multidisciplinary approach in specialized centers is essential for the treatment of patients with SAH, especially in patients with ALGS and complex congenital heart disease such as TOF.
