Vasoconstriction endothelin

In 1985, a peptide was described in the supernatants of endothelial cells that mediated vasoconstriction [1]. This peptide was isolated and sequenced, and the cDNA was cloned. According to its origin from endothelial cells it was named endothelin. 

Endothelin-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 Endothelin-1 binds to two G-protein coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). Endothelin-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. Endothelin-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality. 

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF vasodilation and neurohormonal antagonism of endothelin.9 Nitric oxide s production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is up-regulated in the setting of HF, likely due to increased levels of angiotensin II, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation. 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I ... 

Endothelin eta Human cDNA Acute pancreatitis, artherosderosis, cancer, hypertension, congestive heart failure, diabetes, obesity, inflammation, myocardial ischemia, prostatic hypertrophy, pulmonary fibrosis, stroke, ulcer, pain Vasoconstriction, bronchoconstriction, positive cardiac inotropy, proliferative responses, aldosterone secretion, neuroprotection... 

Endothelin 1 (ETl) is a 21-amino acid peptide released from bronchial cells. It has potent vasoconstrictive agonist properties mediated by two receptor types (A and B). The involvement of the endothelin 1 type A (EDNRA) gene (Afill SNP) in atopy, however, is marginal at best and as yet not widely replicated (181). For... 

Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6-7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure (Figure 13-3). Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators... 

Endothelins exert widespread actions in the body. In particular, they cause dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a prolonged increase. The depressor response results from release of prostacyclin and nitric oxide from the vascular endothelium, whereas the pressor response is due to direct contraction of vascular smooth muscle. Endothelins also exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. They act on the kidneys to cause vasoconstriction and decrease glomerular filtration rate and sodium and water excretion. In the respiratory system, they cause potent contraction of tracheal and bronchial smooth muscle. 

Endothelin receptors are widespread in the body. Two endothelin receptor subtypes, termed ET and ET , have been cloned and sequenced. receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction (Figure 17-7). ETB receptors have approximately equal affinities for ET-1 and ET-3 and are primarily located on vascular endothelial cells, where they mediate release of PGI2 and nitric oxide. Some ETB receptors are also present on smooth muscle cells and mediate vasoconstriction. Both receptor subtypes belong to the G protein-coupled seven-transmembrane domain family of receptors. 

In vitro, U-II is a potent constrictor of vascular smooth muscle its activity depends on the type of blood vessel and the species from which it was obtained. Vasoconstriction occurs primarily in arterial vessels, where U-II can be more potent than endothelin 1, making it the most potent known vasoconstrictor. However, under some conditions, U-II may cause vasodilation. In vivo, U-II has complex hemodynamic effects, the most prominent being regional vasoconstriction and cardiac depression. In some ways, these effects resemble those produced by ET-1. Nevertheless, the role of the peptide in the normal regulation of vascular tone and blood pressure in humans appears to be minor. 

Loomis ED, Sullivan JC, Osmond DA, Pollock DM, Pollock JS. 2005. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther 315 1058-1064. 

Strachan FE, Newby DE, Sciberras DG, McCrea JB, Goldberg MR, Webb DJ. 2002. Repeatability of local forearm vasoconstriction to endothelin-1 measured by venous occlusion plethysmography. Br J Clin Pharmacol 54 386-394. 

As noted in Chapter 3, endothehns rank among the most potent known vasoconstricting agents they have been imphcated in a number of diseases including cerebral vasospasm and pulmonary hypertension. The stereoselective synthesis of an endothelin antagonist begins with the... 

Endothelin not only influences the tone of GI smooth muscle [43] but also stimulates intestinal ion secretion [44]. ET-1 produces damage to the gastric mucosa although it is unclear to what extent this is a result of local vasoconstriction [45]. 

In terms of smaller molecules, there is a claim that n-pentanoyl-tryptophan (5) inhibits the vasoconstrictive effects of endothelin, but no details of biological activity are quoted [82]. 

Claims that compounds with activity in the angiotensin area also inhibit the actions of endothelin have appeared in the literature [157]. The only compounds patented for both these properties are three series of compounds from Roussel-Uclaf [158-160]. Details of activity are shown for only one compound (36) which has very weak activity, IC50 = 14,000 /tM in the rat cortical membrane binding assay. It is claimed to be active at 1 mg/kg i.v. in the rat against an ET-l-induced vasoconstriction [160] which could... 

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