Endothelin mechanism

Gulati A, Srimal RC (1992) Endothelin mechanisms in the central nervous system a target for drug development. Drug Dev Res 26 361-387... 

There are several underlying mechanisms responsible for posttransplant HTN. Some causes of HTN in transplant recipients may include renal dysfunction, increased sensitivity to endothelin-1 and angiotensin, increased density of glucocorticoid receptors in the vascular smooth muscle, and decreased production of vasodilatory prostaglandins.57 However, one of the most easily recognized causes of posttransplant HTN is the use of corticosteroids and calcineurin inhibitors.58,59 Corticosteroids usually cause sodium and water retention,57 thus increasing blood pressure, whereas calcineurin inhibitors are associated with a number of effects that may result in HTN, including... 

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. 

Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P. J., The endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic... 

Mechanism of Action An antihypertensive that blocks endothelin-l, the neurohormone that constricts pulmonary arteries. Therapeutic Effect Improves exercise ability and slows clinical worsening of pulmonary arterial hypertension (PAH). Pharmacokinetics Highlybound to plasma proteins, mainlyalbumin. Metabolized in the liver. Eliminated by biliary excretion. Half-life Approximately 5 hr. 

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11-1) arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 (see Chapter 17) constricts and nitric oxide (see Chapter 19) dilates blood vessels. 

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... 

Lekli I, Szabo G, Juhasz B, Das S, Das M, Varga E, Szendrei L, Gesztelyi R, Varadi J, Bak I, Das DK, Tosaki A. 2008. Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats The role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol 294 H859-H866. 

A number of cardiovascular disease states that eventually result in chronic congestive heart failure are associated with alterations in cardiac performance. Several hormonal factors such as angiotensin II, endothelin, and alterations in signal transduction mechanisms including adenylyl cyclase and phospholipase C (PLC) have been reported to play an important role in the alterations of cardiac performance. 

Touyz, R.M., G. Yao, E. Viel, F. Amiri, and E.L. Schiffrin. 2004. Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells. J. Hypertens. 22 1141-1149. 

Shubieta, H.E., McDonough, PM., Harris, A.N., Knowlton, K.U., Glembotski, C.C., Brown, J.H., and Chien, K.R. 1990. Endothelin induction of inositol phosphate hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J.Biol. Chem. 265 20555-20562. 

Zeidan, A., Purdham, D. M., Rajapurohitam, V., Javadov, S., Chakrabarti, S., and Karmazyn, M. 2005. Leptin induces vascular smooth muscle cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy. J. Pharmacol. Exp. Ther. 315 1075-1084. 

Two different mechanisms have been proposed to explain the cellular events involved in the Ox-LDL-induced endothelin secretion in endothelial cells. Boulanger et al. [126-127] demonstrated that the peptide secretion is mediated by the stimulation of the scavenger receptors by Ox-LDL and that protein kinase C interferes in this process, while Martin-Nizard et al. [128] have reported that lysophosphatidylcholine (LPC) in Ox-LDL exerts a major role in the induction of the secretion of immunoreactive endothelin in endothelial cells. However, M. Jougasaki et al. [133] recently published opposing results. They showed that Ox-LDL suppresses the endothelin secretion by LPC in cultured vascular endothelial cells. 

Visual hallucinations are very rare adverse effects of contrast media, with isolated reports after vertebral angiography or myelography. The mechanism of this adverse reaction could be similar to that reported in transient cortical blindness after infusion of contrast agents. However, other possibilities include a toxic effect of contrast media on the optic nerve, transient impairment of cerebral blood flow, which could be mediated through the release of the potent vasoconstrictor endothelin, or the formation of microclots. Two cases of visual hallucinations after coronary angiography have been reported (416). 

D Amico M, Beriino L, Marione S, Filippelh A, De Novellis V, Rossi F (1996) Endothelin-1 in peiiaqueducal gray of mice induces analgesia via glutamatergic receptors. Pain 65 205-209 Da Cunha JM, Rae GA, Ferreira SH, Cunha Fde Q (2004) Endothelins induce ETB receptor-mediated mechanical hypernodception in rat hindpaw roles of cAMP and protein kinase C. Eur J Pharmacol 501 87-94... 

Zamai et al. from the same company have also published data on sequence-directed peptide inhibitors [80]. They used the model of big ET-1 which they proposed on the basis of computerized structure prediction, molecular mechanics minimization and molecular dynamics [81]. The effect of the sequence-directed inhibitors on the in vitro chymotrypsin-catalyzed hydrolysis of big ET-1 was investigated as a strategy for inhibiting formation of endothelin. 

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