Vasoconstriction endothelins causing

There is one other toxin, about which very little is known, which affects the heart and very rapidly causes death. This is sarafotoxin from the Middle Eastern Burrowing Asp Atractapsis engaddensis) it interacts with a specific receptor (the endothelin receptor) which causes blood vessel constriction (vasoconstriction). Sarafotoxin causes massive constriction of the blood vessels with a concomitant rise in blood pressure. This blood pressure rise can be so rapid and great that death results from blood vessel (e.g. aortic) rupture. 

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. 

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. 

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. 

A variety of vasoactive substances may modulate the CM-induced vasoconstriction, including prostaglandins, ANF, adenosine, endothelin, vasopressin, noradrenahne and angiotensin [53A, 55]. Of particular interest has been the possible role of superoxide radicals in the pathogenesis of CMIN. Not only do they induce renal vasoconstriction, but, as noted above, they also cause direct renal cell injury. Superoxide dismutase prevents the fall in GFR associated with CM, while in a dehydrated animal model, renal levels of superoxide dismutase is diminished which may account for the demonstrated increased susceptibility to... 

Endothelin-1 is a potent vasoconstrictor peptide derived from endothelial cells.100 Its physiological function is mediated by two receptors the ET-A and ET-B. Table 1. Figure 11. ET-A and ET-B receptors are located in vascular smooth muscle and their activation causes vasoconstriction, whereas ET-B receptor is also located in the endothelium and its activation results in vasodilation by increasing nitric oxide or prostacyclin. Endothelin is released following myocardial ischemia and reperfusion. Endothelin reduces infarct size in a perfused rat heart model of ischemia and reperfusion through activation of protein kinase C and KATp channel.101 Furthermore, in neonatal rat ventricular myocytes, endothelin is shown to activate the calcineurin-NFAT (nuclear factor of activated cells) pathways and enhance the expression of Bcl-2.102 However, endogenous blockade of endothelin at the level of the ET-A receptor reduced infarct size in a pig model of coronary occlusion and reperfusion.103... 

The microcirculatory changes associated with shock are complex and difficult to study. Although some mediators such as endothelin-1 cause vasoconstriction, other mediators, such as adenosine and nitric oxide, yield vasodilation. These changes result in hypoperfusion or hyperperfusion depending on the area. As these microcirculatory changes fail to maintain adequate organ perfusion, more widespread sympathetic nervous system activation and vasoconstriction ensue. 

FIGURE 44 Endothelial cells synthesize and release substances that cause vasoconstriction or vasorelaxation. Endothelin is a potent, slow-acting and long-lasting vasoconstrictor peptide that exerts a wide variety of effects. 

Endothelin-1 (ET-1) is a 21-amino-acid peptide that is produced by the vascular endothelium. It is a very potent vasoconstrictor that binds to VSM endothelin receptors ETa and ETB(Fig. 29.1). The ET-1 receptors are linked to the Gq protein and IP3 signal transduction pathway (Fig. 29.11). Therefore, ET-1 causes sarcoplasmic reticulum release of calcium, increasing the VSM contractility. Vascular endothelial cells secrete the majority of ET-1. The endothelins bind to two receptor subtypes ETa, and ETb. Invasculartissue, ETa is located predominantly on smooth muscle cells, whereas ETb is found on both endothelial and smooth muscle cells. Activation of ETa by ET-1 leads to potent vasoconstriction from an increase in cytosolic calcium levels via influx of extracellular calcium and release from intracellular stores (Fig. 29.1). The actions of ETb are more complicated. Like ETa, ET-1 activation of ETb on VSM cells leads to vasoconstriction. Furthermore, some studies suggest that in the pulmonary hypertensive state, blockade of both ETa and ETb is necessary to achieve maximal vasodilation. Activation of ET-B by ... 

Sarafotoxins (SRTX), CSCKDMTDKE CL NFCHQDVTIw (SRTX-a) (disulfide bonds C -C /C -C ), a family of vasoactive peptides initially isolated from the venom of Atractaspis engaddensis. The highly toxic peptides (SRTX-a, -h, -c, -e) are structurally and functionally related to endothelins (ET). Each of the members of the ET-SRTX family contains four Cys, and about 60-70% of their 21 amino acid residues are identical. The SRTX cause strong vasoconstriction of coronary arteries. Death after intoxication with SRTX peptides is the result of cardiac ischemia or infarction. Sarafotoxins and sarafotoxin-like peptides are produced by various snake... 

Chronic hypoxia causes pulmonary arterial smooth muscle cell depolarisation, elevated endothelin-1, and vasoconstriction. Resting [Ca li in smooth muscle cells from intrapulmonary arteries of rats exposed to 10 % O2 for 21 days was 293.9 25.2 nM (vs. 153.6 28.7nM in normoxia) (Shimoda et al. 2000). Resting [Ca " ] was decreased after extracellular Ca removed but not with nifedipine (10" M), an L-type Ca " channel antagonist. After chronic hypoxia, the endothelin-1-induced increase in [Ca ]i was reduced and was aboHshed after extracellular Ca removal or nifedipine. Removal of extracellular Ca " reduced endothehn-1-induced tension however, nifedipine had only a slight effect. 

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