Vasoactive peptides endothelins

Biological function and chemistry of endothelin, vasoactive peptide with macro-cyclic fragments formed by disulfide bridges between cysteine residues 99CCC1211. 

Endothelins are a family of vasoactive peptides secreted by endothelial cells. The three major endothelin peptides are all composed of 21 amino acids. Endothelins are the most potent vasoconstrictors known. Contraction of vascular smooth muscle in response to endothelin is associated with an increase in intracellular calcium. Increases in endothelin levels have been reported in patients with vasospastic, hypoxic, and ischemic diseases. The two identified isoforms of endothelin receptors have differing affinity for the three endothelin peptides. Selective and nonselective endothelin receptor antagonists are in development for potential use in the treatment of hypertension and other disorders associated with increased vascular resistance. 

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 hormones from vascular endothelium may also be involved in the regulation of vascular resistance. For example, nitric oxide (see Chapter 19 Nitric Oxide, Donors, Inhibitors) dilates and endothelin-1 (see Chapter 17 Vasoactive Peptides) constricts blood vessels. 

Bosentan, an orally active competitive inhibitor of endothelin (see Chapter 17 Vasoactive Peptides), has been shown to have some benefits in experimental animal models of heart failure, but results in human trials have not been impressive. This drug is approved for use in pulmonary hypertension (see Chapter 11 Antihypertensive Agents). It has significant teratogenic and hepatotoxic effects. 

B. Endothelins Endothelins (ETs), a group of vasoactive peptides, acts as growth factor, exerting different functions like induction of proliferation, protein synthesis or changes... 

Mesangial cells are contractile and a number of vasoactive peptides are shown to induce MC contraction in vitro such as angiotensin II, vasopressin, norepinephrine, endothelin-1, thromboxane, adenosine, and serotonin [55], The absence of podocyte markers such as nephrin, podocin, Wilms tumor-1 (WT1), and endothelial markers such as von Willebrand factor and PECAM-1, is recommended. 

A. Classification and Prototypes Vasoactive peptides comprise a large class of endogenous substances that function as neurotransmitters as well as local and systemic hormones. The better-known peptides include angiotensin, bradykinin, atrial natriuretic peptide, endothelin, vasoactive intestinal peptide, substance P, calcitonin gene-related peptide, vasopressin, glucagon, and several opioid peptides. Vasopressin is discussed in Chapters 15 and 37, the opioid peptides in Chapter 31, and glucagon in Chapter 41. The peptides discussed in this chapter and their effects are summarized in Table 17-1. 

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... 

Endothelins comprise a family of three vasoactive isopeptides of 21 amino acids that have an essential role in the regulation of the vascular and bronchiolar tone and the control of natriuresis in the kidney. Endothelin peptides are also involved in nociception and have a critical role in the progression of prostate and ovarian cancer. 

Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). This chapter focuses on the smooth muscle actions of the peptides. 

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