Endothelin inhibitor

Angiotensin I converting enzyme Acquired immunodeficiency syndrome Aspartic protease inhibitor Bowman Birk protease inhibitor protein Chymotrypsin Cysteine protease inhibitor Endothelin-converting enzyme Elastase... 

Key Words Quenched fluorescence substrate peptidase inhibitor endothelin-... 

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

A great number of ECE-inhibitors and mixed and selective ETA and ETB receptor antagonists have been developed in the past. For specific inhibitors of ECE, however, only very limited effects on the endothelin system were found. The limited potency of ECE inhibition might be due to the generation of mature... 

Endothelins. Table 3 Summary of clinical trials with endothelin receptor antagonists or ECE-inhibitors... 

Warner TD (ed.) (2001) Handbuch der Experimentellen Pharmakologie. Band 152 Endothelin and its inhibitors. Springer Verlag, Berlin, Heidelberg, New York... 

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... 

Thiazolylzinc bromide, formed in situ by quenching lithiothiazole with ZnBr2, was coupled with 2-iodopyridine 10 to give thiazolylpyridine 11. Hydrolysis of 11 then led to thiazolylpyridine acid 12, an inhibitor of endothelin conversion enzyme-1 (ECE-1) [15]. 

Bosentan and tezosentan, orally active competitive inhibitors of endothelin (see Chapter 17), have been shown to have some benefits in experimental animal models with heart failure, but results in human trials have been disappointing. Bosentan is approved for use in pulmonary hypertension (see Chapter 11). It has significant teratogenic and hepatotoxic effects. 

The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but several more selective inhibitors are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists (see below), their use has been eclipsed by endothelin antagonists. 

Systemic administration of endothelin receptor antagonists or endothelin-converting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. These observations provide evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions. The activity of the system is higher in males than in females. It increases with age, an effect that can be counteracted by regular aerobic exercise. 

Chu L, Zhang JX, Norota I, Endoh M. 2005. Differential action of a protein tyrosine kinase, inhibitor genistein, on the positive inotropic effect of endothelin-1 and norepinephrine in canine ventricular myocardium. Br J Pharmacol 144 430-442. 

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. 

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