Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure

Abstract

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure.

Nicorandil Inhibits Angiotensin-II-Induced Proliferation of Cultured Rat Cardiac Fibroblasts

“…The increased levels of different humoral factors, such as Ang II and ET-1, may cause the development of cardiac hypertrophy and cardiac fibrosis, leading to an enhancement of cardiac remodeling during the development of heart failure [19,20] . Cardiac fibrosis is a characterization of heart disease and is the result of a variety of structural changes that occur after pathological stimuli to the cardiovascular system [20] .…”

Endothelin-1 levels in chronic congestive heart failure

“…Of the various ET-1 receptor antagonists which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an endothelin-A receptor antagonist, BQ-123 appears to be most promising for the treatment of congestive heart failure [20].…”

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

“…The recognition of its importance in cardiovascular disease is perhaps best illustrated by the observation of Barton and Yanagisawa that within 4 years of ET-1's discovery, its receptors had been cloned and pharmacological antagonists had been developed; these therapeutics were being tested in clinical trials by the early 1990's (8). However, despite intensive study over the past two decades and the relative success of ET-1 antagonists in certain conditions [e.g., pulmonary hypertension (71), congestive heart failure (83)], the precise role of ET-1 in vascular physiology and pathophysiology has stubbornly eluded investigators. This may be due, in part, to several intricacies of the ET-1 system that makes it inherently complex [e.g., receptor localization, receptor dimerization (100)].…”