Endothelin-1: a new target of therapeutic intervention for the treatment of heart failure.
Endothelin-1 has been appreciated in animals and humans as a potential target for inhibition in patients with acutely decompensated congestive heart failure (CHF), as well as patients with a chronic low-output state. There has been intense interest in determining the effects of endothelin-1 on the cardiovascular system. Elevated plasma levels of endothelin-1 in patients with CHF portend a poorer prognosis than similar patients without elevated levels. Endothelin-1 levels correlate inversely with maximum oxygen consumption, and inhibition of the myocardial endothelin pathway in rats with CHF improves survival. An association between endothelin-1 and the development of CHF has recently been supported. Selectively inhibiting the endothelin A receptors in dogs with CHF produced hemodynamic improvement. Similarly, in rabbits, a structural advantage was demonstrated. Benefits in cardiac remodeling have been demonstrated in several models of CHF by nonselectively antagonizing endothelin receptors. In human trials using nonselective endothelin-1 inhibitors, researchers have demonstrated hemodynamic benefit and improvement in cardiac function in patients with decompensated CHF. Inhibition of endothelin-1 in patients with CHF appears to have potential therapeutic value, and ongoing clinical trials will further investigate the safety, efficacy, and role of this new potential therapeutic target for the treatment of CHF.
Duchman
S M
SM
Department of Medicine, The Methodist Hospital and Baylor College of Medicine, Houston, Texas 77030, USA. sduchman@pdg.net
Thohan
V
V
Kalra
D
D
Torre-Amione
G
G
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D010101:Oxygen Consumption; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D016019:Survival Analysis; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan