Basic and therapeutic relevance of endothelin-mediated regulation.
Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.
Goto
K
K
Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan. kgoto@md.tsukuba.ac.jp
D000818:Animals; D004195:Disease Models, Animal; D016232:Endothelins / Q000502:physiology* / Q000627:therapeutic use*; D006331:Heart Diseases / Q000188:drug therapy; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy; D013812:Therapeutics / Q000379:methods
D016232:Endothelins