title: Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1, Partners in Crime?
abstract: Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I2 (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the background of such cardiovascular risk factors, endothelin-1 may potentiate these contractions by promoting prostacyclin production. The latter is reduced by endothelin-A (ETA) receptor antagonists. This receptor subtype is recognized for mediating contractions of smooth muscle cells to endothelin-1. However, it is present also on endothelial cells, where its activation increases intracellular calcium concentration with subsequent initiation of phospholipase A2 that provides arachidonic acid for metabolism by cyclooxygenases. Thus, endothelin-1 favors cyclooxygenase-dependent vasoconstrictor prostanoid formation, including prostacyclin. Activation of endothelial endothelin-B (ETB) receptors promotes the release of nitric oxide, which opposes both EDCF and endothelin-1. This is less pronounced in disease promoting ETA- and smooth muscle ETB receptor-dependent as well as prostanoid-mediated contractions. In addition, the thromboxane prostanoid (TP) receptors on vascular smooth muscle cells become hyperresponsive to EDCF under pathophysiological conditions, while IP receptor responsiveness diminishes. A better understanding of the interaction between prostacyclin and endothelin-1 and the determination of the roles of the TP and IP receptors involved in prostanoid-mediated contractions in health and during disease will help to define advanced pharmacological strategies for the therapy of cardiovascular disorders.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong S.A.R., China.
authors.forename: O
authors.initials: O
authors.lastname: Baretella
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong S.A.R., China. Electronic address: vanhoutt@hku.hk.
authors.forename: P M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D017466:Receptors, Endothelin / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism; D012307:Risk Factors; D014662:Vasoconstrictor Agents / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D017466:Receptors, Endothelin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D011464:Epoprostenol
keywords: COX; ET(A) receptor; ET(B) receptor; ET-1; IP receptor; PGI(2); PLA(2); Smooth muscle; TP receptor