Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1, Partners in Crime?

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.