Physiologic role of endothelin in maintenance of vascular tone in humans.

The physiologic significance of endothelin-1 (ET-1) generation in human resistance vessels is unknown. We therefore investigated whether endothelin-converting enzyme (ECE) activity could be demonstrated in human vessels, and the effects of inhibition of the generation or actions of ET-1 on vascular tone in healthy men. Brachial artery infusion of local doses of big ET-1 caused a slow-onset, dose-dependent forearm vasoconstriction that was abolished by co-infusion of the ECE inhibitor phosphoramidon. Phosphoramidon did not affect responses to ET-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% (p = 0.03). Vasoconstriction to ET-1 was completely abolished by co-infusion of the ETA receptor antagonist BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone resulted in progressive vasodilatation, with blood flow increasing by 64% (p = 0.007). These results suggest that endogenous generation of ET-1 contributes to the maintenance of vascular tone in states of normal and elevated blood pressure. ECE inhibitors and ETA receptor antagonists may have potential as vasodilators in the treatment of diseases associated with vasoconstriction, such as hypertension and chronic heart failure.