Amiloride analogues cause endothelium‐dependent relaxation in the canine coronary artery in vitro: possible role of Na+/Ca2+ exchange

Abstract

A number of amiloride analogues were used to test the proposal that Na+/Ca2+ exchange may play a role in the secretion of endothelium‐derived relaxing factor (EDRF). The analogues used were those substituted on either the 5‐amino group or the terminal guanidino nitrogen atom. The former block both Na+ /Ca2+ and Na+ /H+ exchange whilst the latter block the Na+ channel and the Na+ /Ca2+ exchange. Both series of compounds caused relaxation in isolated rings of dog coronary artery (EC50 values, 1–10 μM) presumably due to release of EDRF since removal of endothelium greatly attenuated the response. Amiloride (1–100 μM) had little effect on either endothelium‐intact or denuded arteries. The guanidino substituted analogues also appeared to block selectively the relaxation response to acetylcholine in the coronary artery, independently of their EDRF‐releasing activity. It is proposed that endothelial cells have an active Na+ /Ca2+ exchange operating in the forward mode to extrude Ca2+. This mechanism may be important in the control of EDRF release. 1988 British Pharmacological Society