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

1. 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. 2. Both series of compounds caused relaxation in isolated rings of dog coronary artery (EC50 values, 1-10 microM) presumably due to release of EDRF since removal of endothelium greatly attenuated the response. 3. Amiloride (1-100 microM) had little effect on either endothelium-intact or denuded arteries. 4. The guanidino substituted analogues also appeared to block selectively the relaxation response to acetylcholine in the coronary artery, independently of their EDRF-releasing activity. 5. 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.