Functional state of the endothelium determines the response to endothelin in the coronary circulation

Abstract

Study objective – The aim was to study the effects of endothelin on the heart with special attention to an interaction with endothelium derived relaxing factor (EDRF). Design – Bolus injections of various amounts of endothelin (1-300 ng) were given into the coronary circulation of isolated perfused rabbit hearts while coronary flow was held constant at 35 ml·min⁻¹ and coronary perfusion pressure and other physiological variables were measured. The effects of indomethacin and haemoglobin on the responses were examined. Experimental material – 15 New Zealand white rabbits, 1.0-1.5 kg, were used for the studies. The animals were anaesthetised and the hearts rapidly excised and perfused in the Langendorff manner. Measurements and results – With coronary flow held constant, bolus injections of endothelin up to 300 ng caused no consistent increase in perfusion pressure, but resulted in a slight increase in left ventricular developed pressure. Indomethacin (10 μM) did not alter the response to endothelin; however, when endothelium dependent dilatation was inhibited by haemoglobm (10 μM), a dose dependent endothelin induced constriction was unmasked, with EC50 of 41 (SEM 15) ng, maximum +46(8) mm Hg. This constrictor response was further augmented by air infusion (0.5 ml), EC50 26(10) ng, maximum +102(12) mm Hg, and endothelin now caused a substantial dose dependent reduction in left ventricular contractile function. Endothelium dependent dilatation was not significantly reduced after air embolisation. Conclusions – The remarkable ability of the endothelium to protect against vasoconstrictor action of circulating endothelin in the coronary bed may not be due only to EDRF release, but perhaps also to an additional mechanism related to endothelial barrier of metabolic function.