INHIBITION OF THE CARDIAC PROTEIN-KINASE A-DEPENDENT CHLORIDE CONDUCTANCE BY ENDOTHELIN-1

ENDOTHELIN-1 is a peptide hormone constitutively secreted by vascular and endocardial endothelial cells(1-3). Secretion of endothelin-1 is i ncreased under certain pathophysiological conditions, including corona ry vasospasm, cardiac ischaemia and myocardial infarction. We have exa mined the effect of endothelin-1 on the protein kinase A (PKA)-depende nt chloride current in voltage-clamped guinea pig ventricular myocytes . This conductance, induced by catecholamines through beta-adrenergic receptors, counteracts the simultaneously increased L-type calcium cur rent by shortening the action potential duration(4-6). We report here that endothelin-1, acting through ET(A) (endothelin-1-selective) recep tors, inhibited the current through a pertussis toxin-sensitive mechan ism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help prot ect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of cate cholamines are increased.