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. Secretion of endothelin-1 is increased under certain pathophysiological conditions, including coronary vasospasm, cardiac ischaemia and myocardial infarction. We have examined the effect of endothelin-1 on the protein kinase A (PKA)-dependent 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 current by shortening the action potential duration. We report here that endothelin-1, acting through ETA (endothelin-1-selective) receptors, inhibited the current through a pertussis toxin-sensitive mechanism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help protect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of catecholamines are increased.
James
A F
AF
International Research Laboratories, Ciba-Geigy Japan Ltd, Takarazuka.
Xie
L H
LH
Fujitani
Y
Y
Hayashi
S
S
Horie
M
M
D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D009206:Myocardium / Q000201:enzymology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D002712:Chlorides; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D010566:Virulence Factors, Bordetella; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)