Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle.
In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.
Zhu
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Department of Pharmacology, Yamagata University School of Medicine, Japan.
Yang
H T
HT
Endoh
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D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D006325:Heart Atria; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008322:Mammals; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D010566:Virulence Factors, Bordetella; C087120:RES 701-1; C088196:TAK 044; D000242:Cyclic AMP; D037342:Pertussis Toxin; D007545:Isoproterenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D011224:Prazosin