Responses to endothelins-1, -2, and -3 and sarafotoxin 6c after ischemia/reperfusion in isolated perfused rat heart: role of vasodilator loss.
Coronary constrictor actions of endothelin-1 (ET-1) are enhanced after myocardial ischemia/reperfusion (I/R), possibly owing to enhanced ETA-receptor-mediated constriction and/or loss of the opposing ETB-receptor-mediated vasodilatation. We examined the actions of ET-1, ET-2, and ET-3 and the selective ETB-receptor agonist sarafotoxin 6c (Sx6c) after I/R in perfused rat heart. To examine the effects of a loss of ETB-receptor-mediated vasodilatation on coronary constrictor responses to ET-1, we used repeated doses of Sx6c to desensitize ETB receptors. After I/R, the coronary constrictor effects of all three ETs were enhanced, whereas their initial vasodilator effects were inhibited. The pure coronary dilator effect of Sx6c observed in control hearts was also inhibited after I/R. After desensitization of ETB receptors, the coronary constrictor action of ET-1 was enhanced by an amount equivalent to the vasodilatation that had been lost. This enhancement of constriction was not as marked as that noted after I/R, suggesting that the enhanced coronary constrictor action of ET-1 after I/R is not simply due to loss of opposing ETB-receptor-mediated vasodilatation and that other mechanisms are involved. The most likely explanation is upregulation of functional ETA receptors after I/R because ETB-receptor stimulation did not cause coronary constriction in this preparation. The vasoconstrictor enhancement therefore is likely to be the combined effect of receptor upregulation and vasodilator loss.
Thompson
M
M
School of Pharmacy and Pharmacology, University of Bath, Avon, England.
Westwick
J
J
Woodward
B
B
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology / Q000627:therapeutic use; D016232:Endothelins / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects*; D014757:Viper Venoms / Q000494:pharmacology* / Q000627:therapeutic use
D016232:Endothelins; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D010656:Phenylephrine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D001920:Bradykinin