Tissue selectivity and calcium dependence of contractile responses to endothelin.
The tissue selectivity and calcium dependence of endothelin, a potent vasoconstrictor peptide obtained from endothelial cells, were investigated in a number of rat and guinea pig tissues. Endothelin produced a significant dose-dependent contraction of rat tissues with the following rank order of efficacy: aorta greater than portal vein greater than trachea much greater than vas deferens = lung parenchyma much greater than bladder. In the rat atrium and ventricle, endothelin possessed positive inotropic effects at low doses and arrhythmogenic effects at high doses. Endothelin also produced a significant contraction of guinea pig lung parenchyma and induced relaxations of guinea pig taenia coli precontracted with potassium chloride. The aortic ring contractile response to endothelin was characterized by both rapid and slow phases of contraction. The rapid phase of contraction was abolished by removal of extracellular calcium or preincubation of tissues with the dihydropyridine calcium channel antagonist, nifedipine. Removal of the endothelium from aortic rings resulted in an increase of approximately 10-fold in the contractile potency of endothelin. In comparison, the potency of the dihydropyridine calcium channel activator, (-)-S-BAY K 8644, was increased approximately 15-fold by the same treatment. These findings suggest that endothelin, while displaying some selectivity as a vascular smooth muscle spasmogen, is a general smooth and cardiac muscle spasmogen which utilizes both intra- and extracellular sources of calcium to support its contractions.
Department of Pharmacology, BioMega Inc., Laval, Quebec, Canada.
G T
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Bolger
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Liard
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Jaramillo
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D016232:Endothelins; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009928:Organ Specificity; D010455:Peptides / Q000494:pharmacology*; D051381:Rats
D016232:Endothelins; D010455:Peptides; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium