Potentiation of norepinephrine-induced contractions by endothelin-1 in the rabbit aorta.
Subthreshold concentrations of endothelin-1 potentiated the norepinephrine-induced contraction in isometrically mounted rings of the rabbit aorta. Pretreatment with endothelin-1 (0.1 nM) for 10 minutes increased the sensitivity of the aortic rings to norepinephrine without affecting the maximal contraction. This amplification was unaffected by removal of the endothelium but was prevented by the protein kinase C inhibitors staurosporine (0.01 microM) and calphostin C (0.1 microM). Pretreatment of the aortic rings for 24 hours with phorbol 12-myristate 13-acetate (0.1 microM) also abolished the potentiation. Norepinephrine-induced contraction was potentiated by pretreating with phorbol 12-myristate 13-acetate (10 nM) and by increasing the concentration of K+ in the bath solution from 4.6 to 8.6 mM. The potentiation of the norepinephrine-induced contraction by endothelin-1 (0.1 nM) or by phorbol 12-myristate 13-acetate (10 nM) was not associated with an increase in norepinephrine-induced 45Ca2+ uptake or influx, whereas the potentiation due to an increase in the concentration of K+ in the bath solution from 4.6 to 8.6 mM was associated with an increase in norepinephrine-induced 45Ca2+ uptake. We conclude that endothelin-1 potentiation of the norepinephrine-induced contraction occurs in the absence of changes in stimulated Ca2+ entry and is endothelium independent. It is probable that endothelin-1 increases the sensitivity of the contractile apparatus to Ca2+ by activating protein kinase C-dependent mechanisms.
Henrion
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D
Department of Pharmacology, University of Vermont, College of Medicine, Burlington 05405-0068.
Laher
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I
D000470:Alkaloids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes; D009638:Norepinephrine / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011817:Rabbits; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D000470:Alkaloids; D016232:Endothelins; D009281:Naphthalenes; D011083:Polycyclic Compounds; C061465:calphostin complex; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine