A possible role for the endothelium in porcine coronary smooth muscle responses to dihydropyridine calcium channel modulators.
The role of the endothelium in contraction and relaxation produced by the dihydropyridine calcium channel modulators was examined in porcine coronary smooth muscle. The optically pure dihydropyridine calcium agonists (+)-S202-791 and (-)-Bay k 8644 both produced greater contractions in tissues without endothelium compared with tissues with intact endothelium. In contrast, histamine produced the same degree of contraction in tissues with and without endothelium. In the presence of KCl-induced active muscle tone, the optically pure calcium antagonists (-)-R202-791 and (+)-Bay k 8644 and the nitrovasodilator isosorbide dinitrate all produced the same degree of relaxation in tissues with and without endothelium. These results suggest that the endothelium plays an inhibitory role in dihydropyridine-induced contraction. When coronary rings with intact endothelium were pretreated for 60 min with 10 or 100 nM (-)-R202-791, the contraction to subsequent addition of (+)-S202-791 was significantly greater than in control tissues pretreated with only solvent. However, in rings with denuded endothelium, pretreatment with (-)-R202-791 resulted in a rightward shift of the dose-response curve to (+)-S202-791, and a depression of the maximal contraction compared with controls. Thus, the interaction between the calcium agonist [(+)-S202-791] and antagonist [(-)-R202-791] is more complex than competitive inhibition. We suggest that the calcium agonists produce two effects, a release of endothelium-derived relaxant factor and a direct contraction of smooth muscle; the calcium antagonists can inhibit both processes.(ABSTRACT TRUNCATED AT 250 WORDS)
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004727:Endothelium / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D007536:Isomerism; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009539:Nicotinic Acids / Q000494:pharmacology; D010069:Oxadiazoles; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D002121:Calcium Channel Blockers; D009539:Nicotinic Acids; D010069:Oxadiazoles; C049834:PN 202-791; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D007548:Isosorbide Dinitrate