Effects of a novel calcium channel agonist dihydropyridine analogue, Bay k 8644, on pig coronary artery: biphasic mechanical response and paradoxical potentiation of contraction by diltiazem and nimodipine.
Bay k 8644 is a structural analogue of the 1,4-dihydropyridines whose pharmacological actions on heart and vascular smooth muscle are opposite from those of nifedipine and other similar calcium antagonists. We have examined the action of Bay k 8644 ("calcium channel agonist") on isolated porcine coronary artery rings. The interactions between Bay k 8644 and the vasodilators isosorbide dinitrate (ISDN), diltiazem, and nimodipine were quantitated. Bay k 8644 produced a biphasic, dose-dependent mechanical response, with contraction occurring over the concentration range of 1-350 nM (ED50 = 11.4 nM) and relaxation observed at concentrations greater than 350 nM (IC50 = 5.7 microM). ISDN, diltiazem, and nimodipine relaxed, in a dose-dependent manner, maximal Bay k 8644-induced contractions. When the coronary rings were pretreated for 25-90 min with 80% inhibitory concentrations of these vasodilators, there was little or no effect by ISDN on Bay k 8644-induced contractions; however, there was a surprising potentiation by diltiazem and by nimodipine. Pretreatment of coronary rings with higher concentrations of ISDN or diltiazem caused an inhibition of Bay k 8644-induced contraction, while pretreatment with higher concentrations of nimodipine caused further potentiation of contraction elicited by Bay k 8644. Bay k 8644 increased the tension developed in response to high potassium (potential-operated channel activation) or histamine (receptor-operated channel activation). To account for the biphasic response to Bay k 8644 (dose-dependent contraction and relaxation), and the unexpected potentiation of Bay k 8644-induced contraction by nimodipine and by diltiazem, a molecular model is proposed for vascular smooth muscle in which Bay k 8644 functions as a partial calcium channel agonist at two functionally distinct 1,4-dihydropyridine "receptor sites."
Dubé
G P
GP
Baik
Y H
YH
Schwartz
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009539:Nicotinic Acids / Q000494:pharmacology*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009553:Nimodipine; D011189:Potassium Chloride / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*
D001552:Benzazepines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009539:Nicotinic Acids; D011978:Receptors, Nicotinic; D009553:Nimodipine; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D004110:Diltiazem; D009543:Nifedipine; D007548:Isosorbide Dinitrate