Functional interactions between two Ca2+ channel activators, (S)-Bay K 8644 and FPL 64176, in smooth muscle.
We examined the interactions of two Ca2+ channel activators, (S)-Bay K 8644 and FPL 64176, on smooth muscle L-type Ca2+ channels. FPL 64176 (300 nM) caused a sustained contraction of rat tail artery strips. This contractile response was inhibited by approximately 70% by (S)-Bay K 8644 (EC50 = 14 nM). (S)-Bay K 8644 (100 nM) increased whole-cell Ca2+ currents in A7r5 smooth muscle cells but effectively blocked further stimulation by 1 microM FPL 64176. When added alone, 1 microM FPL 64176 increased Ca2+ channel current amplitude, slowed current activation, and prolonged tail current duration. Furthermore, no inactivation of current during step depolarizations was observed in the presence of FPL 64176. After subsequent addition of (S)-Bay K 8644, Ca2+ channel current activation was accelerated and tail current duration was shortened. Additionally, pronounced inactivation of the Ca2+ channel current became apparent. These results are consistent with a negative allosteric interaction between the (S)-Bay K 8644 binding site and that of FPL 64176, in smooth muscle.
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Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats
D015220:Calcium Channels; D011758:Pyrroles; C071658:FPL 64176; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester