Interactions between a "calcium channel agonist", Bay K 8644, and calcium antagonists differentiate calcium antagonist subgroups in K+-depolarized smooth muscle.
The proposal that calcium antagonists have different sites of action has been tested by attempting to reverse their inhibitory effects with a dihydropyridine which augments Ca2+ entry into cells, Bay K 8644. Bay K 8644 (1-1000 nmol/l) increased the sensitivity to Ca2+ of K+-depolarized taenia preparations from the guinea-pig caecum. Thus Bay K 8644 augmented established submaximal Ca2+-induced contractions and also shifted cumulative concentration-response curves to Ca2+ to the left, even in the presence of an optimal K+-depolarization. The inhibitory effects of nifedipine (10 nmol/l), verapamil (0.2 mumol/l), diltiazem (1 mumol/l) and diclofurime (1 mumol/l) on Ca2+-induced contractions were reversed by Bay K 8644 (1-1000 nmol/l). In contrast, Bay K 8644 did not reverse the effects of cinnarizine (1 mumol/l), flunarizine (1 mumol/l), fendiline (3 mumol/l), prenylamine (3 mumol/l), pimozide (1 mumol/l), bepridil (3 mumol/l), perhexiline (10 mumol/l) or the calmodulin antagonist W-7 (200 mumol/l). Bay K 8644 (1-100 nmol/l) was less effective at reversing the effects of nisoldipine (10 nmol/l), a slowly dissociating dihydropyridine, than the effects of nifedipine. However, preincubation with Bay K 8644 (1 mumol/l) protected the taenia from the inhibitory effects of nisoldipine (10 nmol/l). These findings are compatible with interactions of nisoldipine and Bay K 8644 at a common site. Taenia preparations incubated with Bay K 8644 (1 mumol/l) were protected from the inhibitory effects of nifedipine (10 nmol/l), nisoldipine (10 nmol/l) and to a lesser extent verapamil (0.2 mumol/l) and diltiazem (1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007473:Ion Channels; D009467:Neuromuscular Depolarizing Agents; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D009543:Nifedipine; D011188:Potassium; D002118:Calcium