Sites of action of dihydropyridine drugs in the mouse hemidiaphragm muscle.
The effects of nifedipine and BAY K8644 on directly evoked isometric twitch and potassium (K+)- and caffeine-induced contractures were investigated in mouse hemidiaphragm preparations in which neuromuscular transmission had been irreversibly blocked. Both drugs caused initial potentiation of twitch which at high concentrations (greater than 3 x 10(-5) M) was followed by blockade. A simultaneous slow contracture was seen with nifedipine but not BAY K8644. Control K+ contractures were triphasic. The initial fast and slow phases of this contracture were potentiated by BAY K8644 at all times and concentrations. Both phases were potentiated by nifedipine at low concentrations but, during prolonged exposure to high concentrations, potentiation was replaced by an inhibition. The time course of activation and inactivation of the slow phase was also accelerated by all concentrations of nifedipine. The initial phase of caffeine-induced contracture was potentiated and resolved into two components. From these results at least three sites of action were postulated. Conventional binding to t-tubular Ca2+ channels was linked to effects on the slow phase of K+ contracture. An effect on Ca2+ release from the sarcoplasmic reticulum and an inhibition of Ca2+ transfer from uptake to release compartments in the sarcoplasmic reticulum are also postulated.
Singh
Y N
YN
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Dryden
W F
WF
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003964:Diaphragm; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects*; D009132:Muscles / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007473:Ion Channels; D002110:Caffeine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D011188:Potassium