Negative inotropic effects of disopyramide on guinea-pig papillary muscles.
1. The inhibitory effects of disopyramide on electromechanical responses were investigated in guinea-pig papillary muscles driven by electrical stimuli. Disopyramide up to 10(-5) M did not cause a negative inotropic effect, while the maximum upstroke velocity of the action potential (dV/dtmax) was significantly decreased. 2. At higher concentrations, this drug dose-dependently inhibited the contraction, and dV/dtmax was further decreased. This inhibition of contraction was accompanied by a depression of the slow action potential in partially depolarized preparations by increasing [K+]0 (26 mM). 3. In preparations pretreated with nifedipine (10(-6) M) and ryanodine (10(-6) M), the contraction was almost completely inhibited. In such preparations, ouabain (2 x 10(-6) M) markedly increased the contraction, probably through the Na(+)-Ca2+ exchange mechanism. This contraction was inhibited by disopyramide above 10(-8) M, and an almost complete inhibition was caused at 3 x 10(-5) M. 4. A similar inhibitory effect was observed on the contraction increased by the lowering of [Na+]0 (36 mM). 5. These results suggest that disopyramide at high concentrations inhibits Ca influx through slow Ca2+ channels and at low concentrations, it reduces the contraction increased through the Na(+)-Ca2+ exchange mechanism. Disopyramide had a greater effect on cardiac contractility mediated by the Na(+)-Ca2+ exchange mechanism.
Kondo
N
N
Department of Pharmacology, University of Hawaii, School of Medicine, Honolulu 96822.
Mizukami
M
M
Shibata
S
S
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003864:Depression, Chemical; D004206:Disopyramide / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects
D015222:Sodium Channels; D012433:Ryanodine; D010042:Ouabain; D004206:Disopyramide; D009543:Nifedipine; D011188:Potassium