Voltage- and use-dependent block of the inward calcium current by MCI-176, a new non-dihydropyridine calcium antagonist, in canine ventricular muscles and single ventricular cells of the guinea-pig.
Effects of MCI-176, 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopro pox y-4(3H)- quinazolinone hydrochloride, on action potentials of canine ventricular muscles and on membrane currents of single ventricular cells of the guinea-pig heart were studied with the microelectrode and the patch-clamp ("whole-cell recording") methods. In canine ventricular trabeculae, MCI-176 (10(-5)-10(-4) M) decreased the plateau potential, the action potential duration at 30%-repolarization and the maximum rate of rise of the action potential; and it also decreased the amplitude and the duration of the slow response action potential in a concentration-dependent manner. Those effects were much more apparent at higher stimulus frequency. Under voltage clamp condition of single ventricular cells of the guinea-pig heart, MCI-176 (3 x 10(-5) M) decreased the inward calcium current (ICa) by 25-30% when the membrane potential was held at the resting membrane potential, and the drug abolished it when the membrane potential was held at -30 mV. MCI-176 added at rest decreased ICa ("initial block") and reduced it further with repetitive depolarizations in a beat-to-beat fashion. MCI-176 facilitated the reduction of ICa by increasing the clamp pulse frequency. These results indicate that MCI-176 decreases ICa of mammalian ventricular muscles in a voltage- and use-dependent manner.
Iijima
T
T
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Takahashi
K
K
Taira
N
N
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones
D002121:Calcium Channel Blockers; D007473:Ion Channels; D011799:Quinazolines; D052999:Quinazolinones; C050606:MCI 176