Electropharmacological Effects of a New Dihydropyridine Analog on Isolated Guinea Pig Papillary Muscles and Purkinje Fibers

Publisher Website
Google Scholar
Abstract
The effects of a new dihydropyridine, FR-34235, were compared with those of the dihydropyridine, nifedipine, and verapamil on the normal fast action potentials (APs), slow APs, and contractions of guinea pig papillary muscles and Purkinje fibers. FR-34235 (10-6 M) blocked the contractions of papillary muscles superfused with normal Tyrode solution within 10-12 min. Maximal upstroke velocity (+.ovrhdot.Vmax) and overshoot of the fast APs were not affected, whereas the AP durations at 50 and 90% repolarization (APD50 and APD90) were shortened. The effects of FR-34235 on the fast APS and contractions were reversed within 10 min on washout. To determine the effects of the calcium antagonists on slow APs, the fast Na+ channels were inactivated by partial depolarization (to approximately -45 mV) by elevated [K]0, and isoproterenol (10-6 M) or histamine (10-5 M) was used to induce slow APs on stimulation. Nifedipine (10-7 M) and verapamil (2 .times. 10-6 M) completely blocked the slow APs. FR-34235 depressed (3 .times. 10-8 M) and blocked (10-7 M) the slow APs in a frequency-dependent manner. The effects were reversed by elevated [Ca]0 or washout of the drug. The contractions accompanying the slow APs were depressed and blocked in parallel with the depression of -.ovrhdot.Vmax. In guinea pig Purkinje fibers, FR-34235 had no significant effect on the fast AP parameters but produced a marked depression of automaticity. FR-34235 also blocked the slow APs of the Purkinje fibers in a frequency-dependent manner; all drug effects were reversed within 10 min on washout. The results indicate that FR-34235 blocks the Ca2+ slow channels of guinea pig papillary muscles and Purkinje fibers. In addition to its negative inotropic effect the drug has a potent negative chronotropic effect. This dihydropyridine drug has a significant frequency-dependent component to its action.