Bepridil prolongs the action potential duration of guinea pig ventricular muscle only at rapid rates of stimulation

Abstract

1. We examined the electromechanical effects of the calcium antagonist, bepridil (1-20 microM), on isolated guinea pig ventricular muscles, driven at various stimulus frequencies (0.1, 0.5, 1, 2 and 5 Hz) in Tyrode's solution containing various K+ concentrations (1.4-43.2 mM). 2. Conventional microelectrode and tension-recording techniques were used. 3. We found that bepridil decreased the maximum upstroke velocity (Vmax) of the action potential with no change in the resting membrane potential (RMP). 4. The former effect depended on both stimulus frequency and the drug concentration used. 5. Bepridil lengthened the duration of the action potential at the level of 25% repolarization (APD25) at the highest frequency (5 Hz), but shortened it at lower frequencies (< or = 2 Hz). 6. The drug also lengthened the APD90 at the highest frequency (5 Hz) but without significant effect at lower frequencies (< or = 2 Hz). 7. Bepridil depolarized the RMP at relatively low extracellular K+ concentrations (< or = 2.7 mM), accompanied by a prolongation of APD90. 8. There were no such effects at much higher K+ concentrations (> or = 5.4 mM), and the drug markedly depressed the Vmax and the action potential amplitude. 9. The drug eliminated the positive staircase phenomenon of twitch contraction, in a concentration-dependent manner. 10. All these findings taken together suggest that bepridil prolongs the action potential duration by inhibiting outward potassium currents (IK and IK1), at rapid rates of stimulation (approximately 300/min), which is comparable to the physiological heart rate of a guinea pig. 11. The prolongation of APD seemed to be secondary to the bepridil-induced reduction of intracellular Ca2+ concentration, [Ca2+]i.