COMPARISON OF A CALCIUM-ANTAGONIST, CD-349, WITH NIFEDIPINE, DILTIAZEM, AND VERAPAMIL IN RABBIT SPONTANEOUSLY BEATING SINOATRIAL NODE CELLS

Effects of CD-349, a novel 1,4-dihydropyridine, and other calcium antagonists on membrane potentials in spontaneously beating and the membrane currents in voltage-clamped rabbit sinoatrial (SA) node cells were examined. CD-349 10(-8) M significantly decreased the maximum rate of depolarization and prolonged action potential duration (APD) and the cycle length (CL) without affecting action potential (AP) amplitude (APA) and maximum diastolic potential (MDP). CD-349 affected only the last part of pacemaker potential (phase 4 depolarization) and then lengthened the cycle. These effects of CD-349 became accentuated as the drug concentration increased. Sinus arrest occurred in two of five preparations at 10(-7) M, and occurred in all preparations at a concentration of 10(-6) M. The concentration inducing arrest of CD-349 was about one-tenth lower as compared with that of nifedipine. In voltage-clamped SA node cells, CD-349 in concentrations of 3 x 10(-8) and 10(-7) M decreased the slow inward current; the steady-state outward current and the hyperpolarization-activated inward current were also reduced, but less markedly. Nifedipine decreased the slow inward current, the potency of which was one third less than that of CD-349. Diltiazem and verapamil were weaker in prolonging cycle length and in inducing arrest as compared with CD-349 and nifedipine. These results suggest that CD-349 is a more potent calcium antagonist for decreasing pacemaker activity of rabbit SA node cells as compared with the other three calcium antagonists tested.