PN 200–110, A New Calcium Antagonist

Abstract

The compound isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate (code name PN 200-110 [PN]) was investigated for Ca antagonistic effects in experiments in vitro. Action potentials recorded with intracellular microelectrodes in guinea pig papillary muscles were changed little by PN, 10-7 M, except for a slight shortening of the duration of the plateau phase. Slow action potentials elicited in partially depolarized papillary muscles were gradually diminished and finally blocked by this concentration fo PN. Contractile force was diminished in normal and partially depolarized muscles. The rate of spontaneously beating guinea pig right atria was decreased dose dependently, and the EC25 [25% effective concentration] was 4.5 .times. 10-10 M. The EC25 for the negative inotropic effects measured on paced guinea pig left atria was 1.5 .times. 10-8 M. No membrane-stabilizing effects were found. Ca-induced contraction of rabbit aorta in depolarizing bath solution was inhibited with an apparent pA2 [competitive antagonist activity] of 10.3. Contraction elicited by graded depolarization at a constant Ca concentration was inhibited with an EC50 [median effective concentration] of 1.4 .times. 10-9 M. Under resting conditions PN did not alter net uptake of 45Ca2+. KCl-stimulated uptake was inhibited with an EC50 of 3.6 .times. 10-9 M. Neither noradrenaline[norepinephrine]-induced contractions nor noradrenaline-stimulated net uptake of 45Ca2+ were inhibited by a concentration of PN as high as 10-5 M. PN is evidently selective on cardiac tissue with respect to negative chronotropic vs. inotropic activity and on rabbit aorta with respect to potential-operated vs. receptor-operated channels.