Comparison of cardiodepressant and vasodilator effects of PN 200-110 (isradipine), nifedipine and diltiazem in anesthetized rabbits.

Cardiodepressant and vasodilator effects of PN 200-110 (isradipine) were investigated in anesthetized open-chest rabbits and compared with those of nifedipine, diltiazem or placebo. In order to eliminate compensatory reflexes that may mask negative inotropic and chronotropic effects of blood pressure-lowering agents, the animals were vagotomized and pretreated with 1 mg/kg propranolol. Dose-response curves were obtained with 4 doses of each drug in 6 animals. The doses were chosen to cause comparable decreases in blood pressure. PN 200-110 had the highest efficacy with respect to peripheral vasodilatation (increase in total peripheral conductance) and coronary blood flow, measured with radioactive-labeled microspheres. It did not decrease myocardial contractile force (measured with a strain gauge). The 2 other compounds caused biphasic changes in coronary blood flow and cardiac output. Their efficacy with respect to peripheral vasodilatation was limited by cardiodepression. Their dose-response curve for cardiodepression was flat at the 2 smaller doses and became steeper at the 2 larger doses. Nifedipine did not change heart rate; PN 200-110 decreased it minimally and diltiazem had a dose-dependent negative chronotropic effect. After eliminating autonomic influences on the heart, direct myocardial effects of calcium antagonists become demonstrable in whole animals and can be compared with the vascular effects measured in the same animals.