A comparative study of the pharmacodynamics and pharmacokinetics of nicardipine and nitrendipine in the isolated rabbit heart.

Abstract

The myocardial pharmacodynamic effects of the two dihydropyridine calcium-antagonists nicardipine and nitrendipine were comparatively studied in the isolated, spontaneously beating and retrogradely perfused rabbit heart at stepwise increased drug concentrations within the range 0.5-260 ng X ml-1 (1.1-721 nM). Both drugs produced a progressive and very pronounced inhibition of myocardial contractility as measured by both contraction amplitude and contraction velocity. The corresponding Emax-values were about 100% and IC50-values about 10 and 65 nM, respectively. Myocardial oxygen consumption did not decrease at the lower concentrations of neither nicardipine nor nitrendipine but were at the higher levels inhibited significantly with Emax-values of about 68 and 78% and IC50-values about 21 and 136 nM, respectively. Coronary flow-rate increased at the lower concentrations of the drugs to about 125 and 118% and then decreased to 80 and 77%, respectively. Both drugs, but especially nitrendipine, showed a marked negative chronotropic effect (Emax 33 and 56% and IC50 6 and 81 nM, respectively). The frequency-corrected QT-intervals were progressively decreased by the drugs. Myocardial accumulation and disposition pharmacokinetics of nicardipine, nitrendipine and nimodipine were also studied. The terminal half-lives for the drugs were about 56, 16 and 29 min., respectively. Apparent relative volumes of drug distribution in the myocardium which equals the average concentration ratio for the drugs between this tissue and the perfusion liquid at kinetic steady-states were about 290, 61 and 177 ml X g-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)