Felodipine, Pharmacodynamics and Pharmacokinetics in the Isolated Rabbit Heart

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Abstract
Myocardial pharmacodynamics of the Ca2+-antagonist felodipine, a structural analogue of nifedipine, were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. The concentration of felodipine in the Krebs-Henseleit perfusion liquid was stepwise increased from 0.7 ng/ml to 90.4 ng/ml (1.8 to 235.3 nmol/l). Increasing felodipine concentrations from 0.7 to 3.6 ng/ml produced an increase of up to 115% in coronary flow rate, which then decreased at higher concentrations to 84% of the control value. Oxygen consumption decreased progressively to 28% at concentrations from 3.6 to 90.4 ng/ml. Myocardial contractility measured by amplitude and rate of contraction decreased progressively to 45.7 and 41.5%, respectively, at concentrations from 0.7 to 9.4 ng/ml and further to 4.0 and 3.0%, respectively, at 90.4 ng/ml. Myocardial efficiency expressed as the percentual ratio of contraction amplitude times frequency to oxygen consumption decreased to 11% at the highest concentration of felodipine. Heart beat frequency decreased simultaneously to 45.6%. The electrocardiographic PQ and QRS intervals increased at the highest concentration to 174 and 111%, respectively, whereas the QT interval decreased to 86.6%. Asystolia occurred in several cases at felodipine concentrations of 90.4 ng/ml. Both myocardial accumulation and disposition pharmacokinetics of the drug showed one-compartment characteristics with half-lives of about 97 min. for both processes. Apparent Vd was about 480 ml/g myocardial tissue, which expresses a very pronounced binding and accumulation of felodipine in the rabbit myocardium in vitro. The findings demonstrate that lower concentrations of felodipine produces coronary vasodilation in the isolated rabbit heart accompanied by a marked negative inotropic effect and a less than proportional reduction in oxygen consumption. The drug seemed to cause direct cardiotoxic effects at higher concentrations.