VASCULAR VERSUS MYOCARDIAL SELECTIVITY OF DIHYDROPYRIDINE CALCIUM-ANTAGONISTS AS STUDIED IN-VIVO AND IN-VITRO

The use of in vitro models for the study of cardiovascular effects of drugs may not be representative for the in vivo therapeutic effects. H owever, drug effects in vivo are often difficult to assess because of counteracting reflexes and auto-regulatory rearrangements. To solve th is dilemma, the present study presents a two-step method using bath in vivo and in vitro techniques to investigate vascular versus myocardia l selectivity of three dihydropyridine calcium antagonists: amlodipine , felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potenc y) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, th e inotropic versus chronotropic potency ratio was determined between t he two drug concentrations producing a 25% reduction in cardiac contra ctility (dP/dt max) and in heart rate, respectively. The vascular vers us chronotropic selectivity in vivo was higher for felodipine (121) th an for nifedipine (47) and amlodipine (15). The inotropic versus chron otropic potency ratios obtained from the in vitro studies were: felodi pine (1), amlodipine (2) and nifedipine (20). The in vitro results wer e used to extrapolate the vascular versus cardiac chronotropic selecti vity obtained iii vivo to a vascular versus myocardial selectivity dru g ratio, being 20 and 60 times higher for felodipine than for amlodipi ne and nifedipine, respectively.