Vascular versus Myocardial Selectivity of Dihydropyridine Calcium Antagonists as Studiedin Vivoandin Vitro

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Abstract
The use ofin vitromodels for the study of cardiovascular effects of drugs may not be representative for thein vivotherapeutic effects. However, drug effectsin vivoare often difficult to assess because of counteracting reflexes and auto‐regulatory rearrangements. To solve this dilemma, the present study presents a two‐step method using bothin vivoandin vitrotechniques to investigate vascular versus myocardial 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 potency) 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, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivityin vivowas higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from thein vitrostudies were: felodipine (1), amlodipine (2) and nifedipine (20). Thein vitroresults were used to extrapolate the vascular versus cardiac chronotropic selectivity obtainedin vivoto a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.

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