title: Vascular versus myocardial selectivity of dihydropyridine calcium antagonists as studied in vivo and in vitro.
abstract: The use of in vitro models for the study of cardiovascular effects of drugs may not be representative for the in vivo therapeutic effects. However, drug effects in vivo are 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 both in vivo and in vitro techniques 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 selectivity in vivo was higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from the in vitro studies were: felodipine (1), amlodipine (2) and nifedipine (20). The in vitro results were used to extrapolate the vascular versus cardiac chronotropic selectivity obtained in vivo to a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.
authors.affiliation: Astra Hässle AB, Preclinical R & D, Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Nordlander
authors.forename: T
authors.initials: T
authors.lastname: Abrahamsson
authors.forename: B
authors.initials: B
authors.lastname: Akerblom
authors.forename: P
authors.initials: P
authors.lastname: Thalén
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015736:Felodipine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D009928:Organ Specificity; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017311:Amlodipine; D009543:Nifedipine; D015736:Felodipine