Abstract

The aim of this study was to elucidate time dependence in the development of rebound effect and to quantify the cardiovascular effects of chronic l-propranolol infusions in spontaneously hypertensive rats. Heart rate and systolic and diastolic blood pressures were monitored both during exercise performance and later by using telemetry. The pharmacodynamics were determined after different infusion lengths of l-propranolol (4 mg/kg/day) or placebo for 4, 8, or 12 days. A pronounced reduction in heart rate over time was found, which was interpreted as a positive influence of exercise on heart rate and was less marked in drug-treated animals. A mechanism-based model that accounts for competitive antagonism, spare receptors, the positive influence of exercise on heart rate, and circadian variations was used to describe the data. An empirical effect compartment model with anE_max model was related to a circadian baseline and describes the relationship between plasma concentrations and reduction in blood pressures. The potencies for exercise and postexercise systolic blood pressure were similar with EC₅₀values of 48 and 56 ng/ml, and the corresponding maximal effects were 17.8 and 21.9%, respectively. The EC₅₀ values and maximal effects for diastolic blood pressure were 26 and 5 ng/ml and 20.6 and 21.0%, respectively. The effect of l-propranolol could be quantified by a mechanism-based model in the presence of a positive influence of exercise on the heart rate. The effect ofl-propranolol on the blood pressures is best described by an effect compartment model with circadian variations.