Consequence of exercise on the cardiovascular effects of I-propranolol in spontaneously hypertensive rats

The aim of this study was to elucidate time dependence in the development o f rebound effect and to quantify the cardiovascular effects of chronic l-pr opranolol infusions in spontaneously hypertensive rats. Heart rate and syst olic and diastolic blood pressures were monitored both during exercise perf ormance 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 fo und, which was interpreted as a positive influence of exercise on heart rat e and was less marked in drug-treated animals. A mechanism-based model that accounts for competitive antagonism, spare receptors, the positive influen ce of exercise on heart rate, and circadian variations was used to describe the data. An empirical effect compartment model with an E-max model was re lated to a circadian baseline and describes the relationship between plasma concentrations and reduction in blood pressures. The potencies for exercis e and postexercise systolic blood pressure were similar with EC50 values 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 pre ssure 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 of l-pro pranolol on the blood pressures is best described by an effect compartment model with circadian variations.