Mechanism-based modeling of rebound tachycardia after chronic I-propranolol infusion in spontaneous hypertensive rats

The aims of the study were to characterize the rate and extent of the rebou nd effect after abrupt cessation of a chronic exposure of l-propranolol in spontaneous hypertensive rats, using exercise-induced tachycardia as a phar macodynamic endpoint. Thirty-two spontaneous hypertensive rats were randomi zed to receive either placebo or 4 or 8 mg/kg/day s.c, infusion of l-propra nolol for 11 days using osmotic minipumps. The heart rate was measured afte r standardized physical exercise before and during drug exposure and over 1 2 days after cessation, using a computerized tail-cuff method. Blood sample s were collected after each effect measurement during the infusion. A simil ar reduction in exercise tachycardia was registered for the two doses. No a pparent tolerance development was found, but both doses showed a clear rebo und effect of similar extent and intensity. The maximal rebound effect was observed on the second day after cessation and was found to have a duration of about 6 days. A mechanism-based model was developed to describe the rat e and extent of changes in beta-adrenoceptor up- and down-regulation with i ncreased sensitivity of the transducer complex. The half-life of disappeara nce of up-regulated beta-adrenoceptors was estimated to be 2.0 days (1.0-3. 9 days). The effect-versus-time data was analyzed by nonlinear mixed-effect modeling with the program NONMEM. A dose-dependent reduction in the growth of body weight was observed during drug treatment, which was reversible. A dose- and time-dependent increase in the alpha(1)-acid glycoprotein concen tration was also observed.