L. Brynne et al., Mechanism-based modeling of rebound tachycardia after chronic I-propranolol infusion in spontaneous hypertensive rats, J PHARM EXP, 290(2), 1999, pp. 664-671
Citations number
39
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.