Mechanism-based modeling of rebound tachycardia after chronic l-propranolol infusion in spontaneous hypertensive rats.
The aims of the study were to characterize the rate and extent of the rebound effect after abrupt cessation of a chronic exposure of l-propranolol in spontaneous hypertensive rats, using exercise-induced tachycardia as a pharmacodynamic endpoint. Thirty-two spontaneous hypertensive rats were randomized to receive either placebo or 4 or 8 mg/kg/day s.c. infusion of l-propranolol for 11 days using osmotic minipumps. The heart rate was measured after standardized physical exercise before and during drug exposure and over 12 days after cessation, using a computerized tail-cuff method. Blood samples were collected after each effect measurement during the infusion. A similar reduction in exercise tachycardia was registered for the two doses. No apparent tolerance development was found, but both doses showed a clear rebound 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 rate and extent of changes in beta-adrenoceptor up- and down-regulation with increased sensitivity of the transducer complex. The half-life of disappearance 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 concentration was also observed.
Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden. lena.brynne@biof.uu.se
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Brynne
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Paalzow
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Karlsson
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D010805:Physical Conditioning, Animal; D005082:Physical Exertion / Q000502:physiology; D011433:Propranolol / Q000493:pharmacokinetics / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013610:Tachycardia / Q000139:chemically induced* / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D011433:Propranolol