title: Concentration-effect relationship of l-propranolol and metoprolol in spontaneous hypertensive rats after exercise-induced tachycardia.
abstract: The concentration-effect relationship of l-propranolol and dl-metoprolol were investigated in spontaneous hypertensive rats using reduction in exercise-induced tachycardia as a pharmacodynamic endpoint. The influence of protein binding on the effect relationship was also assessed. The rats were assigned to treatment or placebo groups, where each group received three randomly selected consecutively increasing steady-state infusions. Different pharmacodynamic effect models were fitted to the data, using nonlinear mixed effect modeling. The data were best described by a combined effect model, with a sum of an ordinary Imax and a linear model. At the lower concentration range, the ordinary Imax model dominated, although at higher concentrations, the effect was linearly related to the antagonist concentration. The Imax were 83 +/- 6 and 103 +/- 6 beats . min-1 and the IC50 were 18.1 +/- 4.3 and 50.6 +/- 15.2 ng/ml for l-propranolol and dl-metoprolol, respectively. The slope in the linear model was steeper for l-propranolol than for dl-metoprolol, 28.9 +/- 2.8 and 4.48 +/- 0.39 beats . ml . (min . microgram)-1, respectively. Plasma protein binding of l-propranolol was saturable. The unbound IC50 for l-propranolol was 1.14 +/- 0.27 ng/ml. The concentration-effect relationship of l-propranolol was altered at higher plasma concentrations, due to saturable protein binding. The Imax and the linear concentration-effect relationship may be interpreted as a specific beta-antagonist effect and a membrane-stabilizing effect, respectively. Using exercise-induced tachycardia as a pharmacodynamic endpoint, to study the effect of beta-antagonists in spontaneous hypertensive rats, seems to give reliable results and can be a useful model to extrapolate to humans.
authors.affiliation: Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Brynne
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: L K
authors.initials: LK
authors.lastname: Paalzow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D010805:Physical Conditioning, Animal; D011433:Propranolol / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D000319:Adrenergic beta-Antagonists; D001798:Blood Proteins; D011433:Propranolol; D008790:Metoprolol