In vitro and in vivo pharmacodynamic properties of metoprolol in fructose-fed hypertensive rats.
BACKGROUND
This study of metoprolol pharmacokinetic and pharmacodynamic properties investigates cardiac beta1-adrenoceptors activity and its involvement in the hypertensive stage in 6-week-old fructose-fed male Sprague-Dawley rats.


METHODS
A microdialysis probe was inserted in the carotid artery to monitor metoprolol levels, blood pressure, and heart rate after drug administration (3-10 mg/kg intravenously). The relationship between levels and cardiovascular effects was studied using a pharmacokinetic-pharmacodynamic model with effect compartment. Dissociation constant and inverse agonism were evaluated in isolated atria.


RESULTS
Metoprolol pharmacokinetics were similar in both groups. Metoprolol induced a greater hypotensive effect in fructose-fed animals (Emax: -24 +/- 1 mm Hg, n = 6, P < 0.05 vs. control) than in control rats (Emax: -14 +/- 1 mm Hg, n = 6). Bradycardic response was similar in both groups; metoprolol chronotropic potency was greater in fructose-fed rats (IC50: 123 +/- 15 ng/mL, P < 0.05 vs. control) compared to control animals (IC50: 216 +/- 36 ng/mL) after administration of 3 mg/kg. Metoprolol constants of dissociation for beta1-adrenoceptors and inverse agonism were similar in both groups.


CONCLUSIONS
Results demonstrate the beta1-adrenoceptors involvement in the fructose hypertension. A greater potency to metoprolol in vivo chronotropic effect was found in fructose-fed rats. This greater potency was not caused by alteration in the activity of beta1-adrenoceptors.
Di Verniero
Carla Andrea
CA
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Silberman
Ezequiel Aníbal
EA
Mayer
Marcos Alejandro
MA
Opezzo
Javier Alberto Walter
JA
Taira
Carlos Alberto
CA
Höcht
Christian
C
D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000008:administration & dosage*; D006207:Half-Life; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology
D058671:Adrenergic beta-1 Receptor Antagonists; D000959:Antihypertensive Agents; D018342:Receptors, Adrenergic, beta-1; D005632:Fructose; D008790:Metoprolol