Hypothalamic Antihypertensive Effect of Metoprolol in Chronic Aortic Coarctated Rats

Abstract

1. The aim of the present study was to investigate the possible hypothalamic antihypertensive effect of metoprolol and its action on aminergic neurotransmission in sham-operated (SO) rats and aortic coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. 2. Hypothalamic metoprolol concentrations and their cardiovascular effects were measured after the intravenous administration of 3 mg/kg metoprolol. Based on metoprolol concentrations reached in the anterior hypothalamus, in a second experiment the anterior hypothalamus of SO and ACo animals was perfused with Ringer's solution containing approximately 7.5 microg/mL metoprolol. The cardiovascular effects of metoprolol perfusion and changes in hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindol acetic acid (5-HIAA) levels were measured during the perfusion. 3. After i.v. administration of metoprolol, a greater hypotensive effect was observed in ACo rats than in SO animals (Delta mean arterial pressure (MAP) -23.8 +/- 2.1 vs-13.8 +/- 1.3 mmHg, respectively; n = 5 for both groups). Metoprolol rapidly reached the central nervous system (CNS) in both groups of rats and its levels were similar in SO and ACo rats. Intrahypothalamic perfusion with metoprolol induced a significative decrease in blood pressure in ACo animals (DeltaMAP -13.3 +/- 1.5 mmHg; n = 5; P < 0.05 vs Ringer perfusion), but not in SO rats (DeltaMAP 3.4 +/- 2.7 mmHg; n = 5). Metoprolol perfusion reduced hypothalamic levels of DOPAC in ACo rats (65 +/- 7% of basal levels; n = 5; P < 0.05 vs Ringer perfusion), but not in SO animals (87 +/- 5% of basal levels; n = 5). There were no changes in hypothalamic concentrations 5-HIAA observed in either experimental group. 4. In conclusion, metoprolol exerts a greater hypotensive effect in chronic ACo animals, suggesting a participation of beta-adrenoceptors in the maintenance of the hypertensive stage. Metoprolol distribution in the CNS is not affected by ACo. The hypotensive effect of metoprolol perfusion in ACo rats suggested that hypothalamic beta-adrenoceptor blockade is part of the antihypertensive effect of metoprolol in chronic ACo rats. The effects of metoprolol on DOPAC levels suggest a reduction of dopamine turnover in hypertensive animals, but not in SO rats.

Applicability of reverse microdialysis in pharmacological and toxicological studies

“…In a previous study, Höcht, Opezzo, and Taira (2005a) evaluated the possible hypothalamic antihypertensive effect of metoprolol and its action on aminergic neurotransmission in sham operated and aortic coarctated hypertensive rats using the reverse microdialysis technique. Intrahypothalamic perfusion with metoprolol induced a significative decrease of blood pressure in coarctated hypertensive animals but not in normotensive rats.…”

“…On the other hand, metoprolol perfusion reduced hypothalamic levels of DOPAC in hypertensive rats but not in sham operated animals. Therefore, the authors concluded that the hypotensive effect of metoprolol perfusion in aortic coartated rats suggest that hypothalamic β-adrenergic blockade is part of the antihypertensive effect of metoprolol in chronic coarctated rats (Höcht et al, 2005a). Local administration of antihypertensive drugs by reverse microdialysis in central nuclei involucred in blood pressure regulation allows elucidating the mechanism of action of this therapeutic class.…”