Nebivolol but not metoprolol prevents functional, morphologic and molecular abnormalities induced by isoprenaline in rat heart.

AT OZCELIKAY, I OZAKCA, E ARIOGLU INAN, VM ALTAN. ANKARA UNIVERSITY FACULTY OF PHARMACY, PHARMACOLOGY 06100, Turkey

The importance of chronic stimulation of beta-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of beta-blockers in the treatment of heart failure. Nebivolol is a third-generation beta-blocker which has further properties including stimulation of endothelial nitric oxide synthase and/or beta3-adrenoceptors in addition to selective beta1-adrenoceptor blockage. The aim of this study was to compare the effects of nebivolol with those of metoprolol (selective beta1-adrenoceptor blocker) on functional, morphologic and molecular alterations in a model of cardiac hypertrophy induced by isoprenaline infusion. Rats infused by isoprenaline (100 µg/kg/day, 14 days) were randomized into three groups according to the treatment with metoprolol (M, 30 mg/kg/day), nebivolol (N, 10 mg/kg/day) or placebo (ISO) for 13 days starting on day 1 after implantation of minipump. Sham-operated rats were used as controls (C). After the treatment protocol, isolated papillary muscle was used to examine the inotropic responses of isoprenaline (nonselective beta-adrenoceptor agonist), noradrenaline (selective beta1-adrenoceptor agonist), BRL37344 (selective beta3-adrenoceptor agonist) and forskolin (membrane-permeable cyclic AMP activator). Stastical analysis was performed using 1-way analysis of variance followed by the Newman-Keuls multiple comparison test. Both beta-blockers caused a similar reduction on isoprenaline-induced tachycardia (beat/min): C vs ISO: 388±2 vs 531±3, p<0,001; M vs N: 471±6 vs 474±8; p>0,05). Contrary to ISO and M groups, nebivolol elicited a significant improvement on cardiac mass (expressed as left ventricular weight-to-body weight ratio) and mRNA expression levels of SERCA2a and ANP (markers of cardiac hypertrophy). Although both beta-blocker treatments ameliorated the changes in mRNA expressions of beta1- and beta3-adrenoceptors, only nebivolol treatment improved the depressed responses to isoprenaline and BRL37344 in papillary muscle. In addition, nebivolol, but not metoprolol treatment prevented the decrease in response obtained at the 1µM concentration of forskolin. However, neither metoprolol nor nebivolol resulted in a beneficial effect on noradrenaline responses. Our results indicate that nebivolol partially prevents the abnormalities in beta-adrenoceptor-mediated responses correlating with the development of cardiac hypertrophy induced by isoprenaline infusion in rats. The beneficial effects of nebivolol can be associated with other mechanisms beyond its beta1-adrenoceptor blocking effect.