Antihypertrophic Effects of Nebivolol on Neonatal Cardiomyocyte Hypertrophy Models

The antihypertrophic effect of nebivolol over cardioselective beta-blockers (beta-blockers) is attributed to the activation of cardiac nitric oxide signaling. However, the precise role of nebivolol on hypertrophied cardiomyocytes remains unclear. In the current study, in vitro cardiomyocyte hypertrophy model was induced with isoprenaline (10 mu M), angiotensin II (1 mu M), and phenylephrine (20 mu M) in neonatal cardiomyocytes isolated from 0- to 2-day-old Sprague-Dawley rats. In addition to hypertrophic agents, cardiomyocytes were treated with nebivolol (1 mu M), metoprolol (10 mu M), N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 mu M), KT5823 (1 mu M), DETA-NONOate (1-10 mu M), and BAY412272 (10 mu M). After 24 hours of treatment, cardiomyocyte size and transcriptional changes in cardiac hypertrophy markers were evaluated. Cardiomyocyte size increased equally in response to all hypertrophic agents. Nebivolol reduced the enhancement in cell size in response to both isoprenaline and angiotensin II; metoprolol did not. The antihypertrophic effect of nebivolol was prevented with L-NAME blockage indicating the role of NOS signaling on cardiomyocyte hypertrophy. The increased mRNA levels of atrial natriuretic peptide induced by isoprenaline decreased with nebivolol, but both beta-blockers reduced the angiotensin II-induced increase in atrial natriuretic peptide expression. Combined, these results reveal that by activating NOS signaling, nebivolol exerts antihypertrophic effects on neonatal cardiomyocytes independent from the action mechanism of hypertrophic stimulus.