Involvement of β3-Adrenoceptor in Altered β-Adrenergic Response in Senescent Heart

Background: In senescent heart beta-adrenergic response in parallel with beta(1)- and beta(2)-adrenoceptor down-regulation. A negative inotropic effect of beta(3)-adrenoceptor could be involved. In this study, the authors tested die hypothesis that beta(3)-adrenoceptor plays a role in beta-adrenergic dysfunction in senescent heart. Methods: beta-Adrenergic responses were investigated in vivo (echocardiography-dobutamine. electron paramagnetic resonance) and in vitro (isolated left ventricular papillary muscle, electron paramagnetic resonance) in young, adult (3-month-old) and senescent (24-month-old) rats. Nitric oxide synthase (NOS) immunolabeling (confocal microscopy), nitric oxide production (electron paramagnetic resonance) and beta-adrenoceptor Western blots were performed in vitro. Data are mean percentages of baseline +/- SD. Results: An impaired positive inotropic effect (isoproterenol) was confirmed in senescent hearts in vivo (117 +/- 23 vs. 162 +/- 16%; P < 0.05) and in vitro (127 +/- 10 vs. 179 +/- 15%; P < 0.05). In the young adult group, the positive inotropic effect was not significantly modified by the nonselective NOS inhibitor N-G-nitro-L-arginine methylester (L-NAME; 183 +/- 19%), the selective NOS1 inhibitor vinyl-L-N-5(1-imino-3-butenyl)-L-ornithine (L-VNIO; 172 +/- 13%), or the selective NOS2 inhibitor 1400W (193 19%). In the senescent group, in parallel with beta(3)-adrenoceptor up-regulation and increased nitric oxide production, the positive inotropic effect was partially restored by L-NAME (151 +/- 8%; P < 0.05) and L-VNIO (149 +/- 7%; P < 0.05) but not by 1400W (132 +/- 11%; not significant). The positive inotropic effect induced by dibutyryl-cyclic adenosine monophosphate was decreased in the senescent group with the specific beta(3)-adrenoceptor agonist BRL 37344 (167 +/- 10 vs. 142 +/- 10%; P < 0.05). NOS1 and NOS2 were significantly up-regulated in the senescent rat. Conclusions: In senescent cardiomyopathy beta(3)-adrenoceptor overexpression plays all important role it] the altered beta-adrenergic response via induction of NOS1-nitric oxide.