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

Author:

Birenbaum Aurélie1,Tesse Angela2,Loyer Xavier2,Michelet Pierre3,Andriantsitohaina Ramaroson4,Heymes Christophe5,Riou Bruno6,Amour Julien1

Affiliation:

1. Assistant Professor, UMPC Univ Paris 06, EA 3975, Department of Anesthesiology and Critical Care, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris.

2. Research Associate.

3. Assistant Professor, Department of Anesthesiology and Critical Care, Hôpital Sainte-Maguerite, Marseille.

4. Research Director, Unité Médicale de Recherche (UMR)–Institut National de la Santé et de la Recherche Médicale (INSERM) 771-Centre National de Recherche Scientifique (CNRS) 6214, Angers.

5. Research Director, INSERM U689, Paris.

6. Professor of Anesthesiology and Critical Care, UMPC Univ Paris 06, Head of the Laboratory of Anesthesiology (Equipe d'Accueil {lsqb;EA{rsqb; 3975), and Chairman, Department of Emergency Medicine and Surgery, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris.

Abstract

Background In senescent heart, beta-adrenergic response is altered in parallel with beta1- and beta2-adrenoceptor down-regulation. A negative inotropic effect of beta3-adrenoceptor could be involved. In this study, the authors tested the hypothesis that beta3-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-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 (183 +/- 19%). In the senescent group, in parallel with beta3-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 beta3-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, beta3-adrenoceptor overexpression plays an important role in the altered beta-adrenergic response via induction of NOS1-nitric oxide.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

Reference37 articles.

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