Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

Aims: Cardiac function is modulated by the sympathetic nervous system through beta-adrenergic receptor (beta-AR) activity and this represents the main regulatory mechanism for cardiac performance. To date, however, the metabolic and molecular responses to beta(2)-agonists are not well characterized. Therefore, we studied the inotropic effect and signaling response to selective beta(2)-AR activation by tulobuterol. Main methods: Strips of rat right ventricle were electrically stimulated (1 Hz) in standard Tyrode solution (95% O-2. 5% CO2) in the presence of the beta(1)-antagonist CGP-20712A (1 mu M). A cumulative dose-response curve for tulobuterol (0.1-10 mu M), in the presence or absence of the phosphodiesterase (PDE) inhibitor IBMX (30 mu M), or 10 min incubation (1 mu M) with the beta(2)-agonist tulobuterol was performed. Key findings: beta(2)-AR stimulation induced a positive inotropic effect (maximal effect = 33 +/- 3.3%) and a decrease in the time required for half relaxation (from 45 +/- 0.6 to 31 +/- 1.8 ms, -30%, p < 0.001) after the inhibition of PDEs. After 10 min of beta(2)-AR stimulation, p-AMPK alpha(T172) (54%), p-PKBT308 (38%), p-AS160(T642) (46%) and p-CREBS133 (63%) increased, without any change in p-pKA(T197). Significance: These results suggest that the regulation of ventricular contractility is not the primary function of the beta(2)-AR. Rather, beta(2)-AR could function to activate PKB and AMPK signaling, thereby modulating muscle mass and energetic metabolism of rat ventricular muscle. (C) 2011 Elsevier Inc. All rights reserved.