Chronic hypoxia usually evokes sustained release of endogenous neurohormones, leading to beta(2)-adrenergic receptor (beta(2)AR) desensitization and downregulation of expression, which impacts cellular contractility. We investigated whether exogenous beta(2)AR could compensate for the functional deficiency of beta(2)AR in rabbit cardiomyocytes under chronic hypoxia, and whether this led to improved contractility and cellular survival. A surgical experimental model of cyanotic heart disease was established in rabbits. Adv.h beta(2)AR was transfected into cardiomyocytes isolated from animals subjected to 6-week systemic hypoxia. The levels of cellular contractile function, protein expression of h beta(2)AR, p-Akt, p-Erk, and caspase-3, and cellular survival pre- and post-Adv.h beta(2)AR delivery were determined. In the cyanotic cells, decreased shortening and lengthening of TPC and R50 were evident. Cellular diastolic functioning showed greater deterioration compared to the systolic function (P < 0.05). In cyanotic cells, the positive inotropic response to isoproterenol was decreased (P < 0.01), low levels of cellular survival were found, protein levels of beta(2)AR, p-Akt, and p-Erk were downregulated, and protein levels of caspase-3 were upregulated. After Adv.h beta(2)AR delivery, enhanced contractile function was achieved (P < 0.01), TPC and R50 levels recovered up to 99% and 81.7% of the normal control levels, respectively (P < 0.05), and cellular survival improved (P < 0.01). Our results demonstrate that overexpression of the beta(2)AR gene in cardiomyocytes exposed to chronic hypoxia provides significant catecholamine-dependent inotropic support and cellular protection. (C) 2010 Elsevier Inc. All rights reserved.