Regulation of cyclic adenosine monophosphate release by selective beta(2)-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support

Abstract

BACKGROUND: Response to catecholamines is blunted in terminal heart failure due to beta-receptor downregulation and uncoupling from adenylyl cyclase (AC). Improved myocardial responsiveness to catecholamines after ventricular assist device (VAD) support is associated with upregulation of beta(1)-adrenergic receptors (beta(1)-ARs). Little is known about the regulation of AC and beta(2)-AR coupling after VAD; moreover beta(2)-AR stimulation during VAD was claimed to induce myocardial recovery. METHODS: We analyzed in VAD-supported human myocardium the regulation of AC activity upon beta(1)-AR and selective beta(2)-AR stimulation in 8 non-failing hearts (NF) and 17 paired samples of VAD patients. AC messenger RNA was measured by TaqMan. AC was stimulated via beta(2)-AR using clenbuterol (beta(2)-AR agonist) and bisoprolol (beta(1)-AR blocker). Organ bath experiments were done with trabeculae from both ventricles. Samples were stratified according to chronic or acute heart failure history. RESULTS: Isoprenaline-induced AC activity was downregulated (p < 0.001) pre-VAD and increased significantly (p < 0.05) after unloading (mean standard deviation pmole/mg/min) in NF (47.9 +/- 14.9), pre-VAD (24.35 +/- 13.3), and post-VAD (50.04 +/- 50.25). Forskolin stimulation revealed significant (p < 0.05) upregulation of AC activity during VAD, especially in acutely failing hearts (NF, 192.1 +/- 68.7; pre-VAD, 191.1 +/- 60.4; post-VAD, 281.5 +/- 133). However, forskolin stimulation relative to isoprenaline-induced inotropy remained reduced before and after VAD compared with NF. The selective stimulation of beta(2)-AR did not reveal influence of VAD support on beta(2)-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 mu mole/liter clenbuterol revealed negative inotropic responses. CONCLUSIONS: VAD does not influence beta(2)-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by beta(1)-AR upregulation and modulation of AC activity. Restoration of beta-adrenergic responsiveness was restricted to acutely failing hearts. J Heart Lung Transplant 2012;31:1127-35 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.