beta-adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium

Background: Although end-stage dilated cardiomyopathy (DCM) is characterize d by defects in beta -adrenergic receptor (beta -AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the eff ects of ET receptor activation on beta -AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium. Methods and Results: Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardi omyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10(-6) to 0(-9) mol/L) as well as after (-)isoprote renol (10(-6) to 10(-2) mol/L) or forskolin (0.05 to 30.0 mu mol/L) stimula tion. beta -AR and ET receptor profiles were determined by radiolabeled lig and assays. ET-1 inhibited basal cAMP production in all preparations in a c oncentration-dependent manner. However, beta -AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET- 1. beta -AR receptor density was reduced, and a selective reduction of the ETB receptor occurred in both forms of DCM. Conclusions: Under basal conditions, ET receptor stimulation reduced cAMP l evels, which may influence contractility, particularly with DCM.