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

Background: Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in β-adrenergic receptor (β-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 effects of ET receptor activation on β-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 cardiomyopathic (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 (-)isoproterenol (10⁻⁶ to 10⁻² mol/L) or forskolin (0.05 to 30.0 μmol/L) stimulation. β-AR and ET receptor profiles were determined by radiolabeled ligand assays. ET-1 inhibited basal cAMP production in all preparations in a concentration-dependent manner. However, β-AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET-1. β-AR receptor density was reduced, and a selective reduction of the ET_B receptor occurred in both forms of DCM. Conclusions: Under basal conditions, ET receptor stimulation reduced cAMP levels, which may influence contractility, particularly with DCM.