Selective β1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through β2-adrenoceptors in human atrial myocardium

Abstract

We determined the relative contribution of β1- and β2-adrenoceptor stimulation to the positive inotropic responses of human atrial myocardium to catecholamines. (-)Norepinephrine produced stimulation predominantly through β1-receptors and (-)epinephrine through both β1- and β2-receptors. However, there were marked differences in the responses of tissues from patients treated with the β1-selective antagonists atenolol compared with non-β-blocker-treated patients; surprisingly, β2-mediated responses were enhanced, and β1-mediated responses were unaltered. There was an enhanced responsiveness of (-)epinephrine (atenolol treated: -log M EC50, 7.57 ± 0.07; non-β-blocker treated: -log M EC50 6.77 ± 0.17; p < 0.001), and the relative importance of β2-adrenoceptor stimulation was increased for both (-)norepinephrine and (-)epinephrine. In tissues from atenolol-treated patients, salbutamol, a β2-selective partial agonist, had an enhanced potency and a greater intrinsic activity (atenolol treated: -log M EC50, 7.13 ± 0.09; intrinsic activity, 0.86 ± 0.04; non-β-blocker treated: -log M EC50, 5.76 ± 0.44; intrinsic activity, 0.39 ± 0.13). We investigated possible mechanisms underlying the enhanced responsiveness to β2 stimulation. Determination of β2-adrenoceptor affinity for salbutamol showed no change of affinity in atenolol-treated patients. Responses of the tissues to the cyclic AMP analogue dibutyryl cyclic AMP were not different between atenolol-treated and non-β-blocker-treated patients. The results suggest that chronic blockade of β1-adrenoceptors causes enhanced coupling of β2-adrenoceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.