Beta-blockade reduces effects of adenosine and carbachol by transregulation of inhibitory receptors and Gi proteins.

Abstract

Chronic blockade of stimulatory beta-adrenergic receptors may decrease inhibitory receptors of the adrenergic signal transduction system. This transregulation process might reduce the negative inotropic response of the myocardium to inhibitory receptor stimulation. Rats were treated for 6 days with the beta-blocker atenolol (2 mg/day). beta-Adrenergic receptors in cardiac plasma membranes increased from 49 +/- 6 to 75 +/- 9 fmol/mg protein (means +/- SE; P = 0.053), whereas muscarinic M2 receptors decreased (155 +/- 15 vs. 105 +/- 10 fmol/mg protein; P < or = 0.05). Moreover, inhibitory G alpha(i) proteins were reduced by 36%. The functional responses of isolated hearts to inhibitory agonists after prestimulation with isoproterenol (3 nmol/l) were significantly blunted. The Ki value for the negative inotropic response of the maximal rise in developed left ventricular pressure (dP/dt(max)) to adenosine (0.1-100 micromol/l) increased from 5.9 +/- 1.7 to 24.0 +/- 2.5 micromol/l (P < or = 0.001). A similar rightward shift of the dose-response curve was observed for the effects of adenosine on developed left ventricular pressure (LVP) and of carbachol (0.01-10 micromol/l) on LVP and dP/dt. Thus chronic beta-blockade leads to a coordinate transregulation of inhibitory receptors and Gi proteins, reducing the effects of inhibitory receptor activation of the heart. This mechanism may contribute to the beneficial effects of beta-blocker therapy in heart failure.