AJP - Heart and Circulatory Physiology, Vol 272, Issue 4 1672-H1679, Copyright © 1997 by American Physiological Society
Beta-blockade reduces effects of adenosine and carbachol by transregulation of inhibitory receptors and Gi proteins
M. M. Borst, R. Marquetant, W. Kubler and R. H. Strasser
Department of Cardiology, University of Heidelberg, Germany.
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.
