Beta-adrenoceptor stimulation-induced increase in cardiac Gi-protein expression and in carbachol sensitivity

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Abstract
Increased plasma concentrations of catecholamines are assumed to be responsible for the decreased sensitivity to catccholamines of the failing heart. We investigated in rat heart the influence of a 4-day infusion of isoprenaline (Iso; 2·4mg.kg−1. d−1), propranolol (Prop; 9·9mg. kg−1.d−1), Iso+Prop or 0·9% NaCl as control (Ctr) on myocardial G1-mRNA and G1-protein levels and on the negative inotropic effect of carbachol in papillary muscles. In Iso-treated rats, hybridization experiments with 32P-cDNAs revealed a 49±18% (n = 7−8) and 27±7% (n = 8) increase in Gtα.2- and Gtα.3-mRNA respectively, and pertussis toxin-atalyzed ADP-ribosylotion revealed a 22 ± 7% (n = 8) increase in G1-protein as compared to Ctr. These alterations were accompanied by an increased potency of carbachol (mean EC50: 0·04(μM vs. 0·28 μm) in the presence of Iso in isolated electrically driven (1 Hz) papillary muscles. Prop had no effect on G1-protein expression but antagonized all Iso-induced effects. In conclusion, β-adrenergic stimulation leads to an increased expression of G1 and to an enhanced negative inotropic potency of muscarinic agonists. An enhanced muscarinic receptor coupling via G1 might play a pathophysiological role in heart diseases with increased plasma catecholamine levels.

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