Inactivation of GiαProteins Increases Arrhythmogenic Effects ofβ-Adrenergic Stimulation in the Heart

Chronic treatment of rats with carbachol downregulates M-cholinoceptors and inhibitory, pertussis toxin (PTX)-sensitive G protein α-subunits (Giα) and sensitizes the heart to arrhythmogenic effects of isoprenaline (ISO), suggesting a causal relationship. To test this hypothesis by a more direct and quantitative approach, nine groups of rats were treated for 24 h with increasing doses of PTX (1.25–200μg/kg i.v.). Inactivation of cardiac Giαwas determined biochemically by32P-ADP-ribosylationin vitroand functionally by measuring contractile effects of carbachol. Effects of ISO were studied in spontaneously beating right atria (RA) and isolated papillary muscles (PM; paced at 1 Hz). PTX increased heart rate in conscious animals (ECG) with a bell-shaped dose-dependency (maximal increase 120 beats/min at 7.5μg/kg). PTX dose-dependently inactivated 25–85% of total cardiac Giα, which linearly correlated with a loss of the direct negative chronotropic effect of carbachol in atria, but not with a loss of its indirect negative inotropic effect in PM. The latter was resistant up to PTX 20μg/kg (=70% inactivation). The decrease in Giαclosely correlated with an increased efficacy of ISO to induce spontaneous contractile activity (automaticity) in PM. At 3μmol/l ISO, all PM from PTX 200μg/kg beat spontaneously compared to 10% in control. In contrast, pretreatment with PTX only modestly and not clearly dose-dependently increased the inotropic potency of ISO (PTX 100μg/kg: EC5028v81 nmol/l in control) and did not affect the chronotropic effect of ISO. The disparity of the functional consequences of PTX treatment suggest that under physiological conditions, Giαserve mainly to suppress arrhythmogenic, but not or to a minor extent, positive chronotropic or inotropic effects ofβ-adrenoceptor activation.