Chronic Treatment With Carbachol Sensitizes the Myocardium to cAMP-Induced Arrhythmia

Background The present study investigated biochemical and functional consequences of chronic activation of the inhibitory G iα -coupled adenylyl cyclase pathway in the heart. Methods and Results Rats (220 to 260 g) were treated with 4-day infusions of the M-cholinoceptor agonist carbachol (9.6 mg/kg per day) or vehicle. An additional group that received the β-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) served as control. The main finding was that chronic infusion of carbachol led to a marked increase in isoprenaline- or forskolin-induced arrhythmia in electrically driven papillary muscles (in vitro). Compared with control, the potency of isoprenaline and forskolin to induce arrhythmia in cardiac preparations from carbachol-treated rats was increased 36- and 2.2-fold and the efficacy was increased 7.3- and 2.3-fold, respectively. The potency of carbachol to antagonize the isoprenaline- and forskolin-induced arrhythmia was decreased 30-fold. These changes were accompanied by a decrease in left ventricular M-cholinoceptor density by 15% ( P <.05) and a decrease in pertussis toxin–sensitive G proteins (G iα ) by 26% ( P <.05) without a decrease in the corresponding mRNAs. β-Adrenoceptor density and basal and stimulated adenylyl cyclase activity remained unchanged. In contrast, isoprenaline infusion induced a decrease in arrhythmogenic potency of forskolin ( P =NS), which was accompanied by a decrease in β-adrenoceptor density, an increase in G iα protein and mRNA levels, and a decrease in basal and stimulated adenylyl cyclase activity. Conclusions Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional G iα .