Chronic treatment with carbachol sensitizes the myocardium to cAMP-induced arrhythmia

• Published in: Circulation (New York, N.Y.) Vol. 93; no. 4; pp. 763 - 771
• Main Authors: ESCHENHAGEN, T, MENDE, U, MICHEL, M. C, BRODDE, O.-E, RAAP, A, DIEDERICH, M, HERTLE, B, MEMMESHEIMER, C, POHL, A, SCHMITZ, W, SCHOLZ, H, STEINFATH, M, BÖHM, M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.02.1996; American Heart Association, Inc
• Subjects: Adenylate Cyclase Toxin; Adenylyl Cyclases - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - physiopathology; Biological and medical sciences; Carbachol - pharmacology; Cardiac dysrhythmias; Cardiology. Vascular system; Colforsin - pharmacology; Cyclic AMP - pharmacology; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Heart; Heart - drug effects; Heart - physiopathology; In Vitro Techniques; Isoproterenol - pharmacology; Male; Medical sciences; Myocardial Contraction - drug effects; Myocardium - metabolism; Norepinephrine - metabolism; Pertussis Toxin; Rats; Rats, Wistar; Receptors, Adrenergic, beta - metabolism; Receptors, Muscarinic - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Virulence Factors, Bordetella - metabolism; Pharmacologic test; Rat; Arrhythmia; Rodentia; Cyclic AMP; Cardiovascular disease; Exploration; β-Adrenergic receptor; Signal transduction; Vertebrata; Chronic; Mammalia; Heart disease
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.93.4.763

The present study investigated biochemical and functional consequences of chronic activation of the inhibitory Gi alpha-coupled adenylyl cyclase pathway in the heart. 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 beta-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 (Gi alpha) by 26% (P < .05) without a decrease in the corresponding mRNAs. beta-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 beta-adrenoceptor density, an increase in Gi alpha protein and mRNA levels, and a decrease in basal and stimulated adenylyl cyclase activity. Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional Gi alpha.