title: Chronic treatment with carbachol sensitizes the myocardium to cAMP-induced arrhythmia.
abstract: BACKGROUND
  The present study investigated biochemical and functional consequences of chronic activation of the inhibitory Gi alpha-coupled adenylyl cyclase pathway in the heart.
  
  
  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 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.
  
  
  CONCLUSIONS
  Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional Gi alpha.
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: U
authors.initials: U
authors.lastname: Mende
authors.forename: M
authors.initials: M
authors.lastname: Diederich
authors.forename: B
authors.initials: B
authors.lastname: Hertle
authors.forename: C
authors.initials: C
authors.lastname: Memmesheimer
authors.forename: A
authors.initials: A
authors.lastname: Pohl
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.forename: H
authors.initials: H
authors.lastname: Scholz
authors.forename: M
authors.initials: M
authors.lastname: Steinfath
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: M C
authors.initials: MC
authors.lastname: Michel
authors.forename: O E
authors.initials: OE
authors.lastname: Brodde
authors.forename: A
authors.initials: A
authors.lastname: Raap
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D002217:Carbachol / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D037342:Pertussis Toxin; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000378:metabolism
chemical_list: D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine