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 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.
Eschenhagen
T
T
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
Mende
U
U
Diederich
M
M
Hertle
B
B
Memmesheimer
C
C
Pohl
A
A
Schmitz
W
W
Scholz
H
H
Steinfath
M
M
Böhm
M
M
Michel
M C
MC
Brodde
O E
OE
Raap
A
A
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
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