Reduced adenylyl cyclase inhibition by carbachol and GTP during acute myocardial ischaemia.
Acute myocardial ischaemia frequently is complicated by ventricular tachyarrhythmias. These arrhythmias are in part due to an increased susceptibility of myocardial cells to adenylyl cyclase stimulation by catecholamines [1]. As adenylyl cyclase underlies an endogenous dual regulation by stimulatory and inhibitory receptor systems, adenylyl cyclase stimulation can be counteracted by the activation of receptors like the muscarinic M2 receptor [2]. Therefore, the effect of myocardial ischaemia on muscarinic receptor and "inhibitory" guanine nucleotide binding proteins (G(i)) mediated inhibition of adenylyl cyclase was studied. During 5 min of myocardial ischaemia, carbachol mediated inhibition of forskolin and isoproterenol stimulated adenylyl cyclase was reduced by 30% and 50%, respectively. Hormone independent inhibition of adenylyl cyclase by the nonhydrolyzable GTP-analogue guanosine 5'-[beta gamma-imido]triphosphate (Gpp(NH)p) was reduced by 46%. In contrast, the amount of G(i), as determined by pertussis toxin catalyzed ADP-ribosylation, remained constant during 15 min of ischaemia. The impaired function of muscarinic receptor linked signal transduction during early myocardial ischaemia could contribute to the occurrence of ischaemia induced tachyarrhythmias by a reduced ability to counteract adenylyl cyclase activation.
Niroomand
F
F
Medizinische Klinik, Universität Heidelberg, Germany.
Bangert
M
M
Beyer
T
T
Rauch
B
B
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D005576:Colforsin / Q000037:antagonists & inhibitors; D003327:Coronary Disease / Q000201:enzymology* / Q000503:physiopathology; D004285:Dogs; D019204:GTP-Binding Proteins / Q000502:physiology; D006160:Guanosine Triphosphate / Q000502:physiology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D011976:Receptors, Muscarinic / Q000502:physiology
D000067956:Adenylyl Cyclase Inhibitors; D011976:Receptors, Muscarinic; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D006160:Guanosine Triphosphate; D002217:Carbachol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol