Effect of interventions that increase cyclic AMP levels on susceptibility to ventricular fibrillation in unanesthetized dogs.
Although the autonomic nervous system has been implicated in the formation of ventricular fibrillation, the precise mechanism by which this is mediated remains undetermined. In particular, the role of second messengers, generated by beta-adrenoceptor activation, has been postulated to mediate the pro-arrhythmic effects of the sympathetic nervous system. Thus, a 2 min occlusion of the left circumflex coronary artery was initiated during the last minute of exercise in canines with healed myocardial infarctions (produced by ligation of left anterior descending artery). Fifteen dogs were found to be susceptible to the formation of ventricular fibrillation while 17 animals were resistant. Nine resistant dogs were treated with the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX, 1 mg/kg) in combination with an infusion of 8-bromo-cAMP (100-150 micrograms/kg/min beginning 45 min prior to exercise). Heart rate and left ventricular dP/dtmax significantly increased, but failed to elicit, arrhythmias during the exercise and ischemia test. Nine resistant animals were also treated with the adenylate cyclase activator forskolin, (100 micrograms/kg), which provoked the same hemodynamic changes as the cyclic AMP infusion but also failed to induce ventricular fibrillation. Both forskolin (n = 3) and IBMX (n = 3) induced large increases in myocardial cAMP levels (control 5.2 +/- 0.5, forskolin 8.1 +/- 0.8 pmol/mg non-collagen protein; control 5.0 +/- 0.8, IBMX 6.8 +/- 0.3 pmol/mg non-collagen protein). Ten resistant animals were treated with the beta-adrenoceptor agonist isoproterenol (1-10 micrograms/kg/min), which failed to cause ventricular fibrillation despite significant increases in the hemodynamic parameters described above. Finally, experiments were repeated after 8-bromo-cAMP infusion and IBMX pretreatment in 8 susceptible animals with pharmacologic denervation (atropine+propranolol+prazosin). In spite of hemodynamic increases indicative of an increase in myocardial cyclic AMP levels, arrhythmias were not re-introduced. These data suggest that changes in cAMP may not be responsible for ventricular fibrillation in this model of sudden cardiac death.
Avendano
C E
CE
Department of Physiology, Ohio State University, Columbus 43210.
Billman
G E
GE
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009203:Myocardial Infarction / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000503:physiopathology*
D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine