The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat

Abstract

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 ± 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 ± 121. Inclusion of epinephrine (1.0 μM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 ± 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 ± 86. Inclusion of forskolin (0.2 μM), which stimulates adenyl cyclase independently of the β-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 ± 0.9 nM/g dry weight before the onset of ischemia and to 8.2 ± 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increases in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls. Thus, no hearts fibrillated, the incidence of ventricular tachycardia was reduced to 58% (7/12), and the mean number of premature ventricular complexes was greatly reduced (79 ± 29, P<0.001 compared to the number with drug carrier alone). Higher concentrations of both epinephrine and forskolin caused changes that were qualitatively similar to those seen with the lower concentrations. In addition, when hearts were paced at 400 impulses/min, again only epinephrine increased the severity of ischemia-induced arrhythmias. In conclusion, despite its ability to increase cyclic adenosine monophosphate content to a greater extent than epinephrine, forskolin exerts an antiarrhythmic effect. This suggests that increased cyclic adenosine monophosphate content is not necessarily involved in the genesis of ischemia-induced arrhythmias, and that some other facet of adrenoceptor stimulation or catecholamine action may be involved.