Arrhythmogenic effects of selective inhibition of cyclic nucleotide phosphodiesterase isoenzymes in pig myocardium

Background: Regional accumulation of myocardial cyclic AMP may play a role in the genesis of ventricular arrhythmias. Myocardial levels of cAMP are regulated by the activities of adenylyl cyclase and at least four cyclic nucleotide phosphodiesterase (PDE) isoenzymes, suggesting that both activation of adenylyl cyclase or inhibition of PDEs could be arrhythmogenic. Goal: The present experiments were designed to examine the effects of selective and non-selective inhibitors of PDE isoenzymes on heart rhythm in pigs. Methods: The inhibitors were tested by local intramyocardial infusion (20 µ1/min) with or without coinfusion of known activators of adenylyl cyclase (noradrenaline). Epicardial electrocardiogram and aortic blood pressure were recorded. Results: Intramyocardial infusion of noradrenaline (10−6 M) precipitated ventricular tachycardia within 60–90 s after start of the infusion (up to 95% efficacy). Likewise, infusion of milrinone or piroximone (i.e., selective inhibitors of the low Km cGMP-inhibited PDE III) (≥ 10−4 M) produced local pacemaking activity within 3 min The tachycardia could be maintained for more than 10 min by continuous infusion and was readily reversed by stopping the infusion. The order of potency of compounds was milrinone = piroximone»enoximone (measured at 5 · 10−4 M). The maximal frequency of VT induction was 57% (milrinone), 50% (piroximone), and 13% (enoximone). The PDE IV inhibitor rolipram had relatively weak arrhythmogenic effects (7%). The effects of nonselective PDE inhibitors were variable. While VT was induced infrequently by papaverine (up to 17%), it could not be induced by infusing theophylline (up to 10−2 M tested). Coinfusion of noradrenaline and PDE III inhibitors did not facilitate the induction of local pacemaking activity by the catecholamine (only enoximone and piroximone tested). Conclusion: The present data suggest that isozyme selective PDE inhibitors have variable arrhythmogenic effects; the strongest effects are seen with selective PDE III inhibitors (milrinone, piroximone), when infused at a concentration that causes half-maximal inhibition of the PDE III isoenzyme in vitro. The observed arrhythmogenic effects of PDE III inhibitors appear to be mediated by cAMP.