PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca2+Content

Abstract

Rationale: PDE5 (phosphodiesterase 5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms of the antiarrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca2+) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca2+waves are initiated when sarcoplasmic reticulum (SR) Ca2+content reaches a threshold level and the SR releases Ca2+spontaneously and generates a depolarizing inward sodium-calcium exchange current. Objective: To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a proarrhythmic large animal model and establish the role of alterations of intracellular Ca2+cycling/SR Ca2+content. Methods and Results: Arrhythmia burden, monophasic action potentials, and beat-to-beat variability of repolarization were measured in a sheep model using the IKr inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca2+transients, Ca2+waves, and SR Ca2+content were measured in isolated ventricular myocytes. PDE5 inhibition was achieved using acute application of sildenafil, and PKG (protein kinase G) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed afterdepolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced delayed afterdepolarizations and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca2+wave frequency in all cells and abolished waves in 12 of 22 cells. A decrease in SR Ca2+uptake, increased trans-sarcolemmal Ca2+efflux, and reduced trans-sarcolemmal Ca2+influx led to a reduction of SR Ca2+content and Ca2+wave abolition. These effects were dependent on PKG activation. Conclusions: PDE5 inhibition acutely suppresses triggered ventricular arrhythmias in vivo, and cellular data suggests this occurs via suppression of cellular Ca2+waves. These novel antiarrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca2+content and are PKG dependent.