PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca <sup>2+</sup> Content
David Hutchings, Charles M. Pearman, George Madders, Lori S. Woods, David Eisner, Katharine M. Dibb, Andrew W. Trafford
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 (Ca 2+ ) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca 2+ waves are initiated when sarcoplasmic reticulum (SR) Ca 2+ content reaches a threshold level and the SR releases Ca 2+ 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 Ca 2+ cycling/SR Ca 2+ content. Methods and Results: Arrhythmia burden, monophasic action potentials, and beat-to-beat variability of repolarization were measured in a sheep model using the I Kr inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca 2+ transients, Ca 2+ waves, and SR Ca 2+ 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 Ca 2+ wave frequency in all cells and abolished waves in 12 of 22 cells. A decrease in SR Ca 2+ uptake, increased trans-sarcolemmal Ca 2+ efflux, and reduced trans-sarcolemmal Ca 2+ influx led to a reduction of SR Ca 2+ content and Ca 2+ 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 Ca 2+ waves. These novel antiarrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca 2+ content and are PKG dependent.