PDE5 inhibition suppresses ventricular arrhythmias by reducing SR Ca2+ content

Rationale: Phosphodiesterase-5 (PDE5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms of the anti-arrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca2+) waves lead to arrhythmias by inducing delayed after-depolarizations. 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 (NCX) current.

Objective: To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a pro-arrhythmic 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 protein kinase G (PKG) was inhibited with KT5823.
PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed after-depolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced DADs and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca2+ wave frequency in all cells and abolished waves in 12/22 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 anti-arrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca2+ content and are PKG-dependent.