Rationale: Occurrence of diastolic Ca2+ waves in cardiac myocytes leads to arrhythmias by inducing delayed after-depolarisations. Waves are initiated when sarcoplasmic reticulum (SR) content reaches a critical threshold level. The phosphodiesterase-5 inhibitor sildenafil (Sil) is antiarrhythmic in mammalian myocardial ischaemia models, while Sil reduces Ca2+ transient amplitude and sarcoplasmic reticulum (SR) Ca2+ content in rat myocytes. Objective: To determine effects of Sil on propensity to Ca2?+ waves in the large mammal. Methods: Sheep ventricular myocytes were voltage clamped and intracellular Ca2+ measured using Fura-2. Cells were paced at 0.5 Hz with depolarisations from −40 mV to+10 mV. When at steady state, waves were induced with 10–15 mM Ca2+. Upon regular waving, Sil (1µM) was applied. To determine threshold SR content, caffeine (10 mM) was added immediately following a wave, and both wave and caffeine-induced INCX integrated. Differences between groups were determined using students paired t tests. Results: Increasing external Ca2+ to 10–15 mM increased SR content and induced diastolic waves. Sildenafil abolished waves in 9/15 cells. In cells where Sil terminated waves, SR content was reduced below threshold. In addition, Sil treatment was associated with a reduced rate constant of SERCA (kSERCA−66.0±9.9% of control, p Conclusions: Sildenafil suppresses waves induced by elevated external Ca2+ via a PKG-dependent mechanism, and mediated by a reduction in SR content, which itself is caused by reduced SERCA function ± reduced ICa-L. These findings highlight novel antiarrhythmic properties of PDE5 inhibition and translate to suppression of triggered arrhythmias in vivo. Funding: British Heart Foundation.