Effect of Sildenafil on Reperfusion Function, Infarct Size, and Cyclic Nucleotide Levels in the Isolated Rat Heart Model

Abstract

We have previously shown that NO-donor induced elevation in myocardial cGMP levels is associated with improved reperfusion function of the isolated rat heart. The phosphodiesterase 5 (PDE 5) inhibitor, sildenafil could potentially increase myocardial cGMP levels and thus protect the heart against ischaemic/reperfusion injury. Methods: To test our hypothesis we treated the isolated working rat heart with vehicle, OR sildenafil (10, 20, 50, 100, 200 nM), OR sildenafil (50 nM) plus a sarcolemmal (HMR 1098) or a mitochondrial (5-Hydroxydecanoate (5-HD)) K_ATP channel blocker. Hearts were then subjected to 20 min global, or 35 min regional ischaemia at 37^∘C before reperfusion function (aortic output, coronary flow and aortic pressure) and infarct size were documented. Pre-ischaemic, ischaemic and reperfusion myocardial cAMP and cGMP concentrations were determined. Results: Low concentrations of sildenafil (10, 20 and 50 nM) improved reperfusion aortic output (AO) recovery (61.4± 4.5%, 64.8 ± 5.2% and 62.3 ± 5.0% vs. 45.4 ± 3.8% for controls (p < 0.05)) and infarct size, while high concentrations (200 nM) worsened AO recovery (24.9 ± 4.9.0%, p < 0.05). Myocardial cGMP levels of ischaemic tissue were elevated (34.7 ± 2.4 vs. 27.3 ± 2.2 pmol/g ww) and cAMP levels were suppressed (0.59 ± 0.03 vs. 0.87 ± 0.06 nmol/g ww) in the sildenafil (50 nM) treated hearts. Co-perfusion with sildenafil plus HMR 1098 decreased AO recovery (21.7 ± 7.6% vs. 62.3 ± 5.0% for sildenafil alone, p < 0.05) and increased infarct size (29.7 ± 2.04% vs. 8.6 ± 2.39% for sildenafil alone, p < 0.05).Similarly, sildenafil plus 5-HD decreased reperfusion AO recovery (44.4 ± 6.0% vs. 62.3 ± 5.0% for sildenafil alone, p < 0.05) and increased infarct size (33.8 ± 1.62% vs. 8.6 ± 2.39% for sildenafil alone, p < 0.05). Conclusions: (1) Pretreatment with low concentrations of sildenafil (20–50 nM) improves, while higher concentrations (200 nM) worsen reperfusion function in this model. (2) Low concentrations of sildenafil (20–50 nM) decrease infarct size while the higher concentrations had no effect. (3) These protective properties of low concentrations of sildenafil may be related to its cGMP elevating and cAMP suppressing effects in the ischaemic heart. (4) Possible end-effectors for sildenafil in the ischaemic heart include the mitochondrial and sarcolemmal K_ATP channel.