Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model

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 degrees 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.