Combination of the Phosphodiesterase-Inhibitors Sildenafil and Milrinone Induces Cardioprotection with Various Conditioning Strategies.

Ischemic preconditioning and postconditioning are strong measures preserving the heart against ischemia reperfusion injury in experimental setting but are too invasive and impractical for clinical routine. The cardioprotective effects of ischemic pre- and postconditioning can be imitated pharmacologically, e.g. with the phosphodiesterase inhibitors sildenafil and milrinone. We hypothesize that sildenafil-induced preconditioning is concentration-dependent and further that a combined treatment of 'non-protective' versus 'protective' concentrations of sildenafil and milrinone leads to a significant infarct size reduction. Experiments were performed on isolated hearts of male Wistar rats, randomized into 12 groups, mounted onto a Langendorff system and perfused with Krebs-Henseleit buffer. All hearts underwent 33 min ischemia and 60 min of reperfusion. For determination of a concentration-dependent effect of sildenafil, hearts were perfused with increasing concentrations of sildenafil (0.1-1 µM) over 10 min prior ischemia. In a second series of experiments, hearts were treated with 0.3 µM sildenafil or 1 µM milrinone as the 'protective' concentrations. A higher concentration of respective drugs did not further reduce infarct size. Additionally, a combination of 'protective' and 'non-protective' concentrations of sildenafil and milrinone was applied. Sildenafil and milrinone in lower concentrations led to significant infarct size reduction whereas combining both substances in cardioprotective concentrations did not enhance this effect. Sildenafil in a concentration of 0.3 µM induces myocardial protection. Further, treatment with sildenafil and milrinone in lower concentrations had an equally as strong cardioprotective effect regarding infarct size reduction compared to the administration of 'protective' concentrations.