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Vardenafil protects against myocardial and endothelial injuries after cardiopulmonary bypass

^a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
^b Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary
^c Bayer HealthCare, Wuppertal, Germany

Received 10 September 2008; received in revised form 4 March 2009; accepted 10 March 2009.

^_* Corresponding author. Address: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326 OG.2, 69120 Heidelberg, Germany. Tel.: +49 6221 566246; fax: +49 6221 564571. (Email: dzsi{at}hotmail.com).

Objectives: Phosphodiesterase-5 inhibitors and elevated myocardial cyclic guanosine monophosphate levels can induce potent cardioprotection-like effects against ischaemia–reperfusion injury. We investigated the effects of vardenafil, a selective phosphodiesterase-5 inhibitor on myocardial and endothelial functions during reperfusion in a canine model of cardioplegic arrest and extracorporal circulation. Methods: Vehicle-treated (control, n = 8) and vardenafil-treated (30 µg kg^–1 intravenous (IV); n = 8) anaesthetised dogs underwent hypothermic cardiopulmonary bypass with 60 min of hypothermic cardiac arrest. Left and right ventricular end-systolic pressure volume relationship (E _es) was measured by a combined pressure–volume conductance catheter at baseline and after 60 min of reperfusion. Left anterior descending coronary blood flow and endothelium-dependent vasodilatation to acetylcholine were determined. Isolated coronary arterial rings were investigated for vasomotor function using an in vitro organ bath system. Results: Pharmacological preconditioning with vardenafil led to significantly higher plasma cyclic guanosine monophosphate levels and myocardial adenosine triphosphate content to a better recovery of left and right ventricular E _es ( left ventricular E _es given as percent of baseline: 74.2 ± 4.5% vs 50.4 ± 5.0%, p < 0.05) and to a higher coronary blood flow (58 ± 12 vs 24 ± 7 ml min^–1, p < 0.05). Endothelium-dependent vasodilatory responses to acetylcholine – measured both in vivo and in vitro – were improved in the vardenafil group. Conclusions: Application of vardenafil improves myocardial and endothelial functions after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects imply that phosphodiesterase-5 inhibition could be a novel therapeutic option in the protection against ischaemia–reperfusion injury in cardiac surgery.

Key Words: Cardiopulmonary bypass • Ischaemia–reperfusion • Contractility • Endothelium • Vardenafil