Pre-conditioning with the soluble guanylate cyclase activator Cinaciguat reduces ischaemia–reperfusion injury after cardiopulmonary bypass

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• 作者：Tamá ; s Radovits^a ; ^b ; ¹ ; ^{radovitstamas@yahoo.com} ; Sevil Korkmaz^a ; ¹ ; Christiane Miesel-Gr&#xf6 ; schel^a ; Beatrice Seidel^a ; Johannes-Peter Stasch^c ; Bé ; la Merkely^b ; Matthias Karck^a ; Gá ; bor Szabó ; ^a
• 关键词：Cardiopulmonary bypass ; Ischaemia– ; reperfusion ; Myocardial protection ; Pharmacological pre-conditioning
• 刊名：European Journal of Cardio-Thoracic Surgery
• 出版年：2011
• 出版时间：February 2011
• 年：2011
• 卷：39
• 期：2
• 页码：248-255
• 全文大小：411 K

文摘

Objective: Activation of the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) pathway can induce potent cardioprotection-like effects against ischaemia–reperfusion injury and nitro-oxidative stress. We investigated the effects of pharmacological pre-conditioning with Cinaciguat (BAY 58-2667), a novel sGC activator on peroxynitrite-induced endothelial dysfunction in vitro, as well as on myocardial and coronary vascular function during reperfusion in a canine model of cardioplegic arrest and extracorporeal circulation. Methods: Isolated coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function. Vehicle- and Cinaciguat-pre-treated (8.33 μg h⁻¹ or 25 μg h⁻¹ intravenous (IV) for 30 min) anaesthetised dogs (n = 6–7 per group) underwent hypothermic cardiopulmonary bypass with 60 min of hypothermic cardioplegic arrest. Left- and right-ventricular end-systolic pressure–volume relationship (ESPVR) was measured by a pressure–volume conductance catheter at baseline and after 60 min of reperfusion. Coronary blood flow, vasodilatation to acetylcholine and myocardial level of adenosine triphosphate were determined. Results: Pre-incubation of coronary rings with Cinaciguat improved peroxynitrite-induced endothelial dysfunction. Compared with control, pharmacological pre-conditioning with Cinaciguat (25 μg h⁻¹) led to higher myocardial adenosine triphosphate content, to a better recovery of left- and right-ventricular contractility (Δ slope of left ventricular ESPVR given as percent of baseline: 102.4 ± 19.1 % vs 56.0 ± 7.1 % ) and to a higher coronary blood flow (49.6 ± 3.5 ml min⁻¹ vs 28.0 ± 3.9 ml min⁻¹). Endothelium-dependent vasodilatation to acetylcholine was improved in the treatment groups. Conclusions: Pre-conditioning with Cinaciguat improves myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects imply that pharmacological sGC activation could be a novel therapeutic option in the protection against ischaemia–reperfusion injury in cardiac surgery.