Pre-conditioning with the soluble guanylate cyclase activator Cinaciguat reduces ischaemia-reperfusion injury after cardiopulmonary bypass.
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.
Radovits
Tamás
T
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. radovitstamas@yahoo.com
Korkmaz
Sevil
S
Miesel-Gröschel
Christiane
C
Seidel
Beatrice
B
Stasch
Johannes-Peter
JP
Merkely
Béla
B
Karck
Matthias
M
Szabó
Gábor
G
D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004789:Enzyme Activation; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D000071756:Soluble Guanylyl Cyclase; D046509:Tissue Culture Techniques; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
D001565:Benzoates; D002316:Cardiotonic Agents; D018160:Receptors, Cytoplasmic and Nuclear; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase