Abstract 14473: Targeting No-Unresponsive Soluble Guanylate Cyclase Improves Left Ventricular Graft Dysfunction After Heart Transplantation in Rats
Background: It is an established dogma that NO/soluble guanylate cyclase (sGC)/cyclic GMP pathway is an important key mechanism to protect the heart from ischemia/reperfusion (IR) injury. However this pathway is disrupted in several cardiovascular diseases as a result of a decreased NO bioavailability and increased NO-insensitive forms of sGC. Cinaciguat preferentially activates these NO-insensitive, oxidized forms of sGC. Based on the ability of cinaciguat to target NO-unresponsive sGC, we assessed its potential to protect the graft against IR injury in a rat heart transplantation model.
Methods: Prior to explantation the donor Lewis rats received methylcellulose (1%) vehicle (control group) or cinaciguat 10 mg/kg (treatment group). Then, the hearts were excised, stored in cold preservation solution for 1h, and heterotopically transplanted. We evaluated in vivo 1h after transplantation left ventricular (LV) function of the graft. Histopathology and myocardial gene expression were performed. Additionally, the effects of cinaciguat on hydrogen peroxide-induced cytotoxicity in cardiomyocytes were assessed.
Results: One hour after transplantation decreased LV systolic pressure (77±3 vs 123±13 mmHg; control vs treatment; p<0.05), dP/dtmax (1703±162 vs 3350±444 mmHg; control vs treatment; p<0.05) and dP/dtmin (995±110 vs 1925±332 mmHg; control vs treatment; p<0.05) were significantly increased by cinaciguat. After transplantation, coronary blood flow was significantly higher in the cinaciguat group compared with the control. Furthermore, cinaciguat increased ATP levels (1.9±0.4 vs 6.6±0.8 μmol/g; control vs treatment; p<0.05) and improved energy charge potential. After transplantation increased c-jun mRNA expression was downregulated, whereas decreased superoxide dismutase 1 and cytochrome c oxidase mRNA levels were upregulated by cinaciguat. Moreover, cinaciguat significantly decreased myocardial DNA strand breaks induced by IR during transplantation and reduced cardiomyocytes death in a cellular model of oxidative stress.
Conclusions: Targeting NO-unresponsive sGC can attenuate myocardial injury after global myocardial IR. Its clinical use as a precondiotioning agent could be a novel approach in cardiac surgery.
- © 2013 by American Heart Association, Inc.