Thorac Cardiovasc Surg 2011; 59 - eP22
DOI: 10.1055/s-0030-1268953

Protection by cinaciguat, a soluble guanylate cyclase activator against ischemia/reperfusion-induced injury in the transplanted rat heart

S Loganathan 1, S Korkmaz 1, E Barnucz 1, K Hirschberg 1, B Seidel 1, T Radovits 1, S Li 1, A Weymann 1, M Karck 1, G Szabó 1
  • 1Universität Heidelberg, Herzchirurgie, Heidelberg, Germany

Ischemia/reperfusion-injury (IRI) is one of the main limiting factors of cardiac surgery. We previously showed that upregulation of the cGMP-signaling has protective effects on cardiac tissue. In the present study, we investigated the effects of cinaciguat, an activator of the soluble guanylate cyclase (sGC), on IRI in a rat model of heterotopic heart transplantation. Additionally we examined the protective effects of cinaciguat on vascular function and on cardiomyocytes under nitro-oxidative stress.

Heterotopic heart transplantation was performed in Lewis rats pretreated orally with vehicle or cinaciguat. One hour after reperfusion left ventricular (LV) systolic pressure, maximal slope of the systolic pressure increment (dP/dtmax) and the diastolic pressure decrement (dP/dtmin) were evaluated. Myocardial ATP content was measured and gene expression analysis was performed by qPCR. The effects of cinaciguat on vasomotor function on isolated aortic rings exposed to peroxynitrite and on hydrogen peroxide induced cytotoxicity in cultured cardiomyocytes were investigated.

In the cinaciguat treated group, significantly higher LV systolic, dP/dtmax (mmHg/s, 3350±444 vs. 1740±116 in control) and dP/dtmin (mmHg/s, 1925±332 vs. 989±115 in control) were observed. Furthermore, cinaciguat restored cellular energy depletion shown by significantly increased ATP levels. Moreover, cinaciguat significantly increased (+68%) superoxide dismutase 1 and decreased (-73%) c-jun mRNA expression, enhanced the impaired endothelium dependent vasorelaxation, and reduced cardiomyocyte death.

Cinaciguat improves myocardial function by restoring myocardial high energy phosphates, reduction of nitro-oxidative stress, protection of sarcolemmal rupture and regulation of apoptotic signalling pathway. Cinaciguat could be a novel cardioprotective approach in cardiac transplantation.