Pharmacological Activation of Soluble Guanylate Cyclase Improves Vascular Graft Function

Objectives: Oxidative stress interferes with nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway through reduction of endogenous NO and formation of peroxynitrite and leads to vascular dysfunction. We assessed the hypothesis that the sGC activator cinaciguat would protect vascular graft against IR injury in the vessel wall of the bypass graft.

Methods: Lewis rats (n = 6–8/group) were divided into three groups: group 1: control, group 2: donor rats received intravenous saline, and group 3: received intravenous cinaciguat (10 µg/kg) 2 hours before explantation. Although aortic arches of group 1 were immediately mounted in organ bath, aortic segments of groups 2 and 3 were stored for 2 hours in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium-dependent and -independent vasorelaxations were investigated. TUNEL, CD-31, caspase-3, nitrotyrosine immunochemistry were also performed.

Results: Compared with control, saline group showed significantly attenuated endothelium-dependent maximal relaxation (R_max) 2 hours after reperfusion, which was significantly improved by cinaciguat supplementation (R_max control: 91 ±2 %, saline: 41 ± 2% vs. cinaciguat: 55 ± 2%, p < 0.05). Cinaciguat pretreatment significantly reduced DNA fragmentation, nitro-oxidative stress, decreased caspase-3 score. The marker for endothelial integrity (CD-31) was also higher in the cinaciguat group.

Conclusion: Our results support the view that impairment of the intracellular cGMP signaling plays a role in the pathogenesis of the endothelial dysfunction of arterial graft after bypass surgery, which can effectively be prevented by cinaciguat. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery.