The Hepatic Soluble Guanylyl Cyclase-Cyclic Guanosine Monophosphate Pathway Mediates the Protection of Remote Ischemic Preconditioning on the Microcirculation in Liver Ischemia-Reperfusion Injury

Background. Remote ischemic preconditioning (RIPC) protects against liver ischemia reperfusion (IR) injury. An essential circulating mediator of this protection is nitric oxide (NO) induced by lower limb RIPC. One of the mechanisms through which NO generally acts is the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP) pathway. The present study aimed to assess the role of hepatic sGC-cGMP in lower limb RIPC-induced protection against liver IR injury. Methods. Mice were allocated to 4 groups: 1. Sham; 2. IR: 40 min of lobar hepatic ischemia and 2 hr reperfusion; 3. RIPC+IR: 6 cycles of 4x4 min IR of the lower limb followed by IR group procedure; (4) 1H-[1,2,4] oxadiazole[4,3-a] quinoxalin-1-one (ODQ)+RIPC+IR: ODQ (sGC inhibitor) was administered followed by RIPC+IR group procedure. Hepatic microcirculatory blood flow (MBF) was measured throughout the experiment. Plasma transaminases, hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic cGMP levels were measured in groups 1-3 in addition to an RIPC alone group. Results. Compared to liver IR alone, RIPC+IR increased hepatic MBF during liver reperfusion (P<0.05), and reduced plasma transaminases (P<0.05) and ultrastructural markers of injury. In contrast compared to RIPC+IR, ODQ+RIPC+IR decreased hepatic MBF (P<0.05) and ultrastructural markers of injury. However, plasma transaminases were not significantly different in the ODQ+RIPC+IR compared to the RIPC+IR group. Hepatic cGMP levels were significantly elevated in the RIPC compared to sham group. Conclusions. The hepatic sGC-cGMP pathway is required for mediating the protective effects of lower limb RIPC on hepatic MBF in liver IR injury.