Gastroprotective Action of Adiponectin Against Gastric Mucosal Injury Induced by Ischemia and Reperfusion-Involvement of Nitric Oxide, Sensory Afferent Nerves, and Anti-Inflammatory Mediators.

Adiponectin is adipokine exhibiting beneficial metabolic action through lipid and carbohydrate metabolism stimulation, as well as anti-inflammatory action. We have determined the role of adiponectin in gastroprotection against the formation of acute gastric lesions induced by ischemia-reperfusion (I/R). Gastric lesions evoked by I/R are a serious clinical entity; however, the participation of reactive oxygen species (ROS) and lipid peroxidation products and the involvement of nitric oxide (NO), neuropeptides released from sensory afferent nerves, and the hormone gastrin in the potential gastroprotective action of adiponectin remains unknown. Therefore, we determined the interplay between capsaicin-sensitive afferent nerves, the NO/NOS system, lipid peroxidation products, and the expression of pro-inflammatory and antioxidative factors in the gastroprotective action of adiponectin against gastric I/R. injury. Wistar rats was administered with adiponectin in graded doses (1-40 μg/kg i.v.) with or without: (a) blockade of nitric oxide (NO) activity by L-nitro-L-arginine (L-NNA) and (b) deactivation of sensory nerves by capsaicin (125 mg/kg s.c. 10 days before experiment conduction). They were then exposed to 30 min of ischemia by clamping of the celiac artery followed by 3 h of reperfusion after clamp release. After 3 h, the rats were euthanized with pentobarbital and their gastric blood flow (GBF) was determined by laser Doppler flowmetry, their blood was withdrawn to assess plasma gastrin levels, and the area of gastric lesions was measured by planimetry. Gastric biopsy samples were excised to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). In separate groups of animals with chronic gastric fistula, the effect of adiponectin on gastric acid secretion was determined. Adiponectin dose-dependently reduced the gastric lesions induced by I/R and this effect was accompanied by an increase in GBF. Blockade of NO-synthase with L-NNA (20 mg/kg i.p.) reversed the protective effect and the rise in GBF induced by this adipokine, and both these effects were restored when L-arginine was added to L-NNA. Capsaicin denervation also impeded the beneficial action of adiponectin in rats, but these effects were in part restored when exogenous CGRP was combined with adiponectin. Adiponectin dose-dependently decreased gastric acid secretion, the expression of mRNA for pro-inflammatory cytokines, and MDA plus 4-HNE content, while significantly increasing SOD, GSH and plasma gastrin increments. We conclude that adiponectin exerts gastroprotection against I/R-induced gastric lesions, through mechanisms involving NO and neuropeptides such as CGRP being released from sensory nerves, a decrease in lipid peroxidation (MDA+4-HNE), an increase of antioxidative factors (SOD, GSH), and the inhibition of gastric acid secretion.