Hepatoprotective effect of endogenous nitric oxide during ischemia-reperfusion in the rat

The aim of this study was to evaluate the protective or deleterious effects of endogenous nitric oxide (NO) on liver cells during hepatic ischemia-rep erfusion (IR) in the rat. Injury to hepatocytes and endothelial cells was e valuated by determining cytolysis-marker activity in plasma (alanine transa minase [ALT]; aspartate transaminase [AST]) and plasma hyaluronic acid (HA) concentration. Clamping the hepatic pedicle for 45 minutes caused a signif icant increase in plasma AST and ALT activity after 30 minutes of reperfusi on, which reached a maximum (+270% and +740%, respectively) after 6 hours o f reperfusion. Plasma HA concentration was significantly higher (+130%) onl y after 6 hours of reperfusion. Administration of a nonselective NO synthas e (NOS) inhibitor, N omega-nitro-L-arginine (L-NNA; 10 mg/kg iv), 30 minute s before IR, caused marked aggravation of postischemic liver injury, as sho wn by plasma ALT and AST activity and HA concentration. This deleterious ef fect was partially prevented by the simultaneous injection of L-arginine, t he endogenous NO precursor (100 mg/kg iv). interestingly L-arginine alone l imited postischemic damage (AST, -25%; ALT, -45%; HA, -21% vs, untreated IR rats at 6 hours reperfusion). Pretreatment with the Guanosine 3':5'-cyclic monophosphate-independent vasodilator, prazosin, partially reversed L-NNA effects, but it did not protect untreated IR animals. Pretreatment with ami noguanidine, a selective inhibitor of inducible NOS, did not aggravate hepa tic IR injury, Thus, endogenous NO, probably produced by an early and trans ient activation of a constitutive NOS, protects both hepatocytes and endoth elial cells against liver ischemia-reperfusion injury, and this effect is n ot entirely a result of vasorelaxation.