Role of nitric oxide in hepatic ischemia-reperfusion injury

Table 1 Effect of endogenous nitric oxide and nitric oxide synthase on liver ischemia-reperfusion injury

Species	Experimental methods	Ischemic time (min)	NO or NOS effects	Ref.
Pigs	Aminoguanidine, 5 min before ischemia	120	NO derived from iNOS, antioxidant	[25]
Dogs	FK 409, 30 min before ischemia and15 min before and 45 min after reperfusion	60	NO, improves hepatic microcirculation	[34]
Rats	L-arginine, 7 d before IRI	60	NO, antioxidant	[35]
Rats	L-NAME 60 min before ischemia	30	NO, antioxidant	[3]
Mouse	Gadolinium chloride 24 h before ischemia	45	NO derived from eNOS, antioxidant, suppresses Kupffer cell function, regulated basal hepatic blood flow, but did not affect blood flow after reperfusion, attenuated neutrophils infiltration	[21]
	L-NAME methyl ester 15 min prior to ischemia
Rats	L-arginine or Sodium nitroprusside or L-Name prior to ischemia	60	NO, improves peripheral liver blood flow after reperfusion, cytoprotective	[36]
Male rats	Arginine or L-NAME or 8-bromo guanosine 3′5′-cyclic monophosphate or rat atrial natriuretic peptide (ANP 1-28) 30 min before ischemia	45	NO, antioxidant, antiproinflammatory cytokines, improves microcirculation by the cGMP pathway, inhibits neutrophil infiltration and platelet aggregation	[37]
Male rats	IRI group: had partial clamping of portal vein and hepatic artery	90	iNOS expression peaked at 3 h and diminished at 24 h post reperfusion in IRI and ONO-1714 groups	[31]
	ONO-1714 group: as above plus ONO-1714 just prior to reperfusion and 6 h thereafter		ONO-1714 significantly inhibited plasma nitrates at 24 h post reperfusion
	Control group: sham operation		ONO-1714 significantly inhibited plasma ALT at 12 h post reperfusion, together with inhibiting histological damage and peroxynitrate expression in liver
Male rats	Microvessel clamping of portal vein and left hepatic artery L-NAME and AE-ITU given to each of 6 rats exposed to microvessel clamping (time unknown)	60	L-NAME worsened, elevated levels of ALT/AST in IRI groups	[32]
			AE-ITU mildly and significantly decreased levels of AST
Male rats	Portal vein, hepatic artery and bile ducts clamped by microvessel clamp followed by reperfusion	60	Significant elevation of AST/ALT, MDA/SOD in IRI and small-for-size liver transplantation groups	[33]

NO: Nitric oxide; NOS: Nitric oxide synthase; iNOS: Inducible nitric oxide synthase; eNOS: Endothelium-derived nitric oxide synthase; cGMP: Cyclic guanosine monophosphate; L-NAME: L-nitroarginine; ANP: Atrial natriuretic peptide; IRI: Ischemia-reperfusion injury; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; AE-ITU: Aminoethyl-isothiourea; MDA: Malondialdehyde; SOD: Superoxide dismutase.

Table 2 Nitric oxide donors

Model	Drugs	Outcomes	Ref.
Canine liver IRI	FK-409	Promoted hepatic tissue blood flow, decreased serum endothelin-1, cytoprotection	[34]
Isolated hepatocytes	S-nitroso-N-acetylpenicillamine	Drug induced the expression of heat shock protein 70 mRNA and protein resulting in cytoprotection from TNFα	[2]
Murine liver IRI	Sodium nitroprusside	Promotes hepatic tissue blood flow after reperfusion-cytoprotection	[36]
Murine liver IRI	PEG-poly SNO-BSA, a sustained release of NO	Decreased neutrophil accumulation, prevented the excessive production of iNOS	[54]
Murine liver IRI	Macromolecule S-nitrosothiols	Prevented hepatocellular injury	[55]

NO: Nitric oxide; SNO: S-nitrosothiol; iNOS: Inducible nitric oxide synthase; IRI: Ischemia-reperfusion injury; TNF: Tumor necrosis factor.