mesenteric endothelial NO is unchanged or possibly di-The contribution of nitric oxide to mesenteric arterial minished. (HEPATOLOGY 1996;23:130-136.) vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n Å 6). Age-matched (n Å 9) and phenobarbitone-treated rats (n Å 9)
The hemodynamics of advanced cirrhosis are characserved as controls. Responses to the endothelium-depenterized by raised portal pressure, diminished hepatic dent dilators acetylcholine and adenosine 5-triphosportal blood flow, and an extrahepatic collateral phate (ATP) and the smooth muscle dilator (NO donor) splanchnic venous network supplied by a hyperdysodium nitroprusside were investigated after tone was namic mesenteric circulation. 1 Mesenteric vasodilataraised by continuous infusion of methoxamine, before tion is believed to be primarily responsible for the low and during infusion of the NO synthesis inhibitor N Gperipheral vascular resistance of decompensated liver nitro-L-arginine methyl ester (L-NAME; 30 mmol/L) disease, but the mechanism is unknown. Increased lev-{ L-arginine (1 mmol/L). A significant hyporesponels of circulating vasodilators such as glucagon, prostasiveness to methoxamine infusion in cirrhotic preparations (P õ .05) was not fully corrected by L-NAME. There cyclin, adenosine, and atrial natriuretic peptide have was no difference in the percentage vasodilator rebeen implicated, but there is limited evidence to supsponse to acetylcholine in the cirrhotic group compared port their role. 2 with controls; L-NAME significantly and reversibly in-
The hypothesis proposing that endotoxemia associhibited the dilator response in all groups. ATP elicited ated with cirrhosis induces vascular nitric oxide syndose-dependent vasodilatation that, in the absence of Lthase, leading to increased NO synthesis and vasodila-NAME, did not differ between the groups. By contrast, tation, 3 generated a considerable research effort, which in the presence of L-NAME, ATP (5 1 10 08 mol) produced obtained substantial early supportive evidence in anipronounced, reversible vasoconstriction only in cirmal experiments. Inhibitors of NO synthesis reversed rhotic animals (P õ .02). Vasodilatation attributable to the mesenteric or systemic hyporesponsiveness of porsodium nitroprusside (5 1 10 08 mol) was significantly attenuated in cirrhotic rats. The methoxamine data sup-tal hypertensive animals to vasoconstriction induced port the concept of mesenteric hyposensitivity to vasoby methoxamine, noradrenaline, or vasopressin. [4][5][6] NO constrictor agents in cirrhosis that may be at least partly inhibition also reversed systemic and splanchnic vaso-NO mediated. Increased NO activity in smooth muscle dilatation in cirrhotic rats 7 and in rats with portal hyleading to decreased guanylate cyclase availability may pertension induced by partial portal vein ligation. 8 In account for the diminished vasodilator responses to soaddition, cirrhotic rats had enhanced sensitivity to the dium nitroprusside in cirrhotic preparations. The unpressor effect of inhibitors of NO. 9 More recently, the changed responsiveness to vasodilatation by acetylchomesenteric vascular bed of cirrhotic rats has been line (ACh) and the vasoconstriction to ATP observed shown to be hyporesponsive to vasoconstriction by KCl, during NO blockade in cirrhotic animals indicate that an effect partly attributable to NO, 10 while an impaired pressor response to angiotensin II in isolated aortic rings from cirrhotic rats was associated with increased Abbreviations: ACh, acetylcholine; ATP, adenosine 5-triphosphate; SNP, endothelial NO activity. 11 sodium nitroprusside; L-NAME, N G -nitro-L-arginine methyl ester.
The observation that cirrhotic patients with endotox-From the Departments of 1 Surgery and 2 Clinical Pharmacology, Royal Postemia had increased plasma nitrite and nitrate further