COMPARISON OF VASCULAR NITRIC-OXIDE PRODUCTION AND SYSTEMIC HEMODYNAMICS IN CIRRHOSIS VERSUS PREHEPATIC PORTAL-HYPERTENSION IN RATS

Nitric oxide (NO) is postulated to play a role in the pathogenesis of arterial vasodilation in chronic portal hypertension. This present stu dy investigates the relationship between systemic hemodynamics and the vascular production of NO, as estimated by measuring cyclic guanosine monophosphate (cGMP) in aortic tissue in two models of chronic portal hypertension in the rat: the partial portal vein ligation (PVL) model and CCl4-induced cirrhosis. NOS was also examined by Western blotting in aortic and mesenteric vessels. Sham-operated rats and rats given p henobarbital were used as controls. PVL rats and rats with cirrhosis a nd ascites showed a typical pattern of a hyperdynamic circulatory stat e, when compared with their respective controls: mean arterial pressur e; PVL: 113 +/- 2 versus 124 +/- 2, P < .01 and cirrhotics: 103 +/- 5 versus 130 +/- 4 mm Hg, P < .01. Cardiac index; PVL: 32 +/- 2 versus 2 6 +/- 1, P < .01 and cirrhotics: 51 +/- 3 versus 30 +/- 1 mL . min(-1) . 100 gm(-1), P < .0001. Systemic vascular resistance; PVL: 3.7 +/- 0. 1 versus 4.9 +/- 0.2, P < .01 and cirrhotics: 2.1 +/- 0.2 versus 4.4 /- 0.2 mm Hg . min(-1). 100 g(-1), P < .0001. Aortic cGMP was markedly increased in cirrhotic rats with ascites (728 +/- 83 fmol/mg protein) as compared with phenobarbital-treated controls (244 +/- 31 fmol/mg, P < .001). This increase was abolished by chronic administration of N- omega-nitro-L-arginine methyl ester. By contrast, PVL rats had an aort ic cGMP concentration similar to sham-operated controls (282 +/- 16 fm ol/mg vs. 274 +/- 33 fmol/mg, P = not significant) and significantly l ower than that found in cirrhotic rats with ascites. Expression of cir rhotic aortic endothelial nitric oxide synthase (eNOS) was increased b ut PVL aortic eNOS did not differ from that of controls, whereas the m esenteric eNOS was increased in both PVL and cirrhotic rats as compare d with the controls. These resuits suggest that vascular NO production is higher in cirrhotic rats than in PVL rats. This increased producti on may contribute to the more marked abnormalities in systemic hemodyn amics seen in experimental cirrhosis as compared with PVL.