Increased nitric oxide synthase expression in aorta of cirrhotic rats

The characteristic cardiovascular changes in liver cirrhosis are vasodilata tion and increased cardiac output. Augmented activity of the vasorelaxant f actor, nitric oxide (NO), stimulated by cytokines, have been suggested to p lay a role in the pathogenesis, but previous studies show conflicting resul ts. We therefore aimed to evaluate the entire pathway from cytokines to the final metabolites, nitrate/nitrite. The levels of serum Tumor Necrosis Fac tor-alpha (TNF alpha) and nitrate/nitrite (NOx) were measured, and aorta co ntent of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) mRNA and protein were determined by reverse-transcription polymerase chain reac tion and Western blotting in rats with cirrhosis due to chronic bile duct l igation and sham-operated controls. Compared to control rats, serum TNF alp ha levels were significantly elevated in cirrhotic rats (48.4+/-21.1 vs 16. 8+/-9.0 pg/ml, p<0.01); iNOS mRNA was detectable whereas it was absent in c ontrols, and eNOS mRNA levels was significantly higher in aortae of cirrhot ic rats. Aortic eNOS protein content was significantly higher in cirrhotic rats, but iNOS protein was undetectable by Western blotting in both groups. Serum NOx concentrations in the cirrhotic group were significantly higher than those in controls (3.5+/-1.0 vs 2.3+/-0.5 mu M, p<0.01). These results suggest that NO activity in cirrhosis is increased, and is predominantly d ue to eNOS since the detectable iNOS mRNA does not seem to be expressed as protein. The increased NOS activity in the arterial system may play a role in the systemic hemodynamic changes occurring in cirrhosis.