NITRIC-OXIDE CAUSES HYPOREACTIVITY TO PHENYLEPHRINE IN ISOLATED-PERFUSED LIVERS FROM ENDOTOXIN-TREATED RATS

Systemic vascular hyporeactivity to vasoconstrictors has been describe d in rats following endotoxin administration. Inducible nitric oxide s ynthase (iNOS) expression is known to occur in the liver in endotoxemi a, but consequences of iNOS induction on hepatic hemodynamics are unkn own. The reactivity of the hepatic circulation to phenylephrine was te sted in perfused livers from normal rats and rats previously injected with endotoxin (20 mg/kg ip). In control rats (n = 5), phenylephrine-i nduced portal pressure increases were similar in livers perfused with Krebs-Henseleit-bicarbonate (KHB) buffer, KHB plus the NOS inhibitor N -G-monomethyl-L-arginine (L-NMMA, 1 mM), or KHB plus the substrate for NO synthesis, L-arginine (1 mM). In contrast, livers from endotoxin-t reated rats (n = 5) exhibited a marked reduction in the vasoconstricti ve response to phenylephrine (14.6 vs. 55.1% in livers from control ra ts, P < 0.05). Perfusion with L-NMMA restored the phenylephrine respon se, and the L-NMMA effect was reversible with L-arginine. Perfusate NO 2-/NO3- and guanosine 3',5'-cyclic monophosphate (cGMP) levels were in creased in endotoxin-treated rats and significantly reduced by L-NMMA perfusion. In control livers, the NO donor S-nitroso-N-acetyl-DL-penic illamine blocked the portal pressure increase after phenylephrine admi nistration. These results suggest that rat hepatic circulation takes p art in the systemic vascular hyporeactivity to vasoconstrictors observ ed in endotoxemia and that NO is involved in this hyporeactivity to ph enylephrine.