INDUCTION AND ROLE OF NO SYNTHASE IN HYPOTENSIVE HEPATIC-FAILURE

Nitric oxide (NO) plays an important role in the physiological and pat hophysiological control of the vascular system. NO is synthesized by i soforms of the enzyme NO synthase (NOS). Hepatic failure is complicate d by hypotension, low systemic vascular resistance, and resistance to vasoconstrictor drugs. The potential role of NO in these abnormalities was investigated by using in vitro pharmacological interventions on h epatic arteries obtained from both donor and recipient patients at the time of liver transplantation. The presence of NOS mRNA was investiga ted by reverse transcription polymerase chain reaction (RT-PCR) with p rimers designed from human endothelial NOS (eNOS) and inducible NOS (i NOS) cDNA sequences. Arteries from patients with hepatic failure had a n impaired constrictor response to phenylephrine compared with those o f donor arteries. The constrictor effect of phenylephrine was potentia ted by N-G-monomethyl-L-arginine, an inhibitor of NOS, which had no ef fect in donor control arteries. RT-PCR identified human eNOS mRNA in d onor and recipient arteries and human iNOS mRNA in recipient arteries only. Induction of NOS in the vasculature with subsequent NO-induced v asodilatation may therefore contribute to the hemodynamic abnormalitie s observed in hepatic failure and potentially in other pathologies ass ociated with endotoxemia. Whether selective inhibitors of iNOS will im prove hemodynamic control or clinical outcome in these conditions requ ires further study.