Inducible nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites

Background: Overexpression of inducible nitric oxide synthase (iNOS) and increased nitric oxide generation may be associated with the hyperdynamic circulation of patients with cirrhosis. We have, for the first time, used the highly selective iNOS inhibitor, 1400W, to determine whether iNOS activity contributes to the regulation of vascular tone in patients with cirrhosis and ascites. Methods: Bilateral forearm blood flow was measured using strain gauge plethysmography in eight patients with cirrhosis and ascites, and eight matched healthy volunteers during intrabrachial infusion of 1400W (0.1-1 mu mol/min), N-G-monomethyl-L-arginine (L-NMMA, a non-selective NOS inhibitor; 2 8 mu mol), and norepinephrine (a control vasoconstrictor; 60-480 mu mol/min). Results: In patients with cirrhosis, 1400W, L-NMMA, and norepinephrine caused dose dependent reductions in forearm blood flow: peak reductions of 11 (5)%, 37 (4)%, and 48 (5)%, respectively (p < 0.05 for all). In contrast, 1400W had no effect on blood flow (+4 (8)%; NS) in healthy controls despite similar reductions in blood flow with L-NMMA and norepinephrine (39 (5)% and 49 (5)%, respectively; p < 0.05 for both). Conclusions: We have, for the first time, demonstrated that 1400W causes peripheral vasoconstriction in patients with cirrhosis but not healthy matched controls. This suggests that iNOS contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites, and may contribute towards the hyperdynamic circulation associated with this condition.