Cirrhosis serum induces a nitric oxide-associated vascular hyporeactivity of aortic segments from healthy rats in vitro

Objective Arterial vasodilation with concomitant hyperdynamic circulation a re common findings in liver cirrhosis. Nitric oxide acting at a local level has been suggested to be pathophysiologically relevant in this context. Se veral systemic factors in conjunction with nitric oxide might interfere wit h the observed phenomena. Design The study has been designed to demonstrate the influence of cirrhoti c serum on the nitric oxide system and vascular contractility. Methods The contractile response of aortic segments from healthy rats was s tudied in vitro after incubation with serum of healthy and cirrhosis-induce d rats (1 week, 2 weeks, 3 weeks and 4 weeks after bile duct ligation). A c umulative dose response curve to phenylephrine (10(-9) - 10(-4) mol) was es tablished before and after incubation with nitric oxide synthesis blocker N -omega-nitro-L-arginine, the more selective aminoguanidine (nitric oxide sy nthase [NOS]-2 inhibitor) and W7 (NOS-3 inhibitor). NOS-2 expression in inc ubated aortic rings was evaluated by Western blot analysis. Results A 4-hour incubation with serum of cirrhosis-induced rats reduced th e maximum contractile response to phenylephrine to 66.8 +/- 9.1% after 1 we ek, 50.4 +/- 7.8% after 2 weeks, 43.2 +/- 2.8% after 3 weeks and 35 +/- 5.2 % after 4 weeks of bile duct ligation. This reduction in the contractility response to phenylephrine was completely reversed by blocking nitric oxide synthesis with N-omega-nitro-L-arginine and aminoguanidine, but not after W 7. Incubation with cirrhotic serum induced NOS-2 expression in aortic rings . In Western blot analysis, the most intensive signal for NOS-2 protein was obtained in rings incubated with serum from rats 3 weeks and 4 weeks after induction of cirrhosis. Conclusions Cirrhotic serum decreases the contractile response to phenyleph rine even in an early stage of secondary cirrhosis. Reversibility of this e ffect after nitric oxide synthesis blockade suggests an induction of nitric oxide synthesis by systemic factors as a major point in vascular hyporeact ivity to vasoconstrictors in cirrhosis. Eur J Gastroenterol Hepatol 13:957- 962 (C) 2001 Lippincott Williams & Wilkins.