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

Abstract

Arterial vasodilation with concomitant hyperdynamic circulation are common findings in liver cirrhosis. Nitric oxide acting at a local level has been suggested to be pathophysiologically relevant in this context. Several systemic factors in conjunction with nitric oxide might interfere with the observed phenomena. The study has been designed to demonstrate the influence of cirrhotic serum on the nitric oxide system and vascular contractility. The contractile response of aortic segments from healthy rats was studied in vitro after incubation with serum of healthy and cirrhosis-induced rats (1 week, 2 weeks, 3 weeks and 4 weeks after bile duct ligation). A cumulative dose response curve to phenylephrine (10--10-4 mol) was established before and after incubation with nitric oxide synthesis blocker N(omega)-nitro-L-arginine, the more selective aminoguanidine (nitric oxide synthase [NOS]-2 inhibitor) and W7 (NOS-3 inhibitor). NOS-2 expression in incubated aortic rings was evaluated by Western blot analysis. A 4-hour incubation with serum of cirrhosis-induced rats reduced the maximum contractile response to phenylephrine to 66.8 +/- 9.1% after 1 week, 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 W7. 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. Cirrhotic serum decreases the contractile response to phenylephrine even in an early stage of secondary cirrhosis. Reversibility of this effect after nitric oxide synthesis blockade suggests an induction of nitric oxide synthesis by systemic factors as a major point in vascular hyporeactivity to vasoconstrictors in cirrhosis.