STIMULATION OF BILE FLOW IN THE PERFUSED RAT LIVER BY NITRIC OXIDE (NO) DONORS IS MEDIATED IN PART BY CYCLIC GMP (cGMP) BUT NOT BY NO SYNTHASE.

Abstract

NO leads to smooth muscle relaxation in a variety of tissues. This effect of NO is mediated by stimulating the production of cGMP by guanylate cyclase. In the liver, hepatic NO production is induced after exposure to endotoxins and cytokines, conditions associated with cholestasis. Therefore, the aim of the present study was to investigate the effects of the second messenger cGMP and of the NO-donor sodium nitroprusside on bile flow in the isolated perfused rat liver. The administration of DBcGMP (a membrane permeable analog of cyclic GMP; 6.25 μM) increased bile flow from a baseline of 1.04±0.04 to a peak of 1.36±0.08 μl/min/g liver (p<0.01) within 12 min of cGMP administration. In contrast to the known effect of cyclic AMP, DBcGMP did not stimulate the biliary excretion of the transcytotic vesicular pathway marker horseradish peroxidase (HRP), indicating that this choleresis is not due to incresse in vesicular transport induced by DBcGMP. Infusion of the NO-donor and known vasodilator Nanitroprusside (1 mM) increased bile flow from 0.96±0.04 to a peak of 1.64±0.2 μl/min/g liver (p<0.001), within 18 min of nitroprusside administration. This choleresis was partially inhibited by the addition of methylen blue (5 μM), a guanylate cyclase inhibitor (p<0.01), but not by the NO synthase inhibitor L-NAME. These results indicate that NO donors stimulates bile flow and that this effect may be mediated by the second messenger cyclic cGMP but not through stimulation of NO synthase.