Time-dependent reduction of acetylcholine-induced relaxation in aortic rings of cholestatic rats

Changes in vascular responsiveness are the basis for some of the cardiovascular complications in cholestasis. Since the duration of cholestasis is important in determining the degree of the complications, we investigated the time-course dependent evolution of vascular relaxation responsiveness in the aortic rings of cholestatic rats. Acetylcholine-induced endothelium-dependent relaxation was investigated in the isolated aortic rings of unoperated, sham-operated and two-, five-, seven- and fourteen-day bile-duct ligated rats. There was a significant reduction in acetylcholine-induced relaxation of the aortic rings by the second day after the bile-duct ligation operation, compared to those of unoperated and sham-operated groups, but more reduction still occurs in 5- and 7-day bile-duct ligated groups, reaching a plateau by the seventh day. The relaxation response to sodium nitroprusside in the aortic rings of the unoperated and the 7-day bile-duct ligated rats did not differ, implying the intact smooth muscle component of the relaxation pathway. L-NAME ( N(omega)-nitro-L-arginine methyl ester), a nitric oxide (NO) synthase inhibitor, attenuated the acetylcholine-induced relaxation in both groups (unoperated and bile-duct ligated), while L-arginine prevents this inhibitory effect. Indomethacin potentiated the acetylcholine-induced relaxation in the aortic rings of the bile-duct ligated rats while it has no effect on unoperated controls, providing evidence for the possible role of vasoconstrictor prostanoids in cholestasis-induced reduction in acetylcholine-induced relaxation. These results state that the reduced acetylcholine-induced relaxation in the cholestatic aortic rings during the first week, when no portal hypertension was reported to be present, may be due to the decreased acetylcholine-induced NO release from endothelium or increased NO inactivation.