Inducible Nitric-oxide Synthase Attenuates Vasopressin-dependent Ca2+Signaling in Rat Hepatocytes*

Increases in both Ca2+and nitric oxide levels are vital for a variety of cellular processes; however, the interaction between these two crucial messengers is not fully understood. Here, we demonstrate that expression of inducible nitric-oxide synthase in hepatocytes, in response to inflammatory mediators, dramatically attenuates Ca2+signaling by the inositol 1,4,5-trisphosphate-forming hormone, vasopressin. The inhibitory effects of induction were reversed by nitric oxide inhibitors and mimicked by prolonged cyclic GMP elevation. Induction was without effect on Ca2+signals in response to AlF4−or inositol 1,4,5-trisphosphate, indicating that phospholipase C activation and release of Ca2+from inositol 1,4,5-trisphosphate-sensitive Ca2+stores were not targets for nitric oxide inhibition. Vasopressin receptor levels, however, were dramatically reduced in induced cultures. Our data provide a possible mechanism for hepatocyte dysfunction during chronic inflammation.