NITRIC-OXIDE DONOR NOR-3 INHIBITS KETOGENESIS FROM OLEATE IN ISOLATEDRAT HEPATOCYTES BY A CYCLIC GMP-INDEPENDENT MECHANISM

Studies were conducted to clarify the effects of nitric oxide donors N OR 3 -ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide, FK409), SIN-1 (3-morpholinosydnonimine) and SNAP (S-nitroso-N-acetylpenicillamine) o n the accumulation of cGMP and cAMP and Ca2+ mobilization as well as k etogenesis from oleate in isolated rat hepatocytes. NOR 3 caused inhib ition of ketogenesis from oleate along with stimulation of cGMP accumu lation in rat hepatocytes, whereas SIN-1 and SNAP exerted no effect on ketogenesis despite their marked stimulation of cGMP accumulation. Al though the nitric oxide frapping agent, carboxy-PTIO (2-phenyl-4,4,5,5 -tetramethylimidazoline-1-oxyl 3-oxide), antagonized the stimulation b y NOR 3 of cGMP accumulation, it failed to modulate the anti-ketogenic action of NOR 3. Furthermore, neither 8-bromoguanosine-3',5'-cyclic m onophosphate nor N-2,2'-O-dibutyrylguanosine-3',5'-cyclic monophosphat e mimicked the anti-ketogenic action of NOR 3. It is concluded in the present study that NOR 3-induced inhibition of ketogenesis in rat hepa tocytes is not mediated by cGMP. The present study revealed that the r emaining structure of NOR 3 from which nitric oxide had been spontaneo usly released had no anti-ketogenic action. We first and clearly demon strated that nitrite production was dramatically enhanced when NOR 3 w as incubated in the presence of rat hepatocytes. The mechanism whereby NOR 3 inhibits ketogenesis in rat hepatocytes will be discussed.