Nitric oxide donor NOR 3 inhibits ketogenesis from oleate in isolated rat hepatocytes by a cyclic GMP-independent mechanism.
Studies were conducted to clarify the effects of nitric oxide donors NOR 3 ((+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide, FK409), SIN-1 (3-morpholinosydnonimine) and SNAP (S-nitroso-N-acetylpenicillamine) on the accumulation of cGMP and cAMP and Ca2+ mobilization as well as ketogenesis from oleate in isolated rat hepatocytes. NOR 3 caused inhibition of ketogenesis from oleate along with stimulation of cGMP accumulation in rat hepatocytes, whereas SIN-1 and SNAP exerted no effect on ketogenesis despite their marked stimulation of cGMP accumulation. Although the nitric oxide trapping agent, carboxy-PTIO (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide), antagonized the stimulation by NOR 3 of cGMP accumulation, it failed to modulate the anti-ketogenic action of NOR 3. Furthermore, neither 8-bromoguanosine-3',5'-cyclic monophosphate nor N2,2'-O-dibutyrylguanosine-3',5'-cyclic monophosphate mimicked the anti-ketogenic action of NOR 3. It is concluded in the present study that NOR 3-induced inhibition of ketogenesis in rat hepatocytes is not mediated by cGMP. The present study revealed that the remaining structure of NOR 3 from which nitric oxide had been spontaneously released had no anti-ketogenic action. We first and clearly demonstrated that nitrite production was dramatically enhanced when NOR 3 was incubated in the presence of rat hepatocytes. The mechanism whereby NOR 3 inhibits ketogenesis in rat hepatocytes will be discussed.
Nomura
T
T
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
Ohtsuki
M
M
Matsui
S
S
Sumi-Ichinose
C
C
Nomura
H
H
Hagino
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019344:Lactic Acid / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D019301:Oleic Acid / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D012977:Sodium Nitrite / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D001565:Benzoates; D007093:Imidazoles; D009574:Nitro Compounds; D014665:Vasodilator Agents; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D019301:Oleic Acid; D009569:Nitric Oxide; D019344:Lactic Acid; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D000255:Adenosine Triphosphate; C061872:FK 409; D008981:Molsidomine; D010396:Penicillamine; D006152:Cyclic GMP; D012977:Sodium Nitrite; D002118:Calcium