title: Possible involvement of S-nitrosylation of brain cyclooxygenase-1 in bombesin-induced central activation of adrenomedullary outflow in rats.
abstract: We previously reported that both nitric oxide (NO) generated from NO synthase by bombesin and NO generated from SIN-1 (NO donor) activate the brain cyclooxygenase (COX) (COX-1 for bombesin), thereby eliciting the secretion of both catecholamines (CA) from the adrenal medulla by brain thromboxane A(2)-mediated mechanisms in rats. NO exerts its effects via not only soluble guanylate cyclase, but also protein S-nitrosylation, covalent modification of a protein cysteine thiol. In this study, we clarified the central mechanisms involved in the bombesin-induced elevation of plasma CA with regard to the relationship between NO and COX-1 using anesthetized rats. Bombesin (1 nmol/animal, i.c.v.)-induced elevation of plasma CA was attenuated by carboxy-PTIO (NO scavenger) (0.5 and 2.5 μmol/animal, i.c.v.), but was not influenced by ODQ (soluble guanylate cyclase inhibitor) (100 and 300 nmol/animal, i.c.v.). The bombesin-induced response was effectively reduced by dithiothreitol (thiol-reducing reagent) (0.4 and 1.9 μmol/kg/animal, i.c.v.) and by N-ethylmaleimide (thiol-alkylating reagent) (0.5 and 2.4 μmol/kg/animal, i.c.v.). The doses of dithiothreitol also reduced the SIN-1 (1.2 μmol/animal, i.c.v.)-induced elevation of plasma CA, but had no effect on the U-46619 (thromboxane A(2) analog) (100 nmol/animal, i.c.v.)-induced elevation of plasma CA even at higher doses (1.9 and 9.7 μmol/kg/animal, i.c.v.). Immunohistochemical studies demonstrated that the bombesin increased S-nitroso-cysteine-positive cells co-localized with COX-1 in the spinally projecting neurons of the hypothalamic paraventricular nucleus (PVN). Taken together, endogenous NO seems to mediate centrally administered bombesin-induced activation of adrenomedullary outflow at least in part by S-nitrosylation of COX-1 in the spinally projecting PVN neurons in rats.
authors.affiliation: Department of Pharmacology, School of Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Lianyi
authors.initials: L
authors.lastname: Lu
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yokotani
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D001839:Bombesin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D002395:Catecholamines / Q000097:blood*; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D004229:Dithiothreitol / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005033:Ethylmaleimide / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026403:S-Nitrosothiols / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001565:Benzoates; D002395:Catecholamines; D007093:Imidazoles; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D026403:S-Nitrosothiols; D013439:Sulfhydryl Reagents; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; C002385:linsidomine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C021315:S-nitrosocysteine; D008981:Molsidomine; D003545:Cysteine; D005033:Ethylmaleimide; D001839:Bombesin; D004229:Dithiothreitol