title: Chronic nitroglycerine administration reduces endothelial nitric oxide production in rabbit mesenteric resistance artery.
abstract: We investigated whether 10 days' in vivo treatment with nitroglycerine (NTG) would inhibit nitric oxide production by the endothelial cells of resistance arteries ex vivo and, if so, what the underlying mechanism might be. ACh increased the intracellular nitric oxide concentration ([NO]i; estimated using the nitric oxide-sensitive fluorescent dye diaminofluorescein-2) within the endothelial cells of rabbit mesenteric resistance arteries. This effect was significantly smaller in arteries isolated from NTG-treated rabbits than in those from control rabbits. The reduction in endothelial [NO]i in NTG-treated rabbits was prevented when olmesartan (blocker of type 1 angiotensin II receptors (AT1Rs)) was coadministered in vivo with NTG and also when the superoxide scavenger manganese (III) tetrakis-(4-benzoic acid) porphyrin (Mn-TBAP), the protein kinase C (PKC) inhibitor GF109203X or L-arginine (with or without the active form of folate (5-methyltetrahydrofolate)) was incubated with the arteries in vitro. Endothelial cell superoxide production (estimated by ethidium fluorescence) was greatly increased in arteries from NTG-treated rabbits. This was normalized by in vivo coadministration of olmesartan with NTG and also by in vitro application of Mn-TBAP or GF109203X (but not of 5-methyltetrahydrofolate+L-arginine). ACh increased the intracellular Ca2+ concentration (estimated using the Ca2+-sensitive dye Fura 2) within endothelial cells, the increase being not significantly different between NTG-treated rabbits and control rabbits. We conclude that in NTG-treated rabbits, endothelial nitric oxide production in mesenteric resistance arteries is reduced, possibly through a reduction in the bioavailability of L-arginine via an action mediated by superoxide. Activation of the AT1R-PKC pathway may be involved in increasing superoxide production.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
authors.forename: Tamao
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Junko
authors.initials: J
authors.lastname: Kajikuri
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Suzumori
authors.forename: Takeo
authors.initials: T
authors.lastname: Itoh
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004351:Drug Resistance; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016166:Free Radical Scavengers; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D008665:Metalloporphyrins; D013777:Tetrazoles; D014665:Vasodilator Agents; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides; D009569:Nitric Oxide; C437965:olmesartan; D001120:Arginine; D011493:Protein Kinase C; D005996:Nitroglycerin; C070515:bisindolylmaleimide I; D000109:Acetylcholine; D002118:Calcium