title: Gastric S-nitrosothiol formation drives the antihypertensive effects of oral sodium nitrite and nitrate in a rat model of renovascular hypertension.
abstract: Many effects of nitrite and nitrate are attributed to increased circulating concentrations of nitrite, ultimately converted into nitric oxide (NO(•)) in the circulation or in tissues by mechanisms associated with nitrite reductase activity. However, nitrite generates NO(•) , nitrous anhydride, and other nitrosating species at low pH, and these reactions promote S-nitrosothiol formation when nitrites are in the stomach. We hypothesized that the antihypertensive effects of orally administered nitrite or nitrate involve the formation of S-nitrosothiols, and that those effects depend on gastric pH. The chronic effects of oral nitrite or nitrate were studied in two-kidney, one-clip (2K1C) hypertensive rats treated with omeprazole (or vehicle). Oral nitrite lowered blood pressure and increased plasma S-nitrosothiol concentrations independently of circulating nitrite levels. Increasing gastric pH with omeprazole did not affect the increases in plasma nitrite and nitrate levels found after treatment with nitrite. However, treatment with omeprazole severely attenuated the increases in plasma S-nitrosothiol concentrations and completely blunted the antihypertensive effects of nitrite. Confirming these findings, very similar results were found with oral nitrate. To further confirm the role of gastric S-nitrosothiol formation, we studied the effects of oral nitrite in hypertensive rats treated with the glutathione synthase inhibitor buthionine sulfoximine (BSO) to induce partial thiol depletion. BSO treatment attenuated the increases in S-nitrosothiol concentrations and antihypertensive effects of oral nitrite. These data show that gastric S-nitrosothiol formation drives the antihypertensive effects of oral nitrite or nitrate and has major implications, particularly to patients taking proton pump inhibitors.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: Pinheiro
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Jefferson H
authors.initials: JH
authors.lastname: Amaral
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Graziele C
authors.initials: GC
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Portella
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Department of Chemistry, Faculty of Philosophy and Sciences of Ribeirao Preto, University of Sao Paulo, 14040-901, Ribeirao Preto, SP, Brazil.
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Toledo
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil. Electronic address: tanus@fmrp.usp.br.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D005609:Free Radicals / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009573:Nitrites / Q000378:metabolism*; D051381:Rats; D026403:S-Nitrosothiols / Q000378:metabolism*; D012977:Sodium Nitrite / Q000008:administration & dosage
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D005609:Free Radicals; D009573:Nitrites; D026403:S-Nitrosothiols; D012977:Sodium Nitrite
keywords: Hypertension; Nitrates; Nitrites; Nitrosation; Omeprazole; S-Nitrosothiols