title: Vascular responses to nitrite are mediated by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat.
abstract: Sodium nitrite has been shown to have vasodilator activity in experimental animals and in human subjects. However, the mechanism by which nitrite anion is converted to vasoactive nitric oxide (NO) is uncertain. It has been hypothesized that deoxyhemoglobin, xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase, and other heme proteins can reduce nitrite to NO, but studies in the literature have not identified the mechanism in the intact rat, and several studies report no effect of inhibitors of xanthine oxidoreductase. In the present study, the effects of the xanthine oxidoreductase inhibitor allopurinol and the mitochondrial aldehyde dehydrogenase inhibitor cyanamide on decreases in mean systemic arterial pressure in response to i.v. sodium nitrite administration were investigated in the rat. The decreases in mean systemic arterial pressure in response to i.v. administration of sodium nitrite were inhibited in a selective manner after administration of allopurinol in a dose of 25 mg/kg i.v. A second 25 mg/kg i.v. dose had no additional inhibitory effect on the response to sodium nitrite. The decreases in mean systemic arterial pressure in response to sodium nitrite were attenuated by cyanamide and a second 25 mg/kg i.v. dose had no additional inhibitory effect. In L-NAME-treated animals, allopurinol attenuated responses to sodium nitrite and a subsequent administration of cyanamide had no additional effect. When the order of administration of the inhibitors was reversed, responses to sodium nitrite were attenuated by administration of cyanamide and a subsequent administration of allopurinol had no additional inhibitory effect. The results of these studies suggest that nitrite can be reduced to vasoactive NO in the systemic vascular bed of the rat by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase and that the 2 pathways of nitrite activation act in a parallel manner.
authors.affiliation: Department of Pharmacology, Tulane University Medical Center, New Orleans, LA 70112-2699, USA.
authors.forename: Neel H
authors.initials: NH
authors.lastname: Golwala
authors.forename: Christopher
authors.initials: C
authors.lastname: Hodenette
authors.forename: Subramanyam N
authors.initials: SN
authors.lastname: Murthy
authors.forename: Bobby D
authors.initials: BD
authors.lastname: Nossaman
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003484:Cyanamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012977:Sodium Nitrite / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: D014665:Vasodilator Agents; D009599:Nitroprusside; D003484:Cyanamide; D000493:Allopurinol; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019001:Nitric Oxide Synthase; D014968:Xanthine Dehydrogenase; D000444:Aldehyde Dehydrogenase; D012977:Sodium Nitrite; C049347:fasudil; D019331:NG-Nitroarginine Methyl Ester