sodium-nitrite and 1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole

Adequate perfusion of the placental vasculature is essential to meet the metabolic demands of fetal growth and development. Lacking neural control, local tissue metabolites, circulating and physical factors contribute significantly to blood flow regulation. Nitric oxide (NO) is a key regulator of fetoplacental vascular tone. Nitrite, previously considered an inert end-product of NO oxidation, has been shown to provide an important source of NO. Reduction of nitrite to NO may be particularly relevant in tissue when the oxygen-dependent NO synthase (NOS) activity is compromised, e.g. in hypoxia. The contribution of this pathway in the placenta is currently unknown. We hypothesised that nitrite vasodilates human placental blood vessels, with enhanced efficacy under hypoxia. Placentas were collected from uncomplicated pregnancies and the vasorelaxant effect of nitrite (10

Topics: Adult; Arteries; Benzoates; Chorion; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Hypoxia; Imidazoles; Nitrites; Placenta; Pregnancy; Sodium Nitrite; Vasodilation; Veins

Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

Topics: Allopurinol; Animals; Benzoates; Brain Death; Gene Expression; Hemodynamics; Imidazoles; Inflammation; Kidney; Kidney Transplantation; Lipid Peroxidation; Male; Nitrites; Rats; Rats, Inbred Lew; Reperfusion Injury; Signal Transduction; Sodium Nitrite

The new pathway nitrate-nitrite-nitric oxide (NO) has emerged as a physiological alternative to the classical enzymatic pathway for NO formation from l-arginine. Nitrate is converted to nitrite by commensal bacteria in the oral cavity and the nitrite formed is then swallowed and reduced to NO under the acidic conditions of the stomach. In this study, we tested the hypothesis that increases in gastric pH caused by omeprazole could decrease the hypotensive effect of oral sodium nitrite. We assessed the effects of omeprazole treatment on the acute hypotensive effects produced by sodium nitrite in normotensive and L-NAME-hypertensive free-moving rats. In addition, we assessed the changes in gastric pH and plasma levels of nitrite, NO(x) (nitrate+nitrite), and S-nitrosothiols caused by treatments. We found that the increases in gastric pH induced by omeprazole significantly reduced the hypotensive effects of sodium nitrite in both normotensive and L-NAME-hypertensive rats. This effect of omeprazole was associated with no significant differences in plasma nitrite, NO(x), or S-nitrosothiol levels. Our results suggest that part of the hypotensive effects of oral sodium nitrite may be due to its conversion to NO in the acidified environment of the stomach. The increase in gastric pH induced by treatment with omeprazole blunts part of the beneficial cardiovascular effects of dietary nitrate and nitrite.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Antihypertensive Agents; Aorta; Benzoates; Blood Pressure; Free Radical Scavengers; Gastric Juice; Hydrogen-Ion Concentration; Hypertension; Imidazoles; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Omeprazole; Rats; Rats, Wistar; S-Nitrosothiols; Sodium Nitrite; Vasodilation

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.

Topics: Adenosine Triphosphate; Animals; Benzoates; Calcium; Cells, Cultured; Cyclic GMP; Imidazoles; Lactic Acid; Liver; Male; Molsidomine; Nitric Oxide; Nitro Compounds; Oleic Acid; Penicillamine; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Sodium Nitrite; Vasodilator Agents

It is becoming apparent that nitrogen monoxide (NO) such as nitric oxide has regulatory roles for neuronal cell functions. We examined the role of NO using NO donors on [3H]noradrenaline (NA) release from prelabeled rat hippocampal slices. Sodium nitroprusside (SNP), which had no effect by itself, stimulated [3H]NA release in a dose-dependent manner (ED50 = 0.5 mM) in the presence of dithiothreitol (DTT). The stimulatory effect of SNP with DTT, but not high K+, was observed in an extracellular Ca(2+)-free buffer. The maximal effect of SNP was obtained after incubation for 1-2 h with DTT in buffer at physiological pH (7.4). The simultaneous addition of SNP and DTT to the slices induced a small effect, and the effect of SNP declined after 3.5 h. SNP stimulated cyclic GMP accumulation in the slices without DTT. NaNO2 and 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (a generator of nitric oxide), which stimulated cyclic GMP accumulation by themselves, did not stimulate [3H]NA release in the presence and absence of DTT. 3-Morpholinosydnonimine HC1 (a generator of peroxynitrite) had no effect on the release. The stimulatory effect of SNP and DTT on NA release was inhibited 40% by nitric oxide scavengers such as oxyhemoglobin and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide, although cyclic GMP accumulation induced by NO donors was completely inhibited. These findings suggest that SNP reacts with DTT to produce unknown active species, and that cyclic GMP is not a mediator for SNP-stimulated NA release.

Topics: Animals; Benzoates; Calcium; Cyclic GMP; Dithiothreitol; Drug Interactions; Hippocampus; Hydrogen-Ion Concentration; Imidazoles; In Vitro Techniques; Kinetics; Male; Nitric Oxide; Nitroprusside; Nitroso Compounds; Norepinephrine; Oxyhemoglobins; Potassium Chloride; Rats; Rats, Wistar; Sodium Nitrite