nitroarginine and sodium-nitrate

We investigated whether exogenous nitric oxide (NO) donors have a prejunctional and/or postjunctional inhibitory effect on the nitrergic responses and whether this inhibitory effect was mediated by NO itself and in part, by cyclic GMP in mouse duodenal strips. N(omega)-nitro-L-arginine inhibited relaxations induced by electrical field stimulation of nitrergic nerves, but not those with acidified NaNO2. Furthermore, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) inhibited both types of relaxations while 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) and N-ethylmaleimide were ineffective. NO donors, nitroglycerin and sodium nitroprusside, inhibited relaxations induced by nitrergic nerve stimulation, but not those with acidified NaNO2. Hemoglobin, exogenous Cu(2+)/Zn(2+) superoxide dismutase, diethyldithiocarbamic acid and pyrogallol did not influence the relaxation with nitrergic nerve stimulation. However, hemoglobin, diethyldithiocarbamic acid, pyrogallol and diethyldithiocarbamic acid plus pyrogallol attenuated the inhibitory effect of NO donors on relaxation with nitrergic nerve stimulation, and exogenous superoxide dismutase potentiated this inhibitory effect. Moreover, nitrergic nerve-mediated relaxations were inhibited by 8-bromo-cyclic GMP, but not by 8-bromo-cyclic AMP. These results suggest that exogenous NO donors have a prejunctional inhibitory effect on the nerve-mediated nitrergic relaxation and that the inhibitory effects of nitroglycerin and sodium nitroprusside are NO-dependent, but not related to NO metabolites such as peroxynitrite or a nitrosothiol intermediate. However, a contribution of S-nitrosothiol formed intracellularly cannot be entirely ruled out. Also, this prejunctional inhibition is mediated, at least in part, by the cyclic GMP, but not the cyclic AMP, pathway.

Topics: Animals; Dose-Response Relationship, Drug; Duodenum; Electric Stimulation; Enzyme Inhibitors; Ethylmaleimide; Female; Hemoglobins; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; Nitroprusside; Oxadiazoles; Quinoxalines; Thiazines

The effects of a range of nitric oxide (NO)-related compounds on histamine release from human basophils and rat peritoneal mast cells were studied. Basal and immunologic histamine releases from human basophils were not affected by N(omega)-nitro-L-arginine, N(omega)-nitro-L-arginine methyl ester, aminoguanidine or methylene blue (all inhibitors of NO production), sodium nitroprusside (an NO donor), L-arginine (a substrate for NO synthase) or D-arginine (the inactive enantiomer of L-arginine). In rat peritoneal mast cells, NO donors such as sodium nitroprusside, sodium nitrite and sodium nitrate, and lipopolysaccharide (an inducer of NO synthase) had little effect on basal histamine release, while 3-morpholino-sydnonimine (SIN-1, an NO donor), L-arginine and D-arginine increased this release by up to threefold. None of the inhibitors of NO production had any striking effect on histamine release induced by anti-rat immunoglobulin E (IgE), compound 48/80, sodium fluoride, phospholipase C, 1,2-dioctanoyl-sn-glycerol or ionophore A23187. However, haemoglobin was found to inhibit histamine release by anti-rat IgE or A23187 by ca. 40%. Alone of the NO donors, low concentrations of L-arginine produced a mild inhibition of histamine release induced by anti-IgE, compound 48/80 and A23187, but not other ligands, while sodium nitroprusside dose-dependently inhibited (by a maximum of ca. 30%) histamine release by anti-rat IgE, sodium fluoride or A23187. Stimulation with a variety of secretagogues or treatment with L-arginine, D-arginine, lipopolysaccharide, SIN-1 or sodium nitroprusside had no effect on NO production. Similarly, L-arginine, D-arginine or sodium nitroprusside did not change intracellular cGMP levels. On the basis of these results, it is suggested that NO does not play a significant role in the modulation of histamine release from human basophils or rat peritoneal mast cells. The effects of L-arginine, D-arginine and sodium nitroprusside may involve mechanisms unrelated to NO.

Topics: Animals; Antibodies; Arginine; Basophils; Calcimycin; Dose-Response Relationship, Drug; Guanidines; Hemoglobins; Histamine; Humans; Immunoglobulin E; Male; Mast Cells; Methylene Blue; Molsidomine; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Nitroprusside; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Rats; Rats, Sprague-Dawley; Sodium Fluoride; Sodium Nitrite

Nitric oxide (NO) is rapidly oxidized to nitrite (NO-2) and then to nitrate (NO-3) in biological tissues. Although urinary excretion rates of NO-3 are often used as an index of NO production in the body, very little is known regarding the kidney's ability to excrete circulating NO-3. We have evaluated the renal responses to systemic administration of sodium nitrate (NaNO3) in eight anesthetized dogs treated with the NO synthase inhibitor, nitro-L-arginine (NLA; 50 microg . kg-1 . min-1), intrarenally to minimize renal production of NO. Urinary and plasma concentrations of NO-3/NO-2 (NOX) were determined by the Greiss reaction after enzymatic reduction of NO-3 to NO-2. NLA treatment alone resulted in reductions in urinary NOX excretion rates (UNOXV, 1.13 +/- 0.2 to 0.53 +/- 0.1 nmol . min-1 . g-1) and an increase in fractional reabsorption of NOX (FRNOX, 93.8 +/- 0.6 to 97 +/- 0.6%) without changes in arterial plasma concentrations (ANOX, 18.7 +/- 1.4 to 21.2 +/- 3.7 microM). Administration of NaNO3 (10, 20, 30, and 40 microg . kg-1 . min-1) resulted in dose-dependent increases in ANOX (34.5 +/- 8.0, 46.4 +/- 7.3, 60.7 +/- 6.3, and 78.1 +/- 6.3 microM), UNOXV (1.8 +/- 0.7, 4.2 +/- 1.8, 7.0 +/- 2.0, and 11.4 +/- 3.3 nmol . min-1 . g-1), and decreases in FRNOX (93.8 +/- 2.3, 90.3 +/- 3.5, 88.6 +/- 3.2, and 84.6 +/- 3.5%). Absolute net tubular reabsorption of NO-3 showed a linear relationship with filtered loads, with no evidence of a transport maximum. These data show that, in the absence of additions from intrarenal sources, urinary excretion rates of nitrate increases progressively in response to increases in its circulating levels without exhibiting a transport maximum but with progressive decreases in fractional reabsorption.

Topics: Absorption; Anesthesia, General; Animals; Dogs; Glomerular Filtration Rate; Infusions, Intravenous; Kidney; Kinetics; Nitrates; Nitrites; Nitroarginine; Pentobarbital; Regional Blood Flow; Renal Circulation; Sodium, Dietary