Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.13.39 (NO synthase)
 15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminoguanidine, N,N'-diaminoguanidine, methylguanidine, and 1,1-dimethylguanidine were compared to NG-monomethyl-L-arginine (L-NMMA) for their ability to inhibit nitric oxide (NO) formation by cytokine-inducible and vascular constitutive isoforms of NO synthase. These comparisons were performed by assessing (1) cytokine-induced production of nitrite by RINm5F cells, (2) vasoconstrictor responses of isolated rat mesenteric arteries, and (3) in vivo blood pressure responses following intravenous bolus injection into anesthetized rats. Aminoguanidine and L-NMMA were the most potent inhibitors of cytokine-induced NO formation in RINm5F cells, while the other guanidine compounds were 10 (1,1-dimethylguanidine) to 100 (methylguanidine) times less potent. L-NMMA and 1,1-dimethylguanidine were the most potent inhibitors of the vascular constitutive isoform of NO synthase in both assay systems, while aminoguanidine and N,N'-diaminoguanidine were the least potent. These results (1) confirm the selective inhibition of the inducible isoform of NO synthase by aminoguanidine, (2) indicate that N,N'-diaminoguanidine, while approximately 30 times less potent than aminoguanidine in inhibiting inducible NO synthase, has very little effect on constitutive NO synthase activity, and (3) 1,1-dimethylguanidine, like L-NMMA, is a relatively potent inhibitor of both isoforms of NO synthase.
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PMID:Inhibition of nitric oxide formation by guanidines. 750 64

Aminoguanidine, NG-monomethyl-L-arginine (L-NMMA), NGNGdimethyl-L-arginine (asymmetric dimethylarginine; ADMA), creatinine, guanidinosuccinic acid, guanidinoproprionic acid and methylguanidine were added to cultures of activated murine macrophages. Only aminoguanidine, ADMA, L-NMMA and methylguanidine inhibited nitrite production in a dose-dependent manner. In the presence of 100 microM arginine, nitrite production was inhibited by 31.8 +/- 7.1% by ADMA (100 microM; P < 0.01) but the same dose of methylguanidine was without effect. A higher dose of methylguanidine (1000 microM) inhibited nitrite production by 47.6 +/- 5.6% (P < 0.001). The effects of these compounds were also tested on relaxation of human saphenous veins. L-NMMA and ADMA inhibited endothelium-dependent relaxations (EC50 = 4.7 +/- 1.1 microM and 17.9 +/- 4.9 microM, respectively); methylguanidine caused endothelium-independent contractions and reversed the relaxations to bradykinin and sodium nitroprusside (EC50 > 100 microM); aminoguanidine was without effect. The results of this study suggest that of the guanidino compounds which accumulate in renal failure, only ADMA is a potent inhibitor of nitric oxide (NO) synthesis. Methylguanidine is a weak inhibitor of nitric oxide synthesis, whereas the closely related compound aminoguanidine appears to inhibit selectively the inducible isoform of nitric oxide synthase and has no effect on constitutive NO synthase in human veins.
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PMID:Effects of guanidino and uremic compounds on nitric oxide pathways. 751 29

Nitric Oxide (NO) is now recognized as a mediator of several biological functions. In the present study we examined the effects of NO synthase (NOS) inhibitors on the ovulatory process in vivo, and whether this effect can be reversed by a NO generator. Immature eCG-hCG treated rats were injected intraperitonealy (ip) or unilaterally into the periovarian sac (intrabursal injection; ib) with inhibitors of the inducible form of NOS. Aminoguanidine (AG) suppressed ovulation in a dose-dependent manner, reaching a 54% inhibition at a dose of 20 mg/kg when injected ip (p < 0.001 vs. saline control). Likewise, local ib administration inhibited ovulation from the treated ovary; thus a dose of 2 mg/kg resulted in 48% inhibition, as compared to the contralateral ovary (p < 0.01). Similar results were obtained whether AG was administered 2 h prior to the stimulation of ovulation by hCG or deferred up to 4 h afterwards. An additional NOS inhibitor, NG-methyl-L-arginine (L-NMA) suppressed ovulation, albeit to a lower extent. Intrabursal administration of L-NMA (0.1 and 1 mg/kg) resulted in 34% and 32% inhibition, respectively (p < 0.05 vs. the saline treated control). The same doses of NG-methyl-D-arginine (D-NMA) did not inhibit ovulation significantly compared to the saline treated control. When sodium nitroprusside (0.5 mg/kg), a NO generator, was injected concomitantly with AG, it completely reversed its inhibitory action on ovulation. Thus, we have demonstrated the ability of NOS inhibitors to suppress hCG-induced ovulation in the rat in vivo. The specificity of this effect is confirmed by the ability of a NO generator to reverse the inhibitory action of AG. In conclusion, the ovarian NO/NOS system seems to be necessary for follicle rupture during ovulation.
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PMID:The involvement of nitric oxide in the ovulatory process in the rat. 752 65

The effects of aminoguanine on the intestinal vascular permeability following endotoxin administration in vivo has been compared to those of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in the rat. Concurrent administration of aminoguanidine. (12.5-50 mg/kg, s.c.) with endotoxin (E. coli lipopolysaccharide, 3 mg/kg, i.v.), dose dependently increased vascular leakage of radiolabelled albumin in the ileum and colon after 1 h, an effect reversed by the pretreatment with L-arginine (300 mg/kg, s.c.). Aminoguanidine (50 mg/kg, s.c.) also elevated arterial blood pressure over the 1 h investigation period. Similar acute potentiation of endotoxin-provoked vascular injury was observed 1 h following L-NMMA (50 mg/kg s.c.) which also increased blood pressure, indicating the inhibition of constitutive NO synthase. By contrast, administration of aminoguanidine (12.5-50 mg/kg, s.c.) 3 h after endotoxin, at the time of the expression of the inducible NO synthase, reduced the subsequent endotoxin-induced vascular leakage, as did L-NMMA (50 mg/kg). In homogenates of rat ileal or colonic tissue, aminoguanidine inhibited both the constitutive and inducible NO synthase activity showing only 2-fold selectivity for the inducible isoform. Thus, although aminoguanidine inhibits these isoforms of NO synthase, it is not a selective inhibitor of the inducible isoform in the intestinal microvasculature in vivo.
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PMID:Aminoguanidine inhibits both constitutive and inducible nitric oxide synthase isoforms in rat intestinal microvasculature in vivo. 753 62

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.
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PMID:Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis. 753 83

The involvement of the inducible nitric oxide (NO) synthase in the vascular hyporeactivity in portal vein-ligated rats was assessed in isolated perfused mesenteric arterial beds. Aminoguanidine, a selective inhibitor of the inducible NO synthase, restored the pressor responses to methoxamine in arteries of endotoxin-treated rats, but was ineffective in hyporeactive portal vein-ligated vessels. NG-Nitro-L-arginine methyl ester enhanced the responsiveness both in portal vein-ligated and sham-operated rats, without changing the difference between the two groups. These results not only indicate that the inducible NO synthase is not involved in the hyporeactivity to methoxamine in mesenteric arteries of portal hypertensive rats, but also suggest a role for factors other than NO.
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PMID:The role of inducible nitric oxide synthase in vascular hyporeactivity of endotoxin-treated and portal hypertensive rats. 754 25

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.
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PMID:Mechanisms of endotoxin-induced dilatation of cerebral arterioles. 757 18

Overproduction of nitric oxide (NO) following induction of NO synthase in vascular smooth muscle by endotoxin and certain cytokines contributes to the vasodilation and hyporesponsiveness to vasopressors that characterize the septic circulation. Guanosine 3',5'-cyclic monophosphate (cGMP) mediates the effects of NO in vascular smooth muscle. Vessels from animals treated with endotoxin have elevated cGMP levels compared with control animals. Aminoguanidine has been proposed as a selective inhibitor of the inducible form of NO synthase. This study compares the effects of aminoguanidine on phenylephrine-induced contractions and cGMP levels in thoracic aortic rings from endotoxin treated (20 mg/kg intraperitoneally) with sham-treated (1 ml saline intraperitoneally) rats. Endotoxin-treatment depressed phenylephrine-induced contraction and raised tissue levels of cGMP. Aminoguanidine (100 microM and 1 mM) increased phenylephrine-induced tension and decreased cGMP levels in a dose-dependent manner in intact and endothelium-denuded aortas from endotoxin-treated rats but had no effect on vessels from sham-treated rats. These findings are consistent with the hypothesis that endotoxin treatment causes increased vascular production of endothelium-independent NO, which is associated with a diminished response to vasoconstrictors. Aminoguanidine decreases indices of NO production only after endotoxin treatment, providing further evidence that it is a selective inhibitor of inducible NO synthase.
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PMID:Aminoguanidine selectively decreases cyclic GMP levels produced by inducible nitric oxide synthase. 758 1

The gastric mucosa responds to taurocholate (TC) by significantly decreasing acid secretion. We examined the role of nitric oxide (NO) in this phenomenon in comparison with endogenous prostaglandins. A rat stomach was mounted in an ex-vivo chamber and perfused with saline, and the potential difference, luminal pH and acid responses were measured before and after the application of 20 mM TC for 30 min with or without pretreatment with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the cyclooxygenase inhibitor indomethacin. Exposure of the stomach to TC caused a reduction in potential difference, a decrease in acid secretion and an increase in luminal HCO3-. Pretreatment with L-NAME or indomethacin did not affect potential difference and HCO3- responses, but it significantly attenuated the decrease in acid secretion caused by TC. The effect of L-NAME was more potent than that of indomethacin, and, especially in the presence of L-NAME, acid secretion was actually enhanced after exposure to TC. Aminoguanidine, the selective inhibitor of inducible NO synthase, did not have any significant effect on either parameter. This effect of L-NAME was antagonized by the simultaneous administration of L-arginine but not by that of D-arginine, whereas the effect of indomethacin was reversed by PGE2. Acid secretion in normal stomachs was significantly reduced by nitroprusside and PGE2 but was not affected by either L-NAME or indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide and prostaglandins in regulation of acid secretory response in rat stomach following injury. 781 52

We investigated the role of endogenous nitric oxide (NO) and superoxide anions in recombinant human interleukin-1 beta (rhIL-1 beta)-induced bronchial hyperresponsiveness (BHR) and neutrophilia in Brown-Norway rats. Aminoguanidine (100 mg/kg/d) administered subcutaneously for 3 d, an inhibitor of inducible NO synthase, L-arginine (100 mg/kg/d administered subcutaneously for 3 d, a specific precursor for the synthesis of NO, and apocynin (5 mg/kg/orally), an inhibitor of superoxide anion (O2-)-generating NADPH oxidase in macrophages and neutrophils, were administered prior to administration of rhIL-1 beta (500 U) intratracheally. Aminoguanidine in addition to another inhibitor of NO synthase, NW-nitro-L-arginine methyl ester (L-NAME) 100 mg kg/d administered subcutaneously for 3 d augmented bronchial responsiveness to inhaled bradykinin (BK) but not to acetylcholine (ACh), an effect reversed by L-arginine. rhIL-1 beta-treated rats also demonstrated BHR to BK but not to ACh, associated with neutrophilia in bronchoalveolar lavage fluid (BALF). rhIL-1 beta-induced BHR and neutrophilia were neither further increased by aminoguanidine nor inhibited by L-arginine. Apocynin, however, significantly inhibited rhIL-1 beta-induced BHR but not the BALF neutrophilia. Suppression of NO generation and generation of O2- from macrophages and infiltrating neutrophils may be important in rhIL-1 beta-induced airway hyperresponsiveness to bradykinin.
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PMID:Role of nitric oxide and superoxide anions in interleukin-1 beta-induced airway hyperresponsiveness to bradykinin. 792 31


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