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Query: UNIPROT:P06889 (Mol)
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The results of our continuing studies on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage as well as related reports from other laboratories are summarized in this paper. Repetitive ip administration of NG-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor, protected against neuronal necrosis in the gerbil hippocampal CA1 field after transient forebrain ischemia with a bell-shaped response curve, the optimal dose being 3 mg/kg. Repeated ip administration of L-NNA also mitigated rat brain edema or infarction following permanent and transient middle cerebral artery (MCA) occlusion with a U-shaped response. The significantly ameliorative dose-range and optimal dose were 0.01-1 mg/kg and 0.03 mg/kg, respectively. Studies using a NO-sensitive microelectrode revealed that NO concentration in the affected hemisphere was remarkably increased by 15-45 min and subsequently by 1.5-4 h after MCA occlusion. Restoration of blood flow after 2 h-MCA occlusion resulted in enhanced NO production by 1-2 h after reperfusion. Administration of L-NNA (1 mg/kg, ip) diminished the increments in NO production during ischemia and reperfusion, leading to a remarkable reduction in infarct volume. In brain microvessels obtained from the affected hemisphere, Ca(2+)-dependent constitutive NOS (cNOS) was activated significantly at 15 min, and Ca(2+)-independent inducible NOS (iNOS) was activated invariably at 4 h and 24 h after MCA occlusion. Two hour reperfusion following 2 h-MCA occlusion caused more than fivefold increases in cNOS activity with no apparent alterations in iNOS activity. Thus, we report here based on available evidence that there is good reason to think that NOS activation in brain microvessels may play a role in the cellular mechanisms underlying ischemic brain injury.
Mol Chem Neuropathol 1995 Oct
PMID:Nitric oxide synthase in cerebral ischemia. Possible contribution of nitric oxide synthase activation in brain microvessels to cerebral ischemic injury. 857 40

Recent reports suggest that endothelial-dependent relaxant factor, recognized as nitric oxide (NO), reduces myocardial contractility. Here, we showed that both exposures to acetylcholine and bradykinin for 30 min increased cyclic guanylate monophosphate (cyclic GMP) in isolated rat cardiomyocytes. These increases in cyclic GMP were blunted by NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Hypoxia augmented the cyclic GMP accumulation due to exposures to acetylcholine and bradykinin, which were blunted by L-NAME. The increases in cyclic GMP due to acetylcholine and bradykinin during normoxic and hypoxic conditions were not blunted by aminoguanidine, an inhibitor of inducible NO synthase. These findings revealed that NO is produced in cardiomyocytes due to stimulation of NO synthase and modulates their own guanylate cyclase, which was augmented by hypoxia. NO production, through NO synthase in cardiomyocytes, may constitute autocrine regulations of myocardial contractility and paracrine regulations of coronary vasodilation and platelet aggregation.
J Mol Cell Cardiol 1995 Oct
PMID:Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia. 857 31

Bacterial lipopolysaccharide (LPS) and other immunostimulants induce an isoform of NO synthase (iNOS) in vascular smooth muscle (VSM) which produces large quantities of NO and profound vasodilation; this process has been implicated as the cause of gram-negative septic shock. Although regulation of iNOS has been considered to occur at the level of transcription, it is unclear whether post-transcriptional events also contribute to changes in iNOS mRNA expression. We show that cycloheximide (CH), an inhibitor of protein synthesis, induces iNOS mRNA in VSM and potentiates the induction of iNOS mRNA caused by LPS. For many early-response genes, protein-synthesis inhibitors enhance mRNA levels by increasing mRNA stability. Since iNOS mRNA contains multiple copies of a consensus sequence (AUUUA) in common with these eary-response genes and responsible for mRNA destabilization, we tested whether CH induces iNOS mRNA by prolonging mRNA lifetime. In the absence of CH, iNOS mRNA decayed with biphagic kinetics and a half-life of 2 h. In the presence of CH, half-life was prolonged to approximately 7 h. Our observations indicate that in VSM the stability of iNOS mRNA may be under the control of a labile protein factor which awaits identification and characterization. Regulation of mRNA lifetime represents a novel site for control of iNOS gene expression.
Biochem Mol Biol Int 1995 Oct
PMID:Cycloheximide induces nitric oxide synthase mRNA in vascular smooth muscle cells by prolonging mRNA lifetime. 859 83

Macrophages contain arginase and an inducible nitric oxide (NO) synthase that use the same substrate, L-arginine, to produce nitric oxide and urea, respectively. Arginase was inhibited by various amino acids not related to L-arginine. These compounds were bound to the substrate binding site of the enzyme as supported by kinetic studies. Five binding sites were defined in this area by computer-aided analysis, and three complementary sites in a compound were sufficient to give an inhibitory character. NO synthase could not be inhibited by these compounds, but certain derivatives (e.g., putrescine or L-valinol) caused a marked and probably allosteric inhibition. The possible biological importance of these inhibitions in the tumoricid function of macrophages is discussed.
Comp Biochem Physiol B Biochem Mol Biol 1996 Feb
PMID:Computer-aided comparison of the inhibition of arginase and nitric oxide synthase in macrophages by amino acids not related to arginine. 865 90

The study demonstrates weakly to strongly positive reaction staining for NADPH-diaphorase/NO- synthase in the peripheral cells of sebaceous glands in the hairy skin of domesticated mammals. Additionally, the structure of the blood capillary system surrounding these glands is better elucidated. The results obtained are discussed in view of a modulatory action of NO generated by these enzyme activities, implying a direct influence of this substance on the contractile elements of gland-associated blood capillaries. In this way, a simple and self-regulatory mechanism to couple blood flow and glandular metabolism can be proposed.
Cell Mol Biol (Noisy-le-grand) 1996 Mar
PMID:Demonstration of NADPH-diaphorase (NO-synthase) in sebaceous glands of the mammalian integument, with remarks on the glandular capillary net. 869 61

Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.
J Mol Cell Cardiol 1996 Feb
PMID:Modulation of endothelin-1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. 872 59

Acetylcholine-induced, endothelium-dependent relaxation of norepinephrine-precontracted aortic strips, was severely impaired after exposure to a hypoxanthine/xanthine oxidase reaction generating oxygen radicals. This effect was more evident in aortic strips of aging rats (24 months old) in comparison to young rats (3 months old). The addition of authentic .NO (1 microM) completely relaxed aortic strips exposed to oxidative stress both in young and aging rats. In vitro EPR measurements showed that the .NO signal was reduced by enzymatic O2.- generating reaction. The activity of a partial purified preparation of constitutive NO synthase from rat cerebellum was significantly decreased after exposure to exogenous oxygen radicals. Pretreatment of aortic strips with 100 microM alpha-tocopherol-phosphate, produced a significant improvement of acetylcholine-dependent relaxation in the aortic strips exposed to oxidative stress, particularly in the aged vessel. The content of malondialdehyde in aortic tissue did not change after oxidative stress or alpha-tocopherol pretreatment. Alpha-tocopherol was unable to recover the NO synthase activity depressed in vitro by hypoxanthine/xanthine oxidase reaction. This study confirms that an oxidative stress impairs the endothelium-mediated vasodilation. Alpha-tocopherol pretreatment protects the vessel against this damage. The mechanism of action of alpha-tocopherol is unknown, but seems unrelated to an antioxidant activity.
Mol Cell Biochem
PMID:Alpha-tocopherol pretreatment improves endothelium-dependent vasodilation in aortic strips of young and aging rats exposed to oxidative stress. 873 50

Nitric oxide (NO) at high concentration (approx. 33 microM) produced a marked excitation: increase of tension development or increase in amplitude of spontaneous contraction, in 7 out of 8 rabbit nonpregnant myometrial strips. One case produced an inhibition: disappearance of spontaneous contraction. A latent period of several sec usually preceded the excitation. The response of the myometrium to NO approx. 33 microM associated with remarkable increase in tissue cyclic GMP levels. NO approx. 33 microM reduced an inhibition, in 1 out of 3 myometrial strips taken from ovariectomized rabbits. Two cases produced an excitatory. A precursor of NO, L-Arginine 100 microM or an inhibitor of NO synthase, NG-nitro-L-arginine 100 microM also produced a transient weak excitatory response. On the contrary, 8-bromo-cyclic GMP 100 microM produced an inhibition. The excitatory response to NO 33 microM was almost unaffected by pretreatment with indomethacin 10 microM, whereas the spontaneous motility was remarkably depressed. The contractile response of the isolated rabbit myometrium to electrical field stimulation was almost unaffected by the pretreatment with L-arginine 100 microM or NG-nitro-L-arginine 100 microM. The present findings may indicate that NO has inhibitory and excitatory components on the mechanical activity of the rabbit isolated myometrium.
Res Commun Mol Pathol Pharmacol 1996 May
PMID:Excitatory response of rabbit myometrium to nitric oxide in vitro. 877 74

We evaluated the effect of manipulation of nitric oxide (NO) synthesis on epileptiform discharges recorded from immobilized rats during intracerebroventricular injection of alpha-guanidinoglutaric acid (GGA), an endogenous convulsant and a NO synthase (NOS) inhibitor, alone or in combined with a NOS substrate, l-arginine (ARG). GGA alone, or combined with 50 mM ARG, resulted in prolonged electrographical seizures while co-injection of either 100 or 200 mM of ARG with GGA caused significantly protection. These data show that ARG inhibited epileptiform discharges in a dose-dependent fashion, suggesting that the discharges initiated by inhibition of NOS with the intrinsic convulsant GGA are abated by increasing the concentration of the NOS substrate ARG.
Biochem Mol Biol Int 1996 May
PMID:Seizures induced by alpha-guanidinoglutaric acid, a nitric oxide synthase inhibitor, are controlled by L-arginine. 879 31

NO synthase is present in human ovarian granulosa-luteal cells and NO inhibits estradiol secretion by granulosa cells in culture. These findings suggest that NO is an autocrine regulator of ovarian steroidogenesis. The purpose of this investigation was to explore the mechanisms through which NO exerts an inhibitory effect on cytochrome P450 aromatase activity. To examine the effect of NO on aromatase mRNA levels, human granulosa-luteal cells were cultured in the presence or absence of the NO donor SNAP for 16 h. Using a probe for human aromatase, Northern blots revealed a 26% decrease in aromatase mRNA in cells exposed to SNAP. Because this modest decrease in mRNA is unlikely to explain a rapid and profound reduction in estradiol secretion that we have observed, we looked for direct effects of NO on cytochrome P450 aromatase activity. Aromatase activity was assayed in placental microsomes and granulosa-luteal cells by measuring the release of 3H2O from [1 beta-3H] androstenedione. NO (10(-4)-10(-3)M), added as a saturated saline solution, reduced aromatase activity by as much as 90% in a concentration-dependent, non-competitive manner. In contrast, carbon monoxide (CO), a gas known to bind to the heme iron in aromatase, had no effect on aromatase activity when added alone nor could CO reverse the NO-induced inhibition of aromatase. These data suggest that NO binding to the heme is insufficient to inhibit aromatase activity. NO has been reported to alter protein function by reacting with the sulfhydryl group of cysteines, forming a nitrosothiol group. Because a cysteine sulfhydryl group is thought to participate in the catalytic mechanism of all P450 enzymes, experiments were designed to test whether NO might inhibit aromatase via such a mechanism. Addition of increasing amounts of mercaptoethanol, a chemical with free sulfhydryl groups, blocked the NO-induced inhibition of aromatase in microsomes. N-Ethylmaleimide, a chemical which covalently modifies sulfhydryl groups, reduced aromatase activity in a concentration-dependent manner. We conclude that NO inhibits aromatase both by decreasing mRNA for the enzyme and by an acute, direct inhibition of enzyme activity. We hypothesize that the direct inhibition occurs as a result of the formation of a nitrosothiol on the cysteine residue adjacent to the heme in aromatase.
J Steroid Biochem Mol Biol 1996 Apr
PMID:Nitric oxide inhibits aromatase activity: mechanisms of action. 880 86


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