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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Nitric oxide (NO) synthase is a hemoprotein containing several cysteinyl residues including thiolate as its proximal heme ligand. Exposure to NO is known to induce S-nitrosylation of protein thiols and modulation of enzyme activities, including the catalytic activity of NO synthase. Because S-nitrosylation of vicinal thiols promotes disulfide formation, we determined whether exposure to NO results in modulation of the catalytic activity of NO synthase and whether disulfide reduction catalyzed by thioredoxin/thioredoxin reductase (T/TR) and/or by glutaredoxin restores the catalytic activity of NO synthase in pulmonary artery endothelial cells (PAEC). Exposure of intact PAEC, isolated total membranes, plasma membranes, or purified NO synthase to NO significantly reduced NO synthase catalytic activity. Similarly, exposure of isolated total membranes or purified NO synthase to potassium ferricyanide (FeCN) also reduced catalytic activity of NO synthase in a concentration-dependent fashion. Although the catalytic activity of NO synthase was significantly reduced following exposure of intact cells to NO, the expression of NO synthase mRNA was unchanged. NO synthase activity in intact cells or isolated membranes exposed to nitrate, nitrite, or 10 ppm nitrogen dioxide gas was comparable to controls. Incubation in the presence of oxyhemoglobin prevented but did not reverse NO-induced inhibition of NO synthase. Incubation in the presence of T/TR but not glutaredoxin reversed NO-induced reduction of NO synthase activity and a purified enzyme preparation exposed directly to NO. Similarly, FeCN-induced reduction of NO synthase activity was also reversed in the presence of T/TR but not by glutaredoxin. These results demonstrate that the interaction of NO with the regulatory domain of NO synthase protein is responsible for post-translational reduction of its catalytic activity. Thioredoxin-regulated reversal of NO-induced modulation of NO synthase protein suggests that an oxidative conformational change in vicinal thiols, resulting in the formation of intramolecular or intermolecular disulfides or both, is involved.
Am J Respir Cell Mol Biol 1996 Sep
PMID:Nitric oxide-induced inhibition of lung endothelial cell nitric oxide synthase via interaction with allosteric thiols: role of thioredoxin in regulation of catalytic activity. 881 Jun 47

The aim of this study was to assess the nature of vascular hyporeactivity to vasopressor agents in rats with endotoxemia. Endotoxemia was induced in rats by bacterial endotoxin (E. Coli lipopolysaccaharide, LPS). In LPS-treated rats, the reactivity of endothelium-denuded aortic rings to phenylephrine (PE) and potassium chloride (KCl) was characterized by a decreased magnitude of contraction, a slower onset of contraction and a faster rate of relaxation when compared to the control aortic rings. Addition of L-arginine (L-arg), the substrate of nitric oxide synthase (NOS), but not D-arginine (D-arg), reduced further PE-induced contraction in rings from LPS-treated rats. Inhibition of contraction in rings of LPS-treated rats was partially antagonized by the inhibitor of NOS, N omega-nitro-L-arginine methyl ester (L-NAME). Thus, production of non-endothelial nitric oxide (NO) was in part responsible for the hyporesponsiveness to PE. Rings from LPS-treated rats also displayed hyporeactivity and decreased sensitivity to Ca2+ in depolarizing medium (60 mM K+). Hyporeactivity and hyposensitivity to Ca2+ could only be partially reversed by L-NAME. The inhibitory effects of LPS-treatment on both PE-and KCl-induced aortic responses and the reversal effects of L-NAME confirm the contention that NO formation is involved in vascular hyporesponsiveness in endotoxic shock. The partial reversal by L-NAME of the hyporesponsiveness to KCl- and PE-induced contraction, and hyposensitivity to Ca2+ in depolarized aorta suggest that factors other than the action of nonendothelial source of NO formation in vitro from L-arg also contribute to endotoxin-induced vascular hyporesponsiveness to vasopressor agents.
Res Commun Mol Pathol Pharmacol 1996 Jun
PMID:Hyporesponsiveness to Ca2+ of aortic smooth muscle in endotoxin-treated rats: no-dependent and -independent in vitro mechanisms. 882 26

The dose effects of two nitric oxide synthase (NOS) inhibitors: NG-nitro-L-arginine (L-NNA) and N omega-monomethyl-L-arginine (L-NMMA), were evaluated in an established rat model of retinal ischemia using morphometry of the inner retina: inner retinal thickness (IRT) measurements and retinal ganglion cell counts (RGCCs) of the posterior and peripheral retina. By IRT and RGCCs of the posterior retina, there were dose dependent beneficial effects of both inhibitors. However, by RGCCs of the peripheral retina, there was no significant beneficial effect by either inhibitor. In addition, L-NMMA at 0.3 mg/kg aggravated the loss of RGC in both the posterior and peripheral retina. An important role and a possible differential site of action of NOS in the pathophysiology of retinal ischemia are implicated.
Res Commun Mol Pathol Pharmacol 1996 Jun
PMID:Nitric oxide synthase (NOS) inhibitors ameliorate retinal damage induced by ischemia in rats. 882 30

The proposed method of multiple alignment of secondary structures makes it possible to estimate the multidomain enzymes' structural similarity in those cases where, following alignment, the identity appears to be inadequate or too insignificant to estimate protein relationship in spite of their functional analogy. Multiple alignment of sequences, representing the secondary structural elements of the nitric oxide synthase (NOS) N-terminal "tails", localized upstream of the calmodulin (CAM)-binding domain, and the P450 superfamily representative P450BM-3 has revealed the existence of a common secondary structural motif, standing of 60% identity between the polypeptide chain packing of NOS and the full sequence of P450BM3. This fact may point to the existence of their common ancestor. Presence of the linker olygopeptides within NOS permitted us to determine the boundary of the cytochrome-like part of NOS.
Biochem Mol Biol Int 1996 Mar
PMID:Comparative analysis of the secondary structural motifs of P450BM-3 and the regions located upstream of the calmodulin-binding domain in the nitric oxide synthases. 882 15

Effects of clonidine on the elevated arterial diastolic blood pressure induced by infusion of alpha 1-adrenoceptor agonists were studied in pithed rats. Intravenous injection of clonidine resulted in a dose-dependent pressor response at a resting state and a further increase in the moderately elevated diastolic blood pressure induced by infusion of lower doses of phenylephrine and methoxamine. However, clonidine produced a depressor response when diastolic blood pressure was elevated by around 100 mmHg during infusion of higher doses of alpha 1-adrenoceptor agonists. The depressor response to clonidine was dose-dependent at a dose range of 10 to 1000 micrograms/kg. On the other hand, clonidine failed to cause the depressor response while diastolic pressure was elevated by infusion of vasopressin by around 100 mmHg. NG-methyl-L-arginine, a nitric oxide synthase inhibitor, and propranolol, a beta-adrenoceptor antagonist, did not affect the depressor response to clonidine. After pretreatment with yohimbine, an alpha 2-adrenoceptor antagonist, the depressor response to clonidine was inhibited, but prazosin, an alpha 1-adrenoceptor antagonist, did not suppress the depressor response. These results demonstrate that clonidine specifically depresses the pressor response to alpha 1-adrenoceptor agonists in pithed rats via a mechanism which is not mediated by beta-adrenoceptors and independent of endothelium-dependent relaxing factor, and suggest that a yohimbine-sensitive mechanism may be related to the clonidine effect.
Res Commun Mol Pathol Pharmacol 1996 Mar
PMID:Characteristics of depression by clonidine of the pressor response to alpha 1-adrenoceptor agonists in pithed rats. 882 67

The influence of low or high (10 or 25 mM) K(+)-induced membrane depolarization on the mRNA levels for NMDA receptor subunits was investigated by RNase protection assay in cultured rat cerebellar granule cells. Cells, maintained for 7 days in K25+, a condition that promotes their survival and maturation, express the highest levels of NR-1 and NR-2A mRNA, whereas NR-2B is maximally expressed in cells grown in K10+. Acute changes in medium K+ concentration had a significant effect on the mRNA levels for NMDA receptor subunits. A concomitant reduction of NR-2A mRNA and induction of NR-2B was observed following a 24-h shift of the culture medium from K25+ to K10+. Under these circumstances NR-2C, not detected in basal conditions, became expressed. Neuronal nitric oxide synthase, an enzyme linked to NMDA receptor activation, was also influenced by growth conditions. Its expression, higher under low excitation (K10+), is induced in the shift from K25+ to K10+ and is markedly decreased in the opposite situation. These data indicate that several factors may influence the expression of NMDA receptor subunits and consequently may modulate the function of this receptor complex and its adaptation to acute and chronic changes in neuronal activity.
Brain Res Mol Brain Res 1996 Aug
PMID:Acute and chronic changes in K(+)-induced depolarization alter NMDA and nNOS gene expression in cultured cerebellar granule cells. 884 29

We investigated the effects of alpha 1-adrenergic stimulation on nitric oxide (NO) production by cardiac myocytes. Incubation of cultured neonatal rat cardiac myocytes with interleukin-1 beta (IL-1 beta) caused a significant increase in the production of nitrite, a stable metabolite of NO. Addition of phenylephrine significantly augmented nitrite production by IL-1 beta-stimulated but not by unstimulated myocytes in a dose-dependent manner. The effect of phenylephrine was completely abolished in the presence of NG-monomethyl-L-arginine (L-NMMA) or actinomycin D. Northern blotting revealed increased inducible NO synthase mRNA accumulation in cardiac myocytes treated with IL-1 beta and phenylephrine compared with those treated with IL-1 beta alone. After protein kinase C activity was functionally depleted by treating cells with phorbol 12-myristate 13-acetate for 24 h, phenylephrine did not augment IL-1 beta-induced NO production. The effect of phenylephrine was also abolished in the presence of protein kinase C inhibitor calphostin C. These observations suggest that alpha 1-adrenergic stimulation causes an upregulation of cytokine-induced NO production by cardiac myocytes, which is mediated at least partially via activation of protein kinase C.
J Mol Cell Cardiol 1996 Jul
PMID:Alpha-adrenergic stimulation enhances inducible nitric oxide synthase expression in rat cardiac myocytes. 884 41


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