Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Vascular resistance and sensitivity to circulating pressor and vasoconstrictor substances are blunted during pregnancy. This has been attributed mainly to an increased production of endothelium-derived mediators. The aim of the present study was to determine whether pregnancy changes the relative participation of nitric oxide (NO) and prostaglandins (PG) in the modulation of the contractile response to 5-hydroxytryptamine (5-HT) in two anatomically distint segments of the rat aorta. 2. Full concentration-response curves to 5-HT were obtained in isolated rings from the thoracic and abdominal portion of the aorta from pregnant and non-pregnant rats in the presence and absence of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10 micromol/L) or the PG synthesis inhibitor indomethacin (10 micromol/L). Cyclo-oxygenase (COX)-1, COX-2 and endothelial (e) NOS protein expression were determined in the same tissues by immunoblot. 3. The effects of pregnancy were accentuated in the abdominal compared with the thoracic aorta. In addition, the relative participation of the NO and PG pathways seems to be changed during pregnancy. Although NO seems to be the mediator mainly responsible for the effect of pregnancy in the thoracic aorta, our results suggest a complex interaction between NO and PG in the abdominal aorta. Indomethacin significantly reduced the contractile response of both segments of the aorta, whereas expression of COX-1, COX-2 and eNOS were increased only in the abdominal segment of pregnant animals. 4. These results show that the effect of pregnancy is not homogeneous along the aorta. There seems to be a mutual interaction between PG and NO in the abdominal, but not in the thoracic, aorta from pregnant rats: the role of NO becomes evident in the absence of vasodilatory PG, whereas the participation of the latter increases in the absence of NO working as a compensatory mechanism.
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PMID:Effect of pregnancy on the roles of nitric oxide and prostaglandins in 5-hydroxytryptamine-induced contractions in rat isolated thoracic and abdominal aorta. 1574 4

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates
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PMID:Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo. 1585 32

1. Noradrenaline (NA; 0.3 micromol/L) caused a contraction of the rat coronary artery that markedly increased in the presence of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 100 micromol/L) and arachidonic acid (1 micromol/L; P < 0.05). 2. The present experiments attempted to elucidate the endothelium dependency of the contraction and to pharmacologically characterize the factors involved in the contraction induced by NA (0.3 micromol/L) in the presence of L-NAME and arachidonic acid in ring preparations of the rat coronary artery. 3. The NA (0.3 micromol/L)-induced contraction was attenuated by a chemical remover of the endothelium (saponin at concentrations of 0.1 and 0.4 mg/mL) in a concentration-dependent manner (P < 0.05). 4. The cyclo-oxygenase (COX)-1 inhibitor flurbiprofen (0.01-1 micromol/L) and the COX-2 inhibitor nimesulide (0.01-1 micromol/L) attenuated the NA-induced contraction in a concentration-dependent manner and the inhibitory effect of flurbiprofen was significantly more potent than that of nimesulide (P < 0.05). The 5-lipoxigenase inhibitor ZM-230487 (1 micromol/L) did not affect the NA-induced contraction. 5. The thromboxane A2 (TXA2) synthetase inhibitor OKY-046 (30 micromol/L) and the TXA2 antagonist S-1452 (0.1-10 micromol/L) did not attenuate the NA-induced contraction. 6. These results indicate that the contraction induced by NA in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent and is due to endothelial COX metabolites of arachidonic acid.
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PMID:Involvement of endothelial cyclo-oxygenase metabolites in noradrenaline-induced contraction of rat coronary artery. 1612 Jan 89

The present study evaluates the effect of endogenous male sex hormones on the reactivity to alpha2-adrenoceptor activation, and to analyze the role of the endothelium in this response in intact and endothelially denuded superior mesenteric arteries from control and orchidectomized male Sprague-Dawley rats. The concentration-dependent constriction induced by clonidine was analyzed in the absence and presence of the nitric oxide synthase (NOS) inhibitor, Nomega-nitro-L-arginine (L-NAME), cyclooxygenase (COX-1 and COX-2) inhibitors, indomethacin, the specific COX-2 inhibitor NS-398, the thromboxane-prostanoid receptor antagonist SQ29,548 and the thromboxane A2 (TXA2) synthase inhibitor, furegrelate. Endothelial NOS (eNOS), COX-2 and TXA2 synthase protein expression was studied by Western blot analysis. In addition, the basal and clonidine-stimulated production of TXB2, the stable TXA2 metabolite, was also measured. In intact vessels from control male rats, the concentration-dependent constriction induced by clonidine was increased by both L-NAME or endothelial removal, unaltered by indomethacin and decreased by NS-398; in denuded vessels, the clonidine response was decreased by NS-398 and unaltered by L-NAME, indomethacin, SQ29,548 or furegrelate. In intact vessels from orchidectomized rats, the constriction induced by clonidine was increased by L-NAME but practically abolished by indomethacin or NS-398; in endothelially denuded segments the clonidine response was unaltered by L-NAME, but was decreased by indomethacin, NS-398, SQ29,548 or furegrelate. Orchidectomy failed to modify eNOS,COX-2 and TXA2 synthase expression, and increased basal and clonidine-stimulated TXB2 release. These results show that TXA2 produced in smooth muscle cells is increased in mesenteric arteries from orchidectomized rats compared to their controls, and that this prostanoid is functionally involved in the vasoconstrictor response to clonidine only in arteries from the orchidectomized rats.
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PMID:Orchidectomy modulates alpha2-adrenoceptor reactivity in rat mesenteric artery through increased thromboxane A2 formation. 1629 68

We examined whether nitric oxide (NO), derived from constitutive NO synthase (NOS) and/or inducible NOS (iNOS), could contribute to endotoxin-induced inflammatory hyperalgesia via interacting with nuclear factor-kappaB (NF-kappaB), inducible cyclooxygenase (COX-2) and/or polyADP-ribose synthase (PARS). Injection of endotoxin (10 mg kg(-1), i.p.) to mice elicited hyperalgesia, determined by hot plate test, which is prevented by NO precursor (L-arginine), cNOS/iNOS inhibitor (N(G)-nitro-L-arginine methyl ester; L-NAME), NF-kappaB inhibitor (N-acetylserotonin), COX inhibitor (indomethacin), COX-2 inhibitor (DFU) and PARS inhibitor (3-aminobenzamide). Endotoxin caused a decrease in serum nitrite levels prevented by N-acetylserotonin, L-arginine, indomethacin, DFU or 3-aminobenzamide. Endotoxin increased serum 6-keto-PGF(1alpha) levels diminished by L-arginine or aminoguanidine (iNOS inhibitor). L-Arginine, L-NAME, aminoguanidine, DFU or 3-aminobenzamide prevented endotoxin-induced decrease in heart, lungs, kidneys and brain nitrite and malonedialdehyde levels and myeloperoxidase activity. In conclusion, NO reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production, and also contributes to the analgesic effect of NF-kappaB, COX or PARS inhibitors.
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PMID:Nitric oxide reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production in mice. 1631 Mar 74

We studied the contractile activity and glucose metabolism, in terms of production of 14CO2 from [14C] glucose, in isolated uteri of immature rats. Immaturity was due to age or exposure to a restricted diet. The contractile activity in both prepubertal groups persisted for a period of 60 minutes and fell when indomethacin was added to the KRB medium. The production of 14CO2 was greater than for adult rats and fell as a result of the addition of indomethacin. The metabolism of [14C] arachidonic acid showed that the percentage of eicosanoids released in age related immature uteri was greater than that in restricted diet related immature uteri. In animals that are immature as a result of exposure to a restricted diet, 14CO2 fell due to the effect of NAME. Sodium nitroprusside and L-arginine increased the production of 14CO2. This effect was reverted by NAME and indomethacin. Conversely, the uteri of age related prepubertal rats were not affected. The level of activity of nitric oxide synthase was higher in restricted diet related immature animals and fell following the addition of NS-398. We may conclude that in rats exposed to a restricted diet, NO and COX-2 participate in glucose metabolism whereas they would not be involved in age related prepubertal animals.
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PMID:Glucose metabolism in isolated uteri of immature rats. Influence of prostaglandins and nitric oxide. 1643 10

The specific mechanisms by which skin blood flow increases in response to a rise in core body temperature via cutaneous active vasodilation are poorly understood. The primary purpose of this study was to determine whether the cyclooxygenase (COX) pathway contributes to active vasodilation during whole body heat stress (protocol 1; n = 9). A secondary goal was to verify that the COX pathway does not contribute to the cutaneous hyperemic response during local heating (protocol 2; n = 4). For both protocols, four microdialysis fibers were placed in forearm skin. Sites were randomly assigned and perfused with 1) Ringer solution (control site); 2) ketorolac (KETO), a COX-1/COX-2 pathway inhibitor; 3) NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor; and 4) a combination of KETO and L-NAME. During the first protocol, active vasodilation was induced using whole body heating with water-perfused suits. The second protocol used local heaters to induce a local hyperemic response. Red blood cell flux (RBC flux) was indexed at all sites using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC; RBC flux/mean arterial pressure) was normalized to maximal vasodilation at each site. During whole body heating, CVC values at sites perfused with KETO (43 +/- 9% CVCmax), L-NAME (35 +/- 9% CVCmax), and combined KETO/L-NAME (22 +/- 8% CVCmax) were significantly decreased with respect to the control site (59 +/- 7% CVCmax) (P < 0.05). Additionally, CVC at the combined KETO/L-NAME site was significantly decreased compared with sites infused with KETO or L-NAME alone (P < 0.05). In the second protocol, the hyperemic response to local heating did not differ between the control site and KETO site or between the L-NAME and KETO/L-NAME site. These data suggest that prostanoids contribute to active vasodilation, but do not play a role during local thermal hyperemia.
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PMID:Prostanoids contribute to cutaneous active vasodilation in humans. 1648 40

Renal cyclooxygenase (COX)-2 expression and arachidonic acid-stimulated prostaglandin release are increased in streptozotocin-diabetic rats and are reduced by tempol treatment, indicating a role for superoxide. Generation of nitric oxide (NO) and its product with superoxide, peroxynitrite, is also increased in diabetes and can induce COX-2. To investigate a role of NO, rats were treated with L-nitroarginine methyl ester (L-NAME; 100 mg/kg/day) to inhibit NO synthase (NOS) for 14-18 days. In isolated perfused kidneys from diabetic rats, prostaglandin release and vasoconstrictor responses to arachidonic acid were increased and renal cortical expression of COX-2 was 2-fold that of control rats. Treatment of diabetic rats with L-NAME reduced arachidonic acid-stimulated release of prostaglandins and the expression of COX-2. L-NAME increased vasoconstrictor responses to AA in diabetic and non-diabetic rats but abolished the differences between the two. These results, coupled with those using tempol, suggest that NO or its product with superoxide may contribute to the induction of renal COX-2 in the diabetic rat.
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PMID:Effect of inhibition of nitric oxide synthase on renal cyclooxygenase in the diabetic rat. 1675 43

The effects of selective cyclooxygenase (COX) isoform (COX-1, COX-2) inhibition, alone or in combination with nitric-oxide synthase (NOS) blockade, on in vitro tracheal muscle responsiveness to histamine were investigated in healthy and ovalbumin (OVA)-sensitized guinea pigs. Immunohistochemistry showed that COX-1 and COX-2 are constitutively present in normal guinea pig trachea, particularly in the epithelial layer, and that COX-2 expression is enhanced in OVA-sensitized animals both in epithelial and subepithelial tissues. In normal guinea pigs, SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor) or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) significantly increased the contractile response to histamine, these effects being not additive. NOS inhibition by l-N(G)-nitro-arginine methyl ester (l-NAME) did not affect histamine-induced contraction but reversed the increase caused by COX-1 blockade while not modifying the enhancement associated with COX-2 inhibition. In guinea pigs subjected to OVA sensitization and challenge, COX-2, but not COX-1, inhibition enhanced the motor responses to histamine without any influence by l-NAME. In normal, but not in sensitized animals, the removal of epithelial layer from tracheal preparations abolished the enhancing action of DFU on histamine-mediated contraction. A COX-2-dependent release of prostacyclin (PGI(2)), but not prostaglandin E(2), was observed in tracheal tissues from normal and OVA-sensitized guinea pigs. In conclusion, both COX-1 and COX-2 are constitutive in guinea pig trachea, and COX-2 expression is enhanced by OVA sensitization; in normal animals, epithelial COX-2 exerts a PGI(2)-dependent inhibitory control on tracheal contractility, and this isoform is subjected to upstream regulation by epithelial COX-1 and NOS through a complex interplay; and following antigen sensitization, the inhibitory control on tracheal contractility is maintained by COX-2 induced at subepithelial cell sites.
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PMID:Role of cyclooxygenase isoforms and nitric-oxide synthase in the modulation of tracheal motor responsiveness in normal and antigen-sensitized Guinea pigs. 1692 67

The aim of the present study was to determine the effect of social crowding stress and significance of nitric oxide (NO) and prostaglandins (PG) generated by constitutive and inducible nitric oxide synthase (NOS) and cyclooxygenase (COX) in the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic receptor agonist carbachol. Inhibitors of neuronal NOS (nNOS) L-NNA, general NOS L-NAME and inducible NOS (iNOS) aminoguanidine, as well as inhibitors of COX-1, piroxicam, and COX-2, compound NS-398 were administered 15 min prior to carbachol to control or crowded rats (24 rats in cage for 7, during 3 and 7 days). In stressed rats L-NAME, L-NNA and aminoguanidine significantly intensified the carbachol-induced ACTH and corticosterone secretion, like in control rats. Piroxicam, markedly decreased the carbachol-induced ACTH and corticosterone response under either basal or stress conditions. Compound NS-398 did not markedly alter the carbachol-induced HPA response in control and stressed rats. Crowding stress (3 days) significantly impaired the i.c.v. prostaglandin E(2)-induced ACTH response. Corticotropin releasing hormone (CRH) receptor antagonists, alpha-helical CRH [9-14], given i.c.v. did not alter the PGE(2)-evoked corticosterone response in either control or stressed rats, indicating that hypothalamic CRH is not involved in the PGE(2)-induced central stimulation of HPA axis. In control rats L-NAME considerably enhanced, while L-arginine, a physiological NOS substrate, abolished the PGE(2)-induced ACTH and corticosterone response. In stressed rats this NOS blocker significantly increased and L-Arg reduced the stimulatory effect of PGE(2) on ACTH and corticosterone secretion. The carbachol-induced corticosterone response was significantly increased by pretreatment with nNOS inhibitor L-NNA and was considerably reduced by indomethacin, a general COX inhibitor. Pretreatment with both antagonists left the carbachol-induced corticosterone level unchanged, suggesting an independent and reciprocal effect of NO and PG in the cholinergic stimulation of pituitary-adrenocortical response. These results indicate that in the stimulatory action of muscarinic agonist, carbachol, NO is an inhibitory transmitter under basal and crowding stress conditions. This psychosocial stress does not functionally affect the NOS/NO systems. Prostaglandins are involved in the cholinergic muscarinic-induced stimulation of HPA response to a significant extent in non-stressed rats. PGE(2) may be involved in the carbachol-elicited HPA response under basal and stress conditions. Prostaglandins released in response to muscarinic stimulation did not evoke the hypothalamic CRH mediation. NO significantly impairs and PG stimulates the carbachol-induced HPA response in rats under basal and social stress conditions.
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PMID:The involvement of nitric oxide and prostaglandins in the cholinergic stimulation of hypothalamie-pituitary-adrenal response during crowding stress. 1703 98


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