UMLS:C0406810 - FACTA Search

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)

The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous l-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute l-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous l-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI(2), PGE(2) and PGD(2)) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA(2) and PGF(2alpha)) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic l-NAME treatment. Although urinary excretion of PGI(2) and PGE(2) metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.
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PMID:Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids. 1716 89

It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we demonstrated that the selective COX-2 inhibitor NS-398 significantly reduced the probability of long-term potentiation (LTP) induction in the lateral nucleus of the amygdala. Similarly, in COX-2(-/-) mice, LTP induced by external capsule (EC) stimulation was impaired. Second, we evaluated the action of angiotensin-(1-7) in the amygdala. In wild-type mice, angiotensin-(1-7) increased LTP. This LTP-enhancing effect of Ang-(1-7) was not observed in COX-2(+/-) mice. However, in COX-2(-/-) mice, Ang-(1-7) caused an enhancement of LTP similar to that in wild-type mice. The NO synthetase inhibitor L-NAME blocked this angiotensin-(1-7)-induced increase in LTP in COX-2(-/-) mice. Low-frequency stimulation of external capsule fibers did not cause long-term depression (LTD) in drug-free and angiotensin-(1-7)-treated brain slices in wild-type mice. In contrast, in COX-2(-/-) mice, angiotensin-(1-7) caused stable LTD. Increasing NO concentration by the NO-donor SNAP also caused LTD in wild-type mice. Our study shows for the first time that LTP in the amygdala is dependent on COX-2 activity. Moreover, COX-2 is involved in the mediation of angiotensin-(1-7) effects on LTP. Finally, it is recognized that there is a molecular cross-talk between COX-2 and NO that may regulate synaptic plasticity.
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PMID:Angiotensin-(1-7)-induced plasticity changes in the lateral amygdala are mediated by COX-2 and NO. 1735 Nov 41

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg.kg(-1).day(-1)), and NO-aspirin (56 mg.kg(-1).day(-1)). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n = 23), aspirin (n = 22), and NO-aspirin groups (n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 +/- 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 +/- 1.8 and 22.9 +/- 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemia-reperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.
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PMID:Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. 1752 56

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a cerebrovascular dilator and was found neuroprotective in numerous in vitro and in vivo models of cerebral ischemia. However, the mechanism of its cerebrovascular action is poorly known, especially in newborns. Therefore, we tested pial arteriolar responses to the two naturally occurring forms PACAP27 and 38 as well as to shorter sequences (PACAP6-27, 6-38, 1-15, 6-15, 20-31). We also investigated the involvement of nitric oxide synthase (NOS), cyclooxygenase-1 and -2 (COX-1 and -2) activity in PACAP-induced pial arteriolar responses using the NOS inhibitor N-omega-nitro-l-arginine methyl ester (L-NAME 15 mg/kg iv), the non-selective COX inhibitor indomethacin (5 mg/kg iv), and the selective COX-1 and COX-2 inhibitors SC-560 (1 mg/kg iv) and NS-398 (1 mg/kg iv), respectively. Anesthetized, ventilated piglets (n=127) were equipped with closed cranial windows, and pial arteriolar diameters were determined via intravital microscopy. Topical application of both natural PACAPs, but none of the PACAP segments, resulted in prominent, repeatable, dose-dependent vasodilation. Percentage changes ranged 5+/-1-29+/-6 (n=7) and 4+/-1-36+/-7 (n=9) to 10(-)(8) to 10(-)(6) M PACAP27 and 38 (mean+/-SEM), respectively. Vasodilation to both natural PACAPs was significantly reduced by co-application with PACAP6-27 or 6-38, but not by L-NAME. Indomethacin abolished PACAP38 but not PACAP27-induced vasodilation. Arteriolar responses to PACAP38 were also sensitive to SC-560 but not to NS-398 suggesting the unique involvement of COX-1 activity in this response. In summary, PACAP27 and 38 are potent vasodilators in the neonatal cerebral circulation with at least two distinct mechanisms of action: a COX-dependent and a COX-independent pathway.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces pial arteriolar vasodilation through cyclooxygenase-dependent and independent mechanisms in newborn pigs. 1765 92

Exposure of macrophages to heat shock induces rapid synthesis of heat shock proteins (HSPs) which are important for cell homeostasis. Prostaglandins (PGs) and nitric oxide (NO) are important cell regulatory molecules. We have therefore investigated the interactions between these molecules in the LPS-induced expression of iNOS and COX-2 and in the mitochondrial activity of macrophages. Cultures of the murine macrophage cell line, J774, were exposed to heat shock (43 degrees C, 30 min) and stimulated with LPS (1 microg/ml), concomitantly or after 8h of cell recovery. NO production was measured by Griess reaction; PGE(2) by ELISA; HSP70, iNOS and COX-2 by immunobloting; mitochondrial activity by MTT assay. Heat shock induced HSP70, but not iNOS or COX-2 whereas LPS induced iNOS and COX-2 but not HSP70. When heat shock and LPS were given concomitantly, iNOS but not COX-2 expression was reduced. When a period of 8h was given between heat shock and LPS stimulation, iNOS, COX-2, PGE(2) and NO levels were significantly increased. Under these conditions, the expression of COX-2 was reduced by L-NAME (NO-synthesis inhibitor) and of iNOS by nimesulide (PGs-synthesis inhibitor). Such cross-regulation was not observed in cells at 37 degrees C. These treatments significantly reduced MTT levels in cells at 37 degrees C but not in cells submitted to heat shock. These results suggest that HSPs and cross-regulation of iNOS and COX-2 by their products might be of relevance in the control of cell homeostasis during stress conditions.
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PMID:Cross-regulation of iNOS and COX-2 by its products in murine macrophages under stress conditions. 1776 57

This study examined the role of nitric oxide (NO) on the expression of the hepatic vasoregulatory gene during polymicrobial sepsis. Aminoguanidine (AG, 100 mg/kg) or Nomega-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) was injected intraperitoneally at 0, 3, 6, 10, and 20 h after a cecal ligation and puncture (CLP). The heart rate increased 24 h after the CLP, and this increase was attenuated by L-NAME and further attenuated by AG. The mean arterial pressure in the CLP animals did not change significantly 24 h after the onset of sepsis but was increased after the L-NAME injection. Sepsis increased the serum aminotransferase levels, which were attenuated by AG but augmented by L-NAME. CLP increased the mRNA level of the ET-1 and ETB receptors in the liver. This increase was prevented by AG but augmented by L-NAME. The level of iNOS and HO-1 mRNA expression were increased by CLP, which was prevented by both AG and L-NAME. The level of TNF-alpha and COX-2 mRNA expression increased after CLP, and was attenuated by AG. These results show that iNOS and eNOS are regulated differently in sepsis. While eNOS appears to have a protective role in liver microcirculation, the strong upregulation of iNOS might contribute to a microvascular dysfunction and hepatic injury.
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PMID:Role of nitric oxide in the expression of hepatic vascular stress genes in response to sepsis. 1788 72

Peroxynitrite (ONOO(-)), the reaction product of the interaction between superoxide (O(2)(*-)) and nitric oxide (*NO), is a potent proinflammatory and cytotoxic nitrooxidative species. Its role as a mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) is not known. In light of the known proinflammatory properties of ONOO(-), our study addressed its potential involvement in the development of hyperalgesia associated with tissue damage and inflammation. Intraplantar injection in rats of the ONOO(-) precursor O(2)(*-) (1 microM) led to the development of thermal hyperalgesia associated with a profound localized inflammatory response. Both events were blocked by L-NAME (N(G)-nitro-L-arginine methyl ester, 3-30 mg/kg), a nitric oxide synthase inhibitor, or by FeTM-4-PyP(5+) [Fe(III)5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, 3-30 mg/kg], an ONOO(-) decomposition catalyst. These results suggested that locally synthesized ONOO(-) produced in situ by O(2)(*-) and *NO is key in the development of inflammatory hyperalgesia. The direct link between ONOO(-) and hyperalgesia was further supported by demonstrating that intraplantar injection of soluble ONOO(-) itself (1 microM) similarly led to inflammatory hyperalgesia. ONOO(-) generated by the interaction between exogenous administration of O(2)(*-) and endogenous *NO, or provided by direct injection of ONOO(-), activated the transcription factor NF-kappaB in paw tissues, enhancing expression of the inducible but not the constitutive cyclooxygenase enzyme (COX-2 and COX-1, respectively). ONOO(-)-mediated hyperalgesia was blocked in a dose-dependent manner by intraperitoneal injections of indomethacin (10 mg/kg), a nonselective COX-1/COX-2 inhibitor, or NS398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 10 mg/kg] a selective COX-2 inhibitor, as well as by an anti-prostaglandin (PG) E(2) antibody (200 microg). In another established model of inflammation-related hyperalgesia by intraplantar injection of carrageenan in rats, inhibition of ONOO(-) with FeTM-4-PyP(5+) (3-30 mg/kg) inhibited the development of hyperalgesia and the release of PGE(2) in paw tissue exudates. Furthermore, FeTM-4-PyP(5+) synergized with indomethacin and NS397 (1-10 mg/kg) to block both hyperalgesia and edema. Taken together, these data show for the first time that ONOO(-) is a potent mediator of inflammation-derived hyperalgesia operating via the COX-to-PGE(2) pathway. These results provide a pharmacological rationale for the development of inhibitors of peroxynitrite biosynthesis as novel nonnarcotic analgesics. The broad implications of our study are that dual inhibition of both ONOO(-) formation and COX activity may provide an alternative therapeutic approach to the management of pain: effective analgesia with reduced side-effects typically associated with the use of COX inhibitors.
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PMID:Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. 1849 4

Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.
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PMID:Increased expression of renal cyclooxygenase-2 and neuronal nitric oxide synthase in hypertensive Cx40-deficient mice. 1881

The present study investigated the role of kinins, prostaglandins (PGs) and nitric oxide (NO) in mechanical hypernociception, spontaneous nociception and paw oedema after intraplantar (ipl) injection of Tityus serrulatus venom (Tsv) in male Wistar rats. Tsv was ipl-injected in doses of 0.01-10microg/paw. Pre-treatment (30min prior) with DALBK (100nmol/paw) and icatibant (10nmol/paw), B1 and B2 selective kinin receptor antagonists, L-NAME (50mg/kg, i.p., a non-selective nitric oxide synthase inhibitor) or celecoxib, selective COX-2 inhibitor, was given 1h prior per os (5mg/kg, p.o.), significantly reduced the hypernociceptive response (Von Frey method), the spontaneous nociception (determined by counting the number of flinches) and paw oedema (plethysmometer method) induced by Tsv at doses of 1.0 and 10microg/paw for both nociceptive and oedematogenic responses, respectively. Nevertheless, indomethacin (5mg/kg, i.p., 30min prior) was ineffective in altering all of these events. The results of the present study show that Tsv, injected ipl into the rat paw, causes a dose-dependent paw oedema, mechanical hypernociception and flinches (a characteristic biphasic response) in which kinins and NO are substantially involved. Although celecoxib was effective against the oedema and pain caused by Tsv, COX-2 does not seem to be involved in the inflammatory response caused by Tsv.
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PMID:Inflammatory mediators involved in the nociceptive and oedematogenic responses induced by Tityus serrulatus scorpion venom injected into rat paws. 1884 77

Nitric oxide (NO) and cyclooxygenase (COX)-derived prostaglandins are critical regulators of the fetal ductus arteriosus. To examine the interaction of these pathways within the ductus wall, the ductus arteriosus of term and preterm fetal mice was evaluated by pressurized myography. The isolated preterm ductus was more sensitive to NOS inhibition than at term. Sequential NOS and COX inhibition caused 36% constriction of the preterm ductus regardless of drug order. In contrast, constriction of the term ductus was dependent on the sequence of inhibition; NOS inhibition prior to COX inhibition produced greater constriction than when inhibitors were given in reverse order (36+/-6% versus 23+/-5%). Selective COX-1 or COX-2 inhibition prior to N(G)-nitro-l-arginine methyl ester (l-NAME) induced the expected degree of constriction. However, NOS inhibition followed by selective COX-2 inhibition caused unexpected ductal dilation. These findings are consistent with NO-induced activation of COX in the ductus arteriosus wall and the production of a COX-2-derived constrictor prostanoid that contributes to the balance of vasoactive forces that maintain fetal ductus arteriosus tone.
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PMID:Regulation of the fetal mouse ductus arteriosus is dependent on interaction of nitric oxide and COX enzymes in the ductal wall. 1904 98

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