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)

L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. Their effect on endothelial dysfunction in hypertension was studied after treatment with either 200 mg/kg of L-carnitine or propionyl-L-carnitine during 8 weeks of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Endothelial function was assessed in aortic rings by carbachol-induced relaxation (CCh 10(-8) to 10(-4) M) and factors involved were characterized in the presence of the inhibitors: L-NAME, indomethacin, the TXA2/PGH2 Tp receptor antagonist ICI-192,605 and the thromboxane synthetase inhibitor-Tp receptor antagonist, Ro-68,070. The effect on phenylephrine-induced contractions was also observed. To identify the nature of vasoactive COX-derived products, enzyme-immunoassay of incubation media was assessed. Involvement of reactive oxygen species was evaluated by incubating with superoxide dismutase and catalase. Nitric oxide production was evaluated by serum concentration of NO2+NO3.Treatment with both compounds improved endothelial function of rings from SHR without blood pressure change. Propionyl-L-carnitine increased NO participation in WKY and SHR. L-carnitine reduced endothelium-dependent responses to CCh in WKY due to an increase of TXA2 production. In both SHR and WKY, L-carnitine enhanced concentration of PGI2 and increased participation of NO. Results in the presence of SOD plus catalase show that it might be related to antioxidant properties of L-carnitine and propionyl-L-carnitine. Comparison between the effect of both compounds shows that both may reduce reactive oxygen species and increase NO participation in endothelium-dependent relaxations in SHR. However, only L-carnitine was able to increase the release of the vasodilator PGI2 and even enhanced TXA2 production in normotensive rats.
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PMID:L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products. 1595 69

Following injury or surgical resection, the liver has the remarkable ability to regenerate. Despite over 100 years of research, the trigger of the liver regeneration cascade has only recently been identified. Shear stress-induced nitric oxide (NO), released secondary to a hemodynamic event following partial hepatectomy (PHX), has been implicated as the trigger of the liver regeneration cascade. However, it is also known that prostaglandins (PGs) are released following PHX, and in response to shear stress. Therefore, it is hypothesized that PGs, released secondary to an increase in the blood flow-to-liver mass ratio following PHX, trigger the liver regeneration cascade, and that NO and PGs interact during the triggering event. An index of initiation of the liver regeneration cascade, c-fos mRNA expression 15 min after PHX, has been employed. As expected, c-fos mRNA expression increased 15 min after PHX and this increase was inhibited by the NO synthase antagonist, l-NAME. This inhibition was reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. Also, the increase in c-fos mRNA expression was inhibited by indomethacin, a cyclooxygenase antagonist. This inhibition was also reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. These results suggest that there is interaction between NO and PGs in triggering the liver regeneration cascade, and that in a situation where either NO or COX is inhibited, provision of excess exogenous NO or PGs can reverse the inhibition. This suggests that exogenous NO and/or PGs may play a role in potentiation of the liver regeneration cascade.
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PMID:The role of prostaglandins in triggering the liver regeneration cascade. 1600 58

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

In the present study, we examined the effects of L-nitroarginine methylester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, indomethacin (IND), a non-selective COX inhibitor and a combination of these agents (L-NAME+IND) on carrageenan-induced pleurisy in rats. Exudate volume, albumin leakage, leukocyte influx, exudate and plasma nitrite/nitrate (NO(x)) levels and exudate PGE(2) levels increased markedly 6 h after an intrapleural injection of 2% carrageenan. First, the effects of L-NAME and IND alone were investigated. L-NAME non-significantly reduced exudate volume by 26% at 10 mg/kg (i.p.), and significantly by 45% at 30 mg/kg. IND dose-dependently decreased the exudate volume at 0.3-10 mg/kg (p.o.) and the effect reached the maximal level at 1 mg/kg (33%). Second, the effects of L-NAME (10 mg/kg, i.p.), IND (1 mg/kg, p.o.) and L-NAME+IND were examined. L-NAME and IND alone at the dose employed significantly reduced the exudate volume and albumin levels by 21-26%. L-NAME but not IND tended to reduce the increased exudate and plasma NO(x) by 18% and 19%, respectively. IND but not L-NAME significantly reduced leukocyte numbers and PGE(2) levels in the exudates by 25% and 77%, respectively. L-NAME+IND significantly reduced exudate volume, albumin leakage, leukocyte number, PGE(2) and NO(x) by 43%, 41%, 31%, 80% and 37%, respectively. The inhibitory effects of L-NAME+IND on exudate volume, albumin leakage and NO(x) levels were greater than those of L-NAME and IND alone. In conclusion, a non-selective NOS inhibitor and COX inhibitor showed anti-inflammatory effects at the early phase of carrageenan-induced pleurisy, and a combination of both inhibitors had a greater effect than each alone probably via the potentiation of NOS inhibition. The simultaneous inhibition of NOS and COX could be a useful approach in therapy for acute inflammation.
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PMID:Effect of combination of nitric oxide synthase and cyclooxygenase inhibitors on carrageenan-induced pleurisy in rats. 1648 Oct 7

Nitric oxide synthases (NOS) and cyclooxygenase-2 (COX-2) are important enzymes involved in ulcer healing but interactions between them have not been clearly defined. The aim of this study was to investigate the effects of selective or non-selective inhibition of NOS on the expression and activity of COX-2 during healing of acetic acid-induced gastric ulcers in rats. N-[3-(aminomethyl)benzyl] acetamidine (1400 W), a potent selective inhibitor of inducible nitric oxide synthase (iNOS), at a dose of 0.1 mg/kg/day, was found to reduce the ulcer sizes at day 3 and 7 post-ulcer induction. On the other hand, 15 mg/kg/day of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor that suppresses both iNOS and endothelial nitric oxide synthase (eNOS), enlarged the ulcer sizes over the same time periods. The expression of COX-2 and COX activity, together with NF-kappaB activation in the ulcer tissues were down-regulated by L-NAME but not 1400 W. It is concluded that iNOS may contribute to ulcer formation while COX-2 and eNOS promote ulcer healing. eNOS enhances COX-2 expression possibly through the activation of NF-kappaB.
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PMID:Differential effects of selective and non-selective inhibition of nitric oxide synthase on the expression and activity of cyclooxygenase-2 during gastric ulcer healing. 1660 Feb 10

Recently, we have reported that bradykinin (Bk)-induced vasodilation was selectively potentiated by a low concentration of reactive oxygen species (ROS) generated by xanthine/xanthine oxidase system (XOX) in the coronary circulation of the isolated guinea pig heart. In an attempt to identify a mechanism of Bk response that is amplified by XOX, we analyze here the involvement of B1/ B2 receptors and the participation of NOS/COX pathways in the Bk responses before and after intracoronary infusion of XOX in the isolated guinea pig heart. Bk (0.3-3 pmoles) and acetylcholine (Ach) (100-300 pmoles) induced a dose-dependent coronary vasodilation. In the presence of a non-selective nitric oxide synthase (NOS) inhibitor L-NAME (10(-4) M) and non-selective cyclooxygenase inhibitor indomethacin (5 x 10(-5)M), vasodilation induced by Bk or Ach was inhibited. XOX infusion into the coronary circulation augmented Bk-induced vasodilation by approximately 100-300%. This effect was sustained and was observed at least 1h after XOX infusion. In contrast to Bk response, vasodilation induced by Ach was not modified by XOX infusion. Surprisingly, in the presence of L-NAME+indomethacin, Bk-induced response was still amplified by XOX. In relative terms, this effect was even more pronounced. Again, under these experimental conditions, the response to Ach remained largely unchanged. In the presence of B2 receptor antagonist, icatibant (100 nM), Ach-induced vasodilation was unaffected, while Bk-induced vasodilation was abolished before and after XOX. In conclusion, in the isolated guinea pig heart low concentration of exogenous ROS generated by XOXsystem resulted in a sustained augmentation of Bk-induced coronary vasodilatation that cannot be explained by the up-regulation of B1 receptors, or the amplification of activity of NOS-cGMP or COX pathways. The chemical identity of NOS/COX-independent component of Bk response that is up-regulated by XOX remains to be determined. EDHF is the most likely candidate.
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PMID:Free radicals generated by xanthine/xanthine oxidase system augment nitric oxide synthase (NOS) and cyclooxygenase (COX)-independent component of bradykinin-induced vasodilatation in the isolated guinea pig heart. 1684 15

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

Reactive hyperaemia is the increase in blood flow following arterial occlusion. The exact mechanisms mediating this response in skin are not fully understood. The purpose of this study was to investigate the individual and combined contributions of (1) sensory nerves and large-conductance calcium activated potassium (BKCa) channels, and (2) nitric oxide (NO) and prostanoids to cutaneous reactive hyperaemia. Laser-Doppler flowmetry was used to measure skin blood flow in a total of 18 subjects. Peak blood flow (BF) was defined as the highest blood flow value after release of the pressure cuff. Total hyperaemic response was calculated by taking the area under the curve (AUC) of the hyperaemic response minus baseline. Infusates were perfused through forearm skin using microdialysis in four sites. In the sensory nerve/BKCa protocol: (1) EMLA cream (EMLA, applied topically to skin surface), (2) tetraethylammonium (TEA), (3) EMLA + TEA (Combo), and (4) Ringer solution (Control). In the prostanoid/NO protocol: (1) ketorolac (Keto), (2) NG-nitro-l-arginine methyl ester (L-NAME), (3) Keto + l-NAME (Combo), and (4) Ringer solution (Control). CVC was calculated as flux/mean arterial pressure and normalized to maximal flow. Hyperaemic responses in Control (1389 +/- 794%CVC max s) were significantly greater compared to TEA, EMLA and Combo sites (TEA, 630 +/- 512, P = 0.003; EMLA, 421 +/- 216, P < 0.001; Combo, 201 +/- 200, P < 0.001%CVC max s). Furthermore, AUC in Combo (Keto + l-NAME) site was significantly greater than Control (4109 +/- 2777 versus 1295 +/- 368%CVC max s). These data suggest (1) sensory nerves and BKCa channels play major roles in the EDHF component of reactive hyperaemia and appear to work partly independent of each other, and (2) the COX pathway does not appear to have a vasodilatory role in cutaneous reactive hyperaemia.
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PMID:Human cutaneous reactive hyperaemia: role of BKCa channels and sensory nerves. 1790 Nov 23

The avian embryo has a pair of ductus arteriosi that allow the blood to bypass the pulmonary circulation prior to the initiation of lung ventilation. Our objective was to characterize the factors regulating DA tone during the later stages of development in the emu embryo. We examined in vitro the reactivity of the emu ductus from day 39 through 49 of a 50-day incubation. Steady state tension was not altered by the COX inhibitor indomethacin or the nitric oxide synthase inhibitor L-NAME. However, prostaglandin E(2) (PGE(2)) produced a significant relaxation. Norephinephrine and U-46619 produced strong significant contractions in the emu DA and the adrenergic response matured with development. The contractile response to oxygen matured as the embryo developed with significant oxygen-induced contraction on days 45 and 49, but not on day 39 of incubation. The Kv channel inhibitor 4-aminopyridine induced the contraction of the day 48-49 ductus of similar magnitude as the oxygen-induced contraction. The oxygen-induced contraction was reversed by the reducing agent DTT and the electron transport chain inhibitor rotenone. These results suggest that while the emu DA responds to PGE(2), locally produced PGE(2) are not the important regulators of vessel tone. Additionally, relaxation upon addition of the mitochondria electron transport chain inhibitor rotenone suggests that the mitochondria might be acting as vascular oxygen sensors in this system through the production of reactive oxygen species to stimulate the oxygen-induced contraction in a similar fashion to mammals.
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PMID:Maturation of the contractile response of the Emu ductus arteriosus. 1807 13

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


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