Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we evaluated the levels of nitric oxide synthase, both neuronal and induced (nNOS and iNOS, respectively), cyclooxygenase-1 and 2 (COX-1 and COX-2) and protein kinase C gamma (PKCgamma) and correlated these with algogenic behavior following spinal kainic acid (KA) receptor activation in rats. Thirty adult male Sprague-Dawley rats were randomly assigned into six groups (n=5). Groups A, B, and C received 0.5 g kainic acid intrathecally and were analyzed at 3, 6, 24 h after injection, respectively. Groups D, E, and F received saline and were analyzed at 3, 6, 24 h after injection, respectively. We observed for behavioral changes in the rats following intrathecal KA injection and analyzed the protein levels of NOS, COX and PKCgamma by Western blotting techniques. Importantly, we clarified the potential roles of PKCgamma in the regulation of nNOS and COX-2 following intrathecal injection with KA in the rat spinal cord. COX-2 protein was detected but not significantly changed in the lumbosacral spinal cord at 3, 6, and 24 h following intrathecal KA injection (P>0.05). In contrast, nNOS protein was detected at higher levels in comparison with normal spinal cord at 6 and 24 h after intrathecal administration of KA (P<0.05). PKCgamma also increased significantly at 3, 6, and 24 h after intrathecal KA injection when compared with the baseline level (P<0.05). On the other hand, COX-1 and iNOS were not detected in either normal or KA treated spinal cords. These results provide strong in vivo evidence to support the idea that nNOS but not COX-2, plays an important role in spinal KA receptor activation. Furthermore, up-regulation of PKCgamma is involved in KA induced algogenic behavior in rats.
 ...
PMID:Changes in the levels of nitric oxide synthase and protein kinase C gamma following kainic acid receptor activation in the rat spinal cord. 1148 38

Investigation of endothelial regulation of vascular reactivity and tone has led to the discovery of chemical mediators such as nitric oxide (NO) and prostacyclin (PGI2). Evidence has emerged indicating another as yet unidentified hyperpolarizing agent (endothelium-derived hyperpolarizing factor or EDHF) that is different from NO and PGI2 and exerts it effects through calcium-activated potassium channels (KCa). Previous studies to identify EDHF have been carried out using inhibitors that block NOS and COX before application of KCa channel and/or muscarinic receptor antagonists. Such pharmacological manipulation has complicated interpretation of results, clearly pointing to the need for altered approaches to verify previous studies. Evidence has emerged that potential EDHF candidates vary with vessel size, species and tissue beds, indicating that there may be more than one EDHF. To date, the most commonly described and best characterized of them all are a set of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs). These compounds are synthesized both intra- and extravascularly. Until recently, methodology to detect EETs in the microvasculature has been tedious and expensive, limiting the experimentation that is necessary to confirm EETs as an EDHF. This review describes state-of-the-art methods for assaying EETs in biological samples, after summarizing evidence for EETs as an EDHF and introducing emerging concepts of the role of extravascular EETs in linking neuronal activity to localized blood flow during functional hyperemia.
 ...
PMID:Identifying endothelium-derived hyperpolarizing factor: recent approaches to assay the role of epoxyeicosatrienoic acids. 1156 9

The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 +/- 2 and 75 +/- 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 micromol/l N(G)-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 micromol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 +/- 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 micromol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0micromol/l) attenuated the response when administered alone (63 +/- 7% and 37 +/- 5%, respectively) and abolished the response when coadministered (0.1 +/- 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.
 ...
PMID:Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF. 1173 20

The inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are overexpressed in colonic tumors of humans, as well as in colon tumors that develop in rats after the administration of the colon-specific carcinogen, azoxymethane (AOM). iNOS may regulate COX-2 production of proinflammatory prostaglandins, which are known to play a key role in colon tumor development. Experiments were designed to assess the potential chemopreventive properties of highly selective iNOS inhibitors, administered individually and in combination with a selective COX-2 inhibitor, on the development of AOM-induced colonic aberrant crypt foci (ACF). F344 rats were fed experimental diets containing one of the following: 0, 10, 30, or 100 parts/million (ppm) of the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine tetrazole-amide (SC-51); 1800 ppm of the less potent, selective iNOS inhibitor aminoguanidine (AG); 500 ppm of the COX-2 inhibitor celecoxib; 320 ppm of the nonsteroidal anti-inflammatory sulindac (positive control); or 30 ppm of SC-51 with 500 ppm of celecoxib, and 100 ppm of SC-51 with 500 ppm of celecoxib. One and 2 weeks later, rats received s.c. injections of AOM at a dose of 15 mg/kg of body weight. At 17 weeks of age, all rats were sacrificed. Colons were evaluated for ACF, and colonic mucosae were assayed for COX and NOS isoform enzyme activities. Samples of venous blood, collected at various time points, were analyzed for these agents. SC-51, administered alone, demonstrated dose-dependent inhibition of the incidence of colonic ACF. The highest doses of SC-51 (100 ppm) and AG (1800 ppm) significantly suppressed the incidence of colonic ACF (P < 0.01 and < 0.001, respectively) and crypt multiplicity in terms of numbers of aberrant crypts/focus (P < 0.0001). Importantly, the combination of either low or high effective doses of SC-51 (30 or 100 ppm) and celecoxib (500 ppm) suppressed AOM-induced colonic ACF formation (P < 0.05 and < 0.001, respectively) and reduced multiplicity of four or more aberrant crypts/focus (P < 0.0001) to a greater extent than did these agents administered individually. As expected, sulindac inhibited colonic ACF formation (P < 0.001) and reduced the multiplicity of four or more aberrant crypts (P < 0.0001) to approximately 45%. The enzymatic activities of COX-2 and iNOS were significantly induced in the AOM-treated animals, and administration of the iNOS inhibitors, SC-51 and AG, significantly inhibited the activities of both iNOS and COX-2 in the colonic mucosa. The combined administration of SC-51 and celecoxib inhibited the COX-2 activity to a greater extent than did either of these agents administered alone. These findings support the hypothesis that selective iNOS inhibitors may have chemopreventive properties and that coadministration with a selective COX-2 inhibitor may have additional chemopreventive potential.
 ...
PMID:Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. 1178 74

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). Our data point to endothelial bradykinin (Bk) as a trigger for protective endothelial mechanisms. In cultured endothelial cells (CEC) Bk through kinin B2 receptors raised in a concentration-dependent manner (1pM-10 nM) free cytoplasmic calcium ions [Ca2+]i. This rise was accompanied by the release of NO as quantified by a porphyrinic sensor. Other endothelial agonists were weaker-stimulators of [Ca2+]i than Bk. In vivo we analyed the effects of exogenous Bk and of amplifiers of endogenous Bk, such as perindopril and quinapril ("tissue type" angiotensin converting enzyme inhibitors, ACE-I) on endothelial function using our original thrombolytic bioassay and EIA assays for 6-keto-PGF1alpha and t-PA antigen. A major difference found between exogenuous Bk and endogenous Bk (that rendered by "tissue ACE-I") was a) prolonged thrombolytic action (> 4h) of quinapril or perindopril. Moreover, only exogenous Bk evoked an immediate and profound hypotensive action. In vivo, Bk-induced thrombolysis was B2 kinin receptor-dependent, PGI2-mediated. The unexpected action of Bk came to light in CEC. Then appeared incubated for 4 h increased expression of mRNAs for haemoxygenase (HO-1), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGE-S), but hardly for nitric oxide synthase 2(NOS-2). We hypothesize that a network of interactions of Bk-induced enzymes may constitute a delayed phase of Bk effects in the endothelium, whereas the primary phase would be activation by BK of [Ca2+]i-dependent constitutive endothelial enzymes. In blood-perfused rat endotoxemic lungs, NO is the most eminent cytoprotective mediator. Summing up, in peripheral circulation endogenous Bk is the most efficient activator of protective endothelial function. Thrombolytic action of "tissue-type" ACE-Is relies on receptor B-2-mediated, [Ca2+]i-dependent release of PGI2. Bk also may act as a "microcytokine" by inducing mRNAs for HO-1, COX-2, or PGE-S. Activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS. This network of interactions triggered by Bk call for further studies.
 ...
PMID:Bradykinin as a major endogenous regulator of endothelial function. 1205 3

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
 ...
PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

The role of NOS and/or COX induction on sympathetic nerve activation induced by sepsis was investigated in pentobarbital anesthetized rats. Sepsis was induced by i.v. administration of lipopolysaccharide (LPS) in control experiments and during treatment with anti-inflammatory drugs or inhibitors of NOS and COX (five to six rats per group). Mean arterial blood pressure (MBP), rectal temperature (RT) and renal sympathetic nerve activity (RSNA) were recorded for up to 6 h after LPS infusion. LPS administration induced profound increases in RSNA and decreases in MBP. The corticosteroid anti-inflammatory drug dexamethasone had a potent protector effect on blood pressure and survival of the LPS-treated animals and inhibited the RSNA increase. The nonsteroid anti-inflammatory compound indomethacin inhibited the sympathetic activation but did not alter the hypotensive action of LPS. The nonselective NOS inhibitor nitroarginine methyl ester (L-NAME) accelerated the fall in MBP and death of the animals while the inducible NOS inhibitor L-NIL delayed the fall in MBP and reduced the sympatho-activation without affecting survival time in LPS rats. The neuronal NOS inhibitor 7-nitroindazole (7-NINA) did not improve the hypotensive effect and survival of the LPS animals but potentiated the RSNA increase. The COX-1 inhibitor SC560 accelerated hypotension and death of the LPS animals without affecting the RSNA increase. The COX-2 inhibitor NS398 did not modify the effect of LPS on blood pressure but reduced its sympatho-excitatory effect; NS398 also abolished the LPS-induced increase in RT. The results indicate that different mechanisms are involved in the effects of sepsis on MBP, sympathetic activation and fever. Sympathetic nerve activation during sepsis appears to depend on the induction of NOS and COX; the COX pathway is involved in the elevation of temperature and in the activation of sympathetic nerve activity but not in the hypotension. The potent effect of dexamethasone suggests that a NOS- and COX-independent arachidonic acid pathway also plays a role.
 ...
PMID:Involvement of COX and NOS induction in the sympatho-activation during sepsis. 1214 36

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.
 ...
PMID:Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries. 1258 21

Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3-30 microg kg(-1) (captopril<perindopril<quinapril). The thrombolytic response lasted up to 3 h with maximum reduction of the weight of thrombus by 75%. Pretreatment with COX-1 and COX-3 inhibitors (aspirin at a low dose of 1 mg kg(-1), SC 560 and acetaminophen, 0.3-3 mg kg(-1)) slightly augmented thrombolysis by ACE-I, while COX-2 inhibitors (nimesulide and coxibs at doses <1 mg kg(-1) and aspirin at a high dose of 50 mg kg(-1)) or a kinin B2 receptor antagonist (icatibant) abolished it. NOS inhibition by L-NAME blunted and delayed thrombolysis by ACE-I. In parallel to maximum thrombolysis by quinapril (30 microg kg(-1)), plasma levels of 6-keto-PGF1alpha rose significantly from 40 +/- 7 to 554 +/- 91 pg ml(-1) (n=5, mean +/- S.D.), while basal levels of PGE2 (12 +/- 3 pg ml(-1)) and TXB2 (47 +/- 11 pg ml(-1)) remained essentially unchanged. Pretreatment with celecoxib (0.1-1.0 mg kg(-1)) abolished not only thrombolysis by quinapril but also the quinapril-induced rise in plasma 6-keto-PGF1alpha. In cultured bovine aortic endothelial cells, perindoprilate (30 microM) increased cytosolic free calcium [Ca2+]i, but this effect was by three to four orders of magnitude weaker than that of bradykinin (Bk). In aortas of Wistar rats, the transcripts of COX-2 and PGI-S were overexpressed as compared to COX-1. Thus, in blood vessels of Wistar rats, the preferable route of the PGI2 generation might lead through the COX-2 pathway. We conclude that in Wistar rats, ACE-I induces thrombolysis via accumulation of endogenous kinins over the endothelium and a subsequent activation of B2 receptors followed by the release of prostacyclin and nitric oxide. Thrombolysis by ACE-I seems to be mediated mainly through prostacyclin that is made by COX-2. It may well be that an increase in endothelial [Ca2+]i by ACE-I activates phospholipase A2, which supplies COX-2 with the substrate for making thrombolytic prostacyclin.
 ...
PMID:Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats. 1459 56

We have shown recently that development from neonatal to adult life affects cerebrovascular tone of mouse cerebral arteries through endothelium-derived vasodilatory mechanisms. The current study tested the hypothesis that development from fetal to adult life affects cerebral artery vascular smooth muscle (VSM) [Ca(2+)](i) sensitivity and tone through a mechanism partially dependent upon endothelium-dependent signalling. In pressurized resistance sized cerebral arteries ( approximately 150 microm) from preterm (95 +/- 2 days gestation (95 d)) and near-term (140 +/- 2 days gestation (140 d)) fetuses, and non-pregnant adults, we measured vascular diameter (microm) and [Ca(2+)](i) (nm) as a function of intravascular pressure. We repeated these studies in the presence of inhibition of nitric oxide synthase (NOS; with l-NAME), cyclo-oxygenase (COX; with indomethacin) and endothelium removal (E-). Cerebrovasculature tone (E+) was greater in arteries from 95 d fetuses and adults compared to 140 d sheep. Ca(2+) sensitivity was similar in 95 d fetuses and adults, but much lower in 140 d fetuses. Removal of endothelium resulted in a reduction in lumen diameter as a function of pressure (greater tone) in all treatment groups. [Ca(2+)](i) sensitivity differences among groups were magnified after E-. NOS inhibition decreased diameter as a function of pressure in each age group, with a significant increase in [Ca(2+)](i) to pressure ratio only in the 140 d fetuses. Indomethacin increased tone and increased [Ca(2+)](i) in the 140 d fetuses, but not the other age groups. Development from near-term to adulthood uncovered an interaction between NOS- and COX-sensitive substances that functioned to modulate artery diameter but not [Ca(2+)](i). This study suggests that development is associated with significant alterations in cerebral vascular smooth muscle (VSM), endothelium, NOS and COX responses to intravascular pressure. We speculate that these changes have important implications in the regulation of cerebral blood flow in the developing organism.
 ...
PMID:Development affects in vitro vascular tone and calcium sensitivity in ovine cerebral arteries. 1513 Dec 39


<< Previous 1 2 3 4 5 6 7 8 9 Next >>