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. In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological half-life, causes a sustained increase in blood pressure at doses that are ineffective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (NO) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute pressor action of this heavy metal. 2. To test this possibility, we evaluated the effect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which were i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Arg), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1), an NO donor, or (5) CaCl2, a cofactor of brain calcium-calmodulin-dependent cNOS(I). In additional experiments, the levels of L-citrulline (the stable equimolar product derived from enzymatic cleavage of L-Arg by NO synthase) were determined in the brain of vehicle- or cadmium-treated rats. 3. The pressor response to cadmium reached its nadir at 5 min (43+/-4 mmHg) and lasted over 20 min in controls. L-Citrulline/protein content was reduced from 35 up to 50% in the cerebral cortex, pons, hippocampus, striatus, hypothalamus (P<0.01) of cadmium-treated rats compared with controls. Central injection of N(G) nitro-L-arginine-methylester (L-NAME) also reduced the levels of L-citrulline in the brain. 4. Both the magnitude and duration of the response were attenuated by 1.21 and 2.42 micromol SIN-1 (32+/-3 and 15+/-4 mmHg, P<0.05), or 1 micromol CaCl2 (6+/-4 mmHg, P<0.05). Selectivity of action exerted by SIN-1 was confirmed by the use of another NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). Both L-Arg and D-Arg caused a mild but significant attenuation in the main phase of the pressor response evoked by cadmium. However, only L-Arg reduced the magnitude of the delayed, pressor response. Despite their similarity in ability to attenuate the cadmium-induced pressure effect, L-Arg and its isomer exerted differential biochemical changes in brain L-citrulline, as L-Arg normalized cadmium-induced reduction in L-citrulline levels, whereas i.c.v. D-Arg did not. 5. We conclude that the pressor effect of i.c.v. cadmium is due, at least in part, to reduced NO formation, consequent to inhibition of brain NO synthase. Accumulation of cadmium in the central nervous system could interfere with central mechanisms (including NO synthase) implicated in the regulation of cardiovascular function.
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PMID:Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium. 948 63

Rodents with striatal C6 glioma were given carboplatin (65 mg kg(-1) in a 10 mg ml(-1) solution, i.v.) after pretreatment with the NO modulating agents 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine methyl ester (L-NAME), bradykinin or dexamethasone, to determine whether platinum disposition in the glioma and normal brain was altered. There was no significant change in mean glioma platinum disposition after 3 days of dexamethasone (32+/-9.7 microg/g). Treatment with SIN-1 (45.1+/-14.2 microg/g), L-NAME (42.9+/-4.9 microg/g) and bradykinin (45.7+/-11.3 microg/g) all resulted in increased tumour platinum concentration compared with controls (29+/-5.5 microg/g) but these results were not statistically significant. Dexamethasone significantly (p < 0.05) reduced the platinum concentration in normal brain but the other agents had no effect. Although glioma platinum concentration could be increased by some agents that alter tissue NO levels, the patterns of response were unpredictable and the magnitude (approximately 50%) of the increased platinum disposition is unlikely to be biologically significant.
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PMID:Effects of nitric oxide manipulation on the disposition of platinum in an experimental glioma model. 950 52

1. The endothelium-dependent relaxants acetylcholine (ACh; 0.03-10 microM) and A23187 (0.03-10 microM), and nitric oxide (NO), applied either as authentic NO (0.01-10 microM) or as the NO donors 3-morpholino-sydnonimine (SIN-1; 0.1-10 microM) and S-nitroso-N-acetylpenicillamine (SNAP; 0.1-10 microM), each evoked concentration-dependent relaxation in phenylephrine stimulated (1-3 microM; mean contraction and depolarization, 45.8+/-5.3 mV and 31.5+/-3.3 mN; n=10) segments of rabbit isolated carotid artery. In each case, relaxation closely correlated with repolarization of the smooth muscle membrane potential and stimulated a maximal reversal of around 95% and 98% of the phenylephrine-induced depolarization and contraction, respectively. 2. In tissues stimulated with 30 mM KCl rather than phenylephrine, smooth muscle hyperpolarization and relaxation to ACh, A23187, authentic NO and the NO donors were dissociated. Whereas the hyperpolarization was reduced by 75-80% to around a total of 10 mV, relaxation was only inhibited by 35% (n=4-7 in each case; P<0.01). The responses which persisted to ACh and A23187 in the presence of 30 mM KCl were abolished by either the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME; 100 microM) or the inhibitor of soluble guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM; 10 min; n=4 in each case; P<0.01). 3. Exposure to ODQ significantly attenuated both repolarization and relaxation to ACh, A23187 and authentic NO, reducing the maximum changes in both membrane potential and tension to each relaxant to around 60% of control values (n=4 in each case; P<0.01). In contrast, ODQ almost completely inhibited repolarization and relaxation to SIN-1 and SNAP, reducing the maximum responses to around 8% in each case (n=3-5; P<0.01). 4. The potassium channel blockers glibenclamide (10 microM), iberiotoxin (100 nM) and apamin (50 nM), alone or in combination, had no significant effect on relaxation to ACh, A23187, authentic NO, or the NO donors SIN-1 and SNAP (n=4 in each case; P>0.05). Charybdotoxin (ChTX; 50 nM) almost abolished repolarization to ACh (n=4; P<0.01) and inhibited the maximum relaxation to ACh, A23187 and authentic NO each by 30% (n=4-8; P<0.01). Application of ODQ (10 microM; 10 min) abolished the ChTX-insensitive responses to ACh, A23187 and authentic NO (n=4 in each case; P<0.01 5. When the concentration of phenylephrine was reduced (to 0.3-0.5 microM) to ensure the level of smooth muscle contraction was the same as in the absence of potassium channel blocker, ChTX had no effect on the subsequent relaxation to SIN-1 (n=4; P>0.05). However, in the presence of tone induced by 1-3 microM phenylephrine (51.2+/-3.3 mN; n=4), ChTX significantly reduced relaxation to SIN-1 by nearly 50% (maximum relaxation 53.2+/-6.3%, n=4; P<0.01). 6. These data indicate that NO-evoked relaxation of the rabbit isolated carotid artery can be mediated by three distinct mechanisms: (a) a cyclic GMP-dependent, voltage-independent pathway, (b) cyclic GMP-mediated smooth muscle repolarization and (c) cyclic GMP-independent, ChTX-sensitive smooth muscle repolarization. Relaxation and repolarization to both authentic and endothelium-derived NO in this large conduit artery appear to be mediated by parallel cyclic GMP-dependent and -independent pathways. In contrast, relaxation to the NO-donors SIN-1 and SNAP appears to be mediated entirely via cyclic GMP-dependent mechanisms.
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PMID:Evidence that different mechanisms underlie smooth muscle relaxation to nitric oxide and nitric oxide donors in the rabbit isolated carotid artery. 957 30

The intracellular mechanisms underlying the action of the endogenous vasodilators such as NO/EDRF, adenosine, and prostacyclin acting through cGMP and cAMP, respectively, are not well understood. One important action of cyclic nucleotides in smooth muscle relaxation is to lower the cytosolic Ca2+ concentration by enhanced sequestration into the sarcoplasmic reticulum. The present study was undertaken to elucidate the potential role of phosphorylation of phospholamban, the regulator of sarcoplasmic reticulum Ca2+ pump, for the control of coronary vascular tone by NO/EDRF, adenosine, and prostacyclin. Phospholamban was identified in pig coronary artery preparations by immunofluorescence microscopy, Western blotting and in vitro phosphorylation. Segments of pig coronary artery, with either intact or denuded endothelium, were precontracted with prostaglandin F2alpha (PGF2alpha). In endothelium-denuded preparations 3-morpholinosydnonimine (SIN-1), 5'-N-ethylcarboxiamidoadenosine (NECA), and iloprost (ILO) caused both relaxation and phospholamban phosphorylation with the potency: SIN-1 > NECA > ILO. The regulatory myosin light chain was significantly dephosphorylated only by SIN-1. In endothelium-intact pig coronary artery, L-NAME caused additional vasoconstriction and a decrease in phospholamban phosphorylation, while phosphorylation of myosin light chain remained unchanged. An inverse relationship between phospholamban phosphorylation and vessel tone was obtained. Our findings demonstrate significant phospholamban phosphorylation during coronary artery relaxation evoked by NO, prostacyclin, and adenosine receptor activation. Because of the close correlation between phosphorylation of phospholamban and vessel relaxation, we propose that phospholamban phosphorylation is an important mechanism by which endogenous vasodilators, especially endothelial NO/EDRF, control coronary vascular smooth muscle tone.
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PMID:Phosphorylation of phospholamban correlates with relaxation of coronary artery induced by nitric oxide, adenosine, and prostacyclin in the pig. 963 7

1. The aim of the present study was to determine the effect of nitric oxide (NO) on angiotensin-converting enzyme (ACE) activity. 2. A biochemical study was performed in order to analyse the effect of the NO-donors, SIN-1 and diethylamine/NO (DEA/NO), and of an aqueous solution of nitric oxide on the ACE activity in plasma from 3-month old male Sprague-Dawley rats and on ACE purified from rabbit lung. SIN-1 significantly inhibited the activity of both enzymes in a concentration-dependent way between 1 and 100 microM. DEA/NO inhibited the activity of purified ACE from 0.1 microM to 10 microM and plasma ACE, with a lower potency, between 1 and 100 microM. An aqueous solution of NO (100 and 150 microM) also inhibited significantly the activity of both enzymes. Lineweaver-Burk plots indicated an apparent competitive inhibition of Hip-His-Leu hydrolysis by NO-donors. 3. Modulation of ACE activity by NO was also assessed in the rat carotid artery by comparing contractions elicited by angiotensin I (AI) and AII. Concentration-response curves to both peptides were performed in arteries with endothelium in the presence of the guanylyl cyclase inhibitor, ODQ (10 microM), and the inhibitor of NO formation, L-NAME (0.1 mM). NO, which is still released from endothelium in the presence of 10 microM ODQ, elicited a significant inhibition of AI contractions at low concentrations (1 and 5 nM). In the absence of endothelium, 1 microM SIN-1 plus 10 microM ODQ, as well as 10 microM DEA/NO plus 10 microM ODQ induced a significant inhibition on AI-induced contractions at 1 and 5 nM and at 1-100 nM, respectively. 4. In conclusion, we demonstrated that (i) NO and NO-releasing compounds inhibit ACE activity in a concentration-dependent and competitive way and that (ii) NO release from endothelium physiologically reduces conversion of AI to AII.
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PMID:Modulation of angiotensin-converting enzyme by nitric oxide. 964 45

C6 glioma strongly express nitric oxide synthase. Rats bearing C6 tumours were pre-treated with i.v. Ng-nitro-L-arginine methyl ester (L-NAME), 3-morpholinosydnonimine (SIN-1) or saline before local cerebral blood flow (LCBF) or tumour capillary permeability (TCP) was measured by the [14C]iodoantipyrine autoradiographic or [14C]alpha-amino-isobutyric acid techniques. L-NAME and SIN-1 caused significant TBF alterations (-44% and +136%, respectively) with less marked (-15% and +33%) alterations in normal brain. Calculated cerebrovascular resistance changes within tumour were indeed selective. Baseline TCP was increased compared with normal brain (20-fold). L-NAME and SIN-1 administration did not alter TCP. These effects have significant implications for human malignant glioma management. Selective i.v. manipulation of LCBF, without significant changes in TCP, could increase the efficacy of chemotherapy, radiotherapy or provide better peritumoural oedema control.
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PMID:Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma. 972 36

Embryonic development, prostaglandin E (PGE) generation and nitric oxide synthase (NOS) activity during organogenesis were evaluated in an experimental rat model of non-insulin-dependent diabetes (NIDD) generated by neonatal administration of streptozotocin. Gross malformations were detected in 5% of NIDD embryos and these embryos were all non-viable; in the other 95%, growth was retarded but no congenital abnormalities were found. Control embryos were all alive and not malformed. The NIDD 11-day embryos secreted more PGE into the incubation medium than did controls. The NO donor SIN-1 increased PGE production in both control and NIDD embryos. A NOS inhibitor (L-NMMA) reduced PGE generation in both experimental groups, suggesting a modulatory role of NO on embryonic PGE production. Activity of NOS was higher in NIDD 11-day embryos than in controls. Treatment in vivo of control and NIDD rats (Days 7-11 of gestation) with a NOS inhibitor (L-NAME; 5 mg kg(-1) i.p.) reduced embryonic PGE production and induced a higher resorption rate and an increase in neural-tube defects. The results suggest that NO modulates PGE generation in the organogenetic embryo. In the NIDD model, overproduction of NO is observed, this NO probably enhancing embryonic PGE production. The relationship between PGE generation and the appearance of congenital abnormalities is discussed.
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PMID:Increased prostaglandin E generation and enhanced nitric oxide synthase activity in the non-insulin-dependent diabetic embryo during organogenesis. 980 Dec 72

The effects of various spontaneous nitric oxide (NO) donors and NO synthase inhibitors on endothelin- production were examined using porcine cultured aortic endothelial cells. NO donors such as (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 2), (+/-)-(E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 3) and (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridine carboxamide (NOR 4) suppressed effectively the release of endothelin-1 from the cells. Endothelin-1 mRNA expression was also attenuated by these compounds. Other NO donors such as 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamin e (NOC 5), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC 18), s-nitroso-n-acetyl-DL-penicillamine, N-morpholino sydnonimine (SIN-1) had no effects on endothelin-1 production. Endothelial intracellular cyclic guanosine monophosphate (cGMP) levels were significantly increased by all NO donors. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective soluble guanylyl cyclase inhibitor, had no effect on the NOR 3-induced decrease in endothelin-1 secretion, although cGMP production was abolished by ODQ. NOR 3 also inhibited endothelin-1 secretion even in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetrametylimidazole-1-oxyl 3-oxide (carboxy-PTIO), a NO scavenger. NOR 3-induced inhibitory effects on endothelin-1 secretion were abolished by preincubation of the compound in phosphate-buffered saline (37 degrees C, 4 h), a procedure by which about 98% of the parent compound's ability to release NO was lost. NO synthase inhibitors such as N(G)-nitro-L-arginine, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced prepro endothelin-1 mRNA expression and significantly increased endothelin-1 release from endothelial cells. Endothelin-1 secretion was also increased effectively by carboxy-PTIO or ODQ. When the cells were exposed to L-NAME with carboxy-PTIO or ODQ, no significant further increase in endothelin-1 release was observed. These results suggest that endogenous NO inhibits endothelin-1 production through guanylyl cyclase/cGMP-dependent mechanisms. In contrast, it seems unlikely that exogenous NO has an inhibitory effect on endothelin-1 production in endothelial cells. NOR compounds inhibit endothelin-1 production perhaps through NO/cGMP-independent mechanisms, i.e., through an unknown effect of the parent compound itself.
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PMID:Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. 992 Jan 86

It is controversial whether nitric oxide (NO) is protective or deleterious against ischemia-reperfusion injury. We examined the effect of NO on PKC isoform translocation and protection against ischemia-reperfusion injury in perfused heart. An NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester, 3.0 microM), administered only during reperfusion but not during ischemia, inhibited the translocation of PKC-alpha, -delta and -epsilon isoforms to the nucleus-myofibril fraction and the translocation of PKC-alpha to the membrane fraction after ischemia (20 min) and reperfusion (10 min) in the perfused rat heart. NO donors, 3-morpholinosydnonimine (SIN-1) or S-nitroso-N-acetylpenicillamine (SNAP) activated purified PKC in vitro. SIN-1 also induced PKC isoform translocation in perfused heart. On the other hand, PKC selective inhibitor, calphostin C (0.2 microM) or chelerythrine (1.0 microM), aggravated the contractile dysfunction of ischemic heart during reperfusion, when they were perfused during reperfusion. These data suggest that NO generated during reperfusion following ischemia activates PKC isoforms and may protect the heart against contractile dysfunction in the perfused rat heart.
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PMID:Nitric oxide mediates protein kinase C isoform translocation in rat heart during postischemic reperfusion. 1003 21

Nitric oxide (NO) has been proposed to contribute to the development of hyperalgesia by activating the NO/guanosine 3',5'-cyclic monophosphate (cGMP) signal transduction pathway in the spinal cord. We have examined the effects of NO on the responses of primate spinothalamic tract (STT) neurons to peripheral cutaneous stimuli and on the sensitization of STT cells following intradermal injection of capsaicin. The NO level within the spinal dorsal horn was increased by microdialysis of a NO donor, 3-morpholinosydnonimine (SIN-1). SIN-1 enhanced the responses of STT cells to both weak and strong mechanical stimulation of the skin. This effect was preferentially on deep wide dynamic range STT neurons. The responses of none of the neurons tested to noxious heat stimuli were significantly changed when SIN-1 was administered. Intradermal injection of capsaicin increased dramatically the content of NO metabolites, NO-2/NO-3, within the dorsal horn. This effect was attenuated by pretreatment of the spinal cord with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Sensitization of STT cells induced by intradermal injection of capsaicin was also prevented by pretreatment of the dorsal horn with the NOS inhibitors, L-NAME or 7-nitroindazole. Blockade of NOS did not significantly affect the responses of STT cells to peripheral stimulation in the absence of capsaicin injection. The data suggest that NO contributes to the development and maintenance of central sensitization of STT cells and the resultant mechanical hyperalgesia and allodynia after peripheral tissue damage or inflammation. NO seems to play little role in signaling peripheral stimuli under physiological conditions.
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PMID:Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. 1008 34


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