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)

Previously, it was reported that red blood cells (RBCs) are required to demonstrate participation of nitric oxide (NO) in the regulation of rabbit pulmonary vascular resistance (PVR). RBCs do not synthesize NO; hence, we postulated that ATP, present in millimolar amounts in RBCs, was the mediator, which evoked NO synthesis in the vascular endothelium. First, we found that deformation of RBCs, as occurs on passage across the pulmonary circulation with increasing flow rate, evoked increments in ATP release. Here, ATP (300 nM), administered to isolated, salt solution-perfused (PSS) rabbit lungs, decreased total and upstream (arterial) PVR, a response inhibited by NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). In lungs perfused with PSS containing RBCs, L-NAME increased total and upstream PVR. In lungs perfused with PSS containing glibenclamide-treated RBCs, which inhibits ATP release, L-NAME was without effect. Apyrase grade VII (8 U/ml), which degrades ATP to AMP, was without effect on PVR in PSS-perfused lungs. These results are consistent with the hypothesis that ATP, released from RBCs as they traverse the pulmonary circulation, evokes endogenous NO synthesis.
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PMID:Extracellular ATP signaling in the rabbit lung: erythrocytes as determinants of vascular resistance. 1268 60

Current and primary treatment modality in overactive bladder includes the administration of anticholinergics. The demand for new agents has been rising since anticholinergics have proven to come with many side effects. This study was designed to investigate the effects of ylang-ylang essential oil (YYEO) on the relaxation of urinary bladder muscle in vitro and in vivo. Effects of YYEO were assessed on resting tension, and electrical field stimulation- and various drug-induced contraction in vitro by checking the isometric tension changes of muscle strips and same procedures were repeated in the presence of methylene blue, Nw-Nitro-L-arginine methyl ester hydrochloride (L-NAME), or N-ethylmaleimide, and in vivo. YYEO decreased significantly the contractility of strips. There was no statistically significant difference between the treated group only with YYEO and the pretreated group with YYEO and methylene blue or L-NAME. When N-ethylmaleimide was employed, there was a statistically significant decrease in the rate of contraction. In vivo studies showed the same results compared with in vitro study. The results of this study indicate that YYEO has a relaxing effect on the bladder, and such mechanism is thought to be brought about by a pathway mediated by c-AMP.
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PMID:Effects of ylang-ylang essential oil on the relaxation of rat bladder muscle in vitro and white rabbit bladder in vivo. 1280 30

The purine nucleotide ATP mediates pulmonary vasodilation at birth by stimulation of P2Y purine receptors in the pulmonary circulation. The specific P2Y receptors in the pulmonary circulation and the segmental distribution of their responses remain unknown. We investigated the effects of purine nucleotides, ATP, ADP, and AMP, and pyrimidine nucleotides, UTP, UDP, and UMP, in juvenile rabbit pulmonary arteries for functional characterization of P2Y receptors. We also studied the expression of P2Y receptor subtypes in pulmonary arteries and the role of nitric oxide (NO), prostaglandins, and cytochrome P-450 metabolites in the response to ATP. In conduit size arteries, ATP, ADP, and AMP caused greater relaxation responses than UTP, UDP, and UMP. In resistance vessels, ATP and UTP caused comparable vasodilation. The response to ATP was attenuated by the P2Y antagonist cibacron blue, the NO synthase antagonist N(omega)-nitro-l-arginine methyl ester (l-NAME), and the cytochrome P-450 inhibitor 17-octadecynoic acid but not by the P2X antagonist alpha,beta-methylene ATP or the cyclooxygenase inhibitor indomethacin in conduit arteries. In the resistance vessels, l-NAME caused a more complete inhibition of the responses to ATP and UTP. Responses to AMP and UMP were NO and endothelium dependent, whereas responses to ADP and UDP were NO and endothelium independent in the conduit arteries. RT-PCR showed expression of P2Y(1), P2Y(2), and P2Y(4) receptors, but not P2Y(6) receptors, in lung parenchyma, pulmonary arteries, and pulmonary artery endothelial cells. These data suggest that distinct P2Y receptors mediate the vasodilator responses to purine and pyrimidine nucleotides in the juvenile rabbit pulmonary circulation. ATP appears to cause NO-mediated vasodilation predominantly through P2Y2 receptors on endothelium.
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PMID:P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits. 1496 41

The aim of this study was to analyse the possible influence of cyclic AMP-protein kinase A (cAMP-PKA) activation on neuronal nitric oxide (NO) release induced by electrical field stimulation in mesenteric arteries from Wistar Kyoto (WKY) rats. Western blot experiments demonstrated the expression of neuronal NO synthase (nNOS) in mesenteric artery from WKY rats; however, electrical field stimulation alone did not induce detectable NO release. Preincubation with forskolin allowed NO release induced by electrical field stimulation, which was abolished by: the neuronal toxine tetrodotoxin, the nNOS inhibitors 7-nitroindazole or N(omega)-propil-l-arginine (NPLA), and the PKA inhibitors N-(2-(p-Bromocinnamylamino) ethyl 5-isoquinolinesulfonamide hydrochloride (H-89) or (9R,10S,12S)-2,3,9,10,11, 12-Hexahydro-10-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg:3,2,1k)pyrrolo(3,4-l)(1,6) benzodiazocine-10-carboxylic acid hexyl ester (KT-5720). Preincubation with prostacyclin also allowed the NO release induced by electrical field stimulation which was significantly decreased by: the neuronal toxine tetrodotoxin, the nNOS inhibitors 7-nitroindazole or NPLA, and the PKA inhibitors H-89 or KT-5720. The NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) did not modify the vasoconstrictor response induced by electrical field stimulation. However, in the presence of forskolin or prostacyclin, l-NAME increased the vasoconstrictor response to electrical field stimulation. These results indicate that forskolin and prostacyclin allow neuronal NO release induced by electrical field stimulation through a mechanism involving cAMP-PKA activation in rat mesenteric arteries.
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PMID:Protein kinase A increases electrical stimulation-induced neuronal nitric oxide release in rat mesenteric artery. 1503 89

The purpose of this study was to examine the effects of AMP kinase (AMPK) activation on in vivo glucose and long-chain fatty acid (LCFA) uptake in skeletal muscle and to examine the nitric oxide (NO) dependence of any putative effects. Catheters were chronically implanted in the carotid artery and jugular vein of male Sprague-Dawley rats. After 4 days of recovery, rats were given either water or water containing 1 mg/ml nitro-l-arginine methylester (l-NAME) for 2.5 days. After an overnight fast, rats underwent one of five protocols: saline, 5-aminoimidazole-4-carboxamide-1-B-d-ribofuranoside (AICAR) (10 mg. kg(-1). min(-1)), l-NAME, AICAR + l-NAME, or AICAR + Intralipid (20%, 0.02 ml. kg(-1). min(-1)). Glucose was clamped at approximately 6.5 mmol/l in all groups, and an intravenous bolus of 2-deoxy[(3)H]glucose and [(125)I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid was administered to obtain indexes of glucose (K(g)) and LCFA (K(f)) uptake and clearance. At 150 min, soleus, gastrocnemius, and superficial vastus lateralis were excised for tracer determination. Both K(g) and K(f) increased with AICAR in all muscles studied. K(g) decreased with increasing muscle composition of type 1 slow-twitch fibers, whereas K(f) increased. In addition, AICAR-induced increases in K(g) but not K(f) were abolished by l-NAME in the majority of muscles examined. This shows that the mechanisms by which AMPK stimulates glucose and LCFA uptake are distinct.
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PMID:AMP kinase-induced skeletal muscle glucose but not long-chain fatty acid uptake is dependent on nitric oxide. 1516 45

The expression level of neuronal nitric oxide synthase (nNOS) can vary depending on the (patho)physiological conditions. Here we document a marked induction of nNOS mRNA, protein, and total NO production in response to dibutyryl cyclic AMP (db-cAMP) in human A673 neuroepithelial cells. However, the upregulation of nNOS was associated with a decreased level of production of bioactive NO and by an increase in the level of generation of reactive oxygen species (ROS). ROS production could be prevented by the NOS inhibitor L-NAME, suggesting nNOS itself is involved in ROS generation. Sepiapterin supplementation of db-cAMP-treated A673 cells could restore full bioactive NO production, most likely by preventing the uncoupling of nNOS. nNOS was upregulated by other stable analogues of cAMP, by the activator of adenylyl cyclase forskolin, by isoproterenol or by dopamine through activation of D1 receptors, and by inhibitors of phosphodiesterase. cAMP did not change the half-life of the nNOS mRNA. Inhibitors of protein kinase A (PKA), H-89 and R(p)-cAMPS, produced a partial inhibition of basal and cAMP-induced nNOS expression. cAMP response element binding and modulator transcription factors (CREB and CREM), typical target proteins of PKA, were expressed in A673 cells, as was the coactivator CREB binding protein (CBP). cAMP-stimulated induction of nNOS was significantly enhanced in A673 cells stably transfected with wild-type CREB and almost abolished in cells transfected with KCREB (containing a mutation of the DNA binding domain). In A673 cells transfected with CREB(133) (containing a mutation of the phosphorylatable serine 133), the overall level of nNOS expression was reduced, but the expressional stimulation by cAMP remained. This suggests that CREB bypasses, in part, the classical requirement for phosphorylation and association with CBP. Three members of the recently described four-and-a-half-LIM-domain proteins (FHL1-FHL3) were found to be expressed in A673 cells; FHL-1 and FHL-3 were upregulated by cAMP. These proteins can provide direct activation function to both CREB and CREM, and may be responsible for the PKA-independent component of CREB and CREM activity.
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PMID:Cyclic AMP-mediated upregulation of the expression of neuronal NO synthase in human A673 neuroepithelioma cells results in a decrease in the level of bioactive NO production: analysis of the signaling mechanisms that are involved. 1517 Mar 57

Renal NaCl reabsorption is increased in Dahl "salt-sensitive" (DS) rats, due to an increased activity of the Na-K-Cl cotransporter NKCC2. On the other hand, nitric oxide (NO) is an inhibitor of NKCC2 and a deficient nitric oxide synthase (NOS) seems to play an important role in salt-sensitivity of DS rats. Here, we investigated the hypothesis that NKCC2 hyperactivity in DS rats is due to a deficient NOS, via the interactions cyclic GMP (cGMP)/cyclic AMP (cAMP) at the level of the thick ascending Henle's loop (TAL). DS rats DS (males, 250-300 g) and their normotensive controls DR ("salt-resistant") are sacrificed, the kidneys removed and NKCC2 activity is measured in medullary TAL (mTAL) as previously described. Medullary contents of NO are measured with a NitroFlux analyser by heat-reduction of nitrates and nitrites to NO. AMPc levels in mTAL are measured by an EIA immunotest. Neither L-NAME (3 mM), nor L-arginine were able to modify NKCC2 activity in mTAL from DS (pre-hypertensive) or DR rats. Levels of NO in the medullary interstitium and AMPc in mTAL were not significantly different between DS and DR rats. Conversely, in DS rats charged with 2% salt (in the food) during 7 weeks, L-arginine significantly inhibited NKCC2 in DS (35.6 +/- 6.8 vs 25.3 +/- 4.9 nmoles/mg protein/min; p<0.05 non-paired Student's t-test), but not in DR rats. In conclusion, NKCC2 in our mTAL preparation of prehypertensive DS and DR rats is insensitive to L-NAME and L-arginine. This suggests the absence of a functional NOS. NKCC2 hyperactivity of prehypertensive DS is therefore not due to a deficient NOS. This was confirmed by the normal levels of interstitial NO and mTAL cAMP in prehypertensive DS rats. Finally, a salt-load seems to induce NOS expression in mTAL of DS rats. This last observation deserves further investigation.
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PMID:[Role of nitric oxide in the NKCC2 hyperactivity of Dahl "salt-sensitive" rats]. 1550 55

We have examined the expression and activity of inducible nitric oxide synthase (iNOS) and the activity of neuronal constitutive NOS (ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/protein kinase A (cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation (20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction in ncNOS activity and increased insulin release. The GLP-1-induced suppression of glucose-stimulated iNOS activity and expression and its stimulation of insulin release is, at least in part, PKA dependent, since the PKA inhibitor H-89 reverses the effects of GLP-1. These observations have been confirmed by confocal microscopy showing the glucose-stimulated expression of iNOS, its suppression by GLP-1 and its reversion by H-89 in beta-cells. We have also found that the NO scavenger cPTIO and the NOS inhibitor L-NAME potentiate the insulin response to glucose, again suggesting that NO is a negative modulator of glucose-stimulated insulin release. We conclude that the induction of iNOS and the increase in ncNOS activity caused by glucose in rat islets is suppressed by the cyclic AMP/PKA system. The inhibition of iNOS expression by the GLP-1/cyclic AMP/PKA pathway might possibly be of therapeutic potential in NO-mediated beta-cell dysfunction and destruction.
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PMID:Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway. 1555 23

The vasorelaxation activities of MCPT, a newly synthesized xanthine derivative, were investigated in this study. In phenylephrine (PE)-precontracted rat aortic rings with intact endothelium, MCPT caused a concentration-dependent relaxation, which was inhibited by endothelium removed. This relaxation was also reduced by the presence of nitric oxide synthase inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 100 microM), soluble guanylyl cyclase (sGC) inhibitors methylene blue (10 microM), 1 H-[1,2,4] oxidazolol [4,3-a] quinoxalin-1-one (ODQ, 1 microM), adenylyl cyclase (AC) blocker SQ 22536 (100 microM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (1 microM), a Ca2+ activated K+ channels blocker tetraethylammonium (TEA, 10 mM) and a voltage-dependent potassium channels blocker 4-aminopyridine (4-AP, 100 microM). The vasorelaxant effects of MCPT together with IBMX (0.5 microM) had an additive action. In PE-preconstricted endothelium-denuded aortic rings, the vasorelaxant effects of MCPT were attenuated by pretreatments with glibenclamide (1 microM), SQ 22536 (100 microM) or ODQ (1 microM), respectively. MCPT enhanced cAMP-dependent vasodilator isoprenaline- and NO donor/cGMP-dependent vasodilator sodium nitroprusside-induced relaxation activities in endothelium-denuded aortic rings. In A-10 cell and washed human platelets, MCPT induced a concentration-dependent increase in intracellular cyclic GMP and cyclic AMP levels. In phosphodiesterase assay, MCPT displayed inhibition effects on PDE 3, PDE 4 and PDE 5. The inhibition % were 52 +/- 3.9, 32 +/- 2.6 and 8 +/- 1.1 respectively. The Western blot analysis on HUVEC indicated that MCPT increased the expression of eNOS. It is concluded that the vasorelaxation by MCPT may be mediated by the inhibition of phosphodiesterase, stimulation of NO/sGC/ cGMP and AC/cAMP pathways, and the opening of K+ channels.
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PMID:Endothelium-dependent and -independent vasorelaxation by a theophylline derivative MCPT: roles of cyclic nucleotides, potassium channel opening and phosphodiesterase inhibition. 1558 69

Excessive excitatory action of glutamate and nitric oxide (NO) has been implicated in degeneration of striatal neurons. Evidence had been provided that Na+K+-ATPase might be involved in this process. Here we investigated whether glutamate-regulated messengers, such as NO and cyclic GMP, could modulate the activity of membrane Na+K+-ATPase. Our results demonstrated that NO donors sodium nitroprusside (SNP at 30 and 300 microM) and S-nitroso-N-acetylpenicillamine (SNAP at 200 microM) increased alpha2,3Na+K+-ATPase activity which was blocked by the NO chelator, haemoglobin and was independent of [Na+]. This regulation was associated with cGMP synthesis and mimicked by glutamate (300 microM) and 8-Br-cyclic GMP (4 mM). 8-Br-cGMP-induced stimulation of Na+K+-ATPase activity could be blocked by KT5823 (an inhibitor of cGMP-dependent protein kinase, PKG), but not by KT5720 (an inhibitor of cAMP-dependent protein kinase, PKA). N-Methyl-D-aspartate (NMDA) receptors appeared to be involved in the effect of glutamate, since MK-801 (NMDA receptor antagonist) produced a partial reduction in glutamate-induced activation of the enzyme. MK-801 was not synergistic to L-NAME (NOS inhibitor), suggesting that glutamate stimulates the NMDA-NOS pathway to activate alpha2,3 Na+K+-ATPase in rat striatum. This regulation was associated with cyclic GMP (but not cyclic AMP) synthesis. These data indicate the existence, in vitro, of a regulatory pathway by which glutamate, acting through NO and cGMP, can cause alterations in striatal alpha2,3 Na+K+-ATPase activity.
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PMID:Glutamate modulates sodium-potassium-ATPase through cyclic GMP and cyclic GMP-dependent protein kinase in rat striatum. 1562 18


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