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 primary aims of this study were to evaluate the effects of the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) on gastric emptying (GE) of, and the blood pressure (BP), glycemic, insulin, and incretin responses to, oral glucose in older subjects. Eight healthy subjects (4 males and 4 females, aged 70.9 +/- 1.3 yr) were studied on two separate days, in double-blind, randomized order. Subjects received an intravenous infusion of either l-NAME (180 mug.kg(-1).h(-1)) or saline (0.9%) at a rate of 3 ml/min for 150 min. Thirty minutes after the commencement of the infusion (0 min), subjects consumed a 300-ml drink containing 50 g glucose labeled with 20 MBq (99m)Tc-sulfur colloid, while sitting in front of a gamma camera. GE, BP (systolic and diastolic), heart rate (HR), blood glucose, plasma insulin, and incretin hormones, glucose-dependant insulinotropic-polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), were measured. l-NAME had no effect on GE, GIP, and GLP-1. Between -30 and 0 min l-NAME had no effect on BP or HR. After the drink (0-60 min), systolic and diastolic BP fell (P < 0.05) and HR increased (P < 0.01) during saline; these effects were attenuated (P < 0.001) by l-NAME. Blood glucose levels between 90 and 150 min were higher (P < 0.001) and plasma insulin were between 15 and 150 min less (P < 0.001) after l-NAME. The fall in BP, increase in HR, and stimulation of insulin secretion by oral glucose in older subjects were mediated by NO mechanisms by an effect unrelated to GE or changes in incretin hormones.
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PMID:Role of nitric oxide mechanisms in gastric emptying of, and the blood pressure and glycemic responses to, oral glucose in healthy older subjects. 1569 67

The objective of this study was to determine and compare the in vitro responses of equine large colon arterial and venous rings to vasodilatory neuropeptides; calcitonin gene-related peptide (CGRP); substance P (SP); vasoactive intestinal polypeptide (VIP); and acetylcholine (ACh), a standard nonpeptide endothelium-dependent vasodilator. Responses of vessel rings to graded concentrations (10(-11) M to 10(-5) M) of each drug were determined in endothelium-intact, denuded, and Nomega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M)-treated rings that were pre-contracted with norepinephrine. Percentage maximal relaxation (PMR), defined as the % decrease from the contracted state, was determined. Because all rings did not relax at least 50%, EC50 values could not be consistently calculated. Arterial rings with intact endothelium were more sensitive to CGRP, compared with VIP and SP, and venous rings of all conditions were more sensitive to VIP than CGRP or SP. Overall, arteries had a greater PMR for ACh compared with SP and VIP. Intact and L-NAME treated arteries had a greater PMR than denuded arteries; there were no differences in PMR of intact and L-NAME treated arteries. Veins had a greater PMR for VIP than CGRP, SP, or ACh. Calcitonin gene-related peptide caused greater relaxation in intact arteries, whereas VIP causes greater relaxation in veins. Arterial relaxation was dependent upon the presence of intact endothelium. The response of veins to VIP among the conditions tested was not different, suggesting VIP has direct actions on venous smooth muscle. These neuropeptides modulate vasomotor tone via vasorelaxation in colonic arteries and veins.
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PMID:Role of endothelium and nitric oxide in modulating in vitro responses of colonic arterial and venous rings to vasodilatory neuropeptides in horses. 1597 75

Adrenomedullin (AM) is a vascular-derived polypeptide that exerts numerous actions in cardiovascular homeostasis. Recent studies have demonstrated a cytoprotective action of exogenously applied or genetically over-expressed AM in experimental myocardial infarction. The present studies were undertaken to test the hypothesis that AM exerts its effects through direct augmentation of NO generation in the myocardium during early reperfusion. Rat isolated hearts underwent 35 min left coronary artery occlusion followed by 120 min reperfusion. Infarct size (as percentage of ischaemic riskzone) was determined by Evans' blue and tetrazolium double staining. AM 1 nM administered 5 min prior to and during the first 15 min of ischaemia did not significantly influence infarct size. However, the same concentration of AM given during the last 5 min ischaemia and first 15 min of reperfusion significantly limited infarct size (AM reperfusion 15.9 +/- 3.5% vs control 31.4 +/- 2.1%, P < 0.01). AM at reperfusion improved coronary flow and LV contractility. The protective effects of adrenomedullin were abolished in the presence of the NO synthase inhibitor, L-NAME 100 microM (infarct size 24.6 +/- 5.7%, P > 0.05 vs control). AM treatment at reperfusion was associated with augmented phosphorylation of the pro-survival kinase, Akt, determined by immunoblotting of tissue sampled 30 min following reperfusion. These studies provide the first evidence that AM exerts its cytoprotective action specifically during early reperfusion through a NO-dependent mechanism.
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PMID:Adrenomedullin limits reperfusion injury in experimental myocardial infarction. 1601 Jun 1

Alterations of gastric mechanical activity have been reported in mdx mouse, animal model for Duchenne muscular dystrophy. This study examined if alterations in the vasoactive intestinal polypeptide (VIP) system are present in mdx stomach. Gastric mechanical activity was recorded in vitro as changes of endoluminal pressure and neurally or pharmacologically evoked relaxations were analysed in mdxvs normal stomach. Reverse-transcription polymerase chain reaction was used to detect inducible nitric oxide synthase (iNOS) expression. Relaxations to sodium nitroprusside in mdx stomach showed no difference in comparison with normal preparations. In normal stomach, VIP produced relaxation, which was reduced by VIP6-28, antagonist of VIP receptors, but was not modified by Nomega-nitro-L-arginine methyl ester (L-NAME), 1-H-oxodiazol-[1,2,4]-[4,3-a]quinoxaline-1-one (ODQ) or by N-(3-(aminomethyl)-benzyl)acetamidine (1400W) and aminoguanidine, inhibitors of iNOS. In contrast, in mdx stomach VIP responses were antagonized not only by VIP6-28, but also by L-NAME, ODQ, 1400W or aminoguanidine. In normal stomach, the slow relaxation evoked by stimulation at high frequency was reduced by VIP6-28, but it was unaffected by 1400W or aminoguanidine. In mdx stomach, it was reduced by VIP6-28 or 1400W, which did not show additive effects. iNOS mRNA was expressed only in mdx stomach. The results suggest that in mdx gastric preparations, iNOS is functionally expressed, being involved in the slow relaxation induced by VIP.
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PMID:Evidence for a role of inducible nitric oxide synthase in gastric relaxation of mdx mice. 1670 Jul 24

Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1alpha interaction with hepatocyte nuclear factor 4alpha (HNF4alpha, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1alpha in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4alpha is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1alpha, HNF4alpha, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.
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PMID:Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. 1682 89

The neurotransmitter(s) that generate the inhibitory junctional potential (IJP) in the circular muscle of hamster distal colon and their mechanisms have not been elucidated. The aim of the present study, therefore, was to determine the contributing roles of the non-adrenergic, non-cholinergic (NANC) inhibitory transmitter(s) including nitric oxide (NO), adenosine 5'-triphosphate (ATP) and vasoactive intestinal polypeptide (VIP) in the generation of IJP in the hamster distal colon. For this purpose, the effects of the corresponding blockers of these putative NANC inhibitory mediators have been investigated using microelectrode technique. Intracellular membrane potential recordings were made from smooth muscle cells at 35 degrees C in Tyrode's solution that contained atropine (0.5microM), guanethidine (3microM) and nifedipine (0.5microM). Single electrical stimuli (0.5ms, 50V) as well as trains of two and five pulses (20Hz at the same duration and voltage) elicited NANC IJP consisted of initial fast (IJP-F) followed by a slow hyperpolarization (IJP-S). The response had been abolished by tetrodotoxin (TTX, 0.3microM). The nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 200microM) blocked IJP-S but enhanced IJP-F. The later had been blocked with suramin, a universal P2 receptor antagonist, or with CBF3GA, a P2Y receptor antagonist at dose-dependent fashions. The IJP-F had been markedly inhibited by desensitization of P2Y receptor with its putative agonist 2-methylthio-ATP (2-meSATP, 50microM for 30min). IJP-F was sensitive to the P2Y1 receptor specific antagonist A3P5PS (10microM) and to the G-protein inhibitor, pertussis toxin (PTX, 400ng/ml for 2h) as well as to the small and intermediate Ca(2+) sensitive K(+) channels blocker, apamin (0.3microM). IJP-S was blocked by the guanylate cyclase (GC) inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10microM) and was partially sensitive to apamin. Exogenously applied ATP (100microM-1mM) produced typical hyperpolarization that was blocked by suramin, CBF3GA and 2-meSATP desensitization; while exogenously applied NO (3-10microM) produced slowly developing hyperpolarization that was not blocked by L-NAME but ODQ. In the presence of both purinergic and nitrergic inhibitors, stimulation using a train of eight pulses at 25Hz evoked a small slow hyperpolarization that was sensitive to the VIP antagonist (VIP 6-28, 1microM). Exogenous application of VIP (1-10microM) produced similar response that was not evident in the presence of VIP 6-28. These data indicate that NANC IJP that is generated in the circular muscle cells of hamster distal colon is mediated by ATP and NO via P2Y1/P2Y2 receptor and GC-dependent pathways, respectively. A masked role for VIP is also indicated.
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PMID:NANC inhibitory neuromuscular transmission in the hamster distal colon. 1703 41

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.
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PMID:Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. 1832 54

Nitric oxide is widely established as an important neurotransmitter in the control of anal sphincter tone; although, a number of other transmitters have also been tentatively implicated. Whilst alpha-adrenoceptor antagonists reduce anal sphincter pressure in man, the role of noradrenaline as a possible transmitter is poorly characterised. We have investigated the contribution of these transmitters to neurogenic relaxations, and evaluated the possible role of a non-nitrergic, non-adrenergic transmitter. The magnitude and duration of neurogenic responses were examined by measuring responses to electrical field stimulation (EFS) in segments of sheep internal anal sphincter following the development of spontaneous myogenic tone. Neurogenic relaxations induced by EFS were significantly reduced in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) suggesting major involvement of nitric oxide as a neurotransmitter. The duration of neurogenic relaxations was inversely related to the frequency of EFS, with contractile responses often manifest at higher frequencies. The duration of relaxations at high frequencies of EFS was increased by bretylium (adrenergic neurone blocker) and prazosin (alpha(1)-adrenoceptor antagonist). At higher frequencies of EFS, 60% of preparations also produced a residual non-nitrergic, non-adrenergic, apamin-sensitive relaxation which was unaffected by vasoactive intestinal polypeptide (VIP) and inhibitors of purinergic responses [suramin, pyridoxal-phosphate-6-azophenyl 2',4' disulfonic acid (PPADS) and alpha,beta-methylene adenosine triphosphate (ATP)]. However, MRS2179 (P2Y(1) receptor antagonist) showed a modest inhibitory effect. We conclude that endogenous noradrenaline acts via postjunctional alpha(1)-adrenoceptors to antagonize neurogenic relaxations that are largely mediated by nitric oxide. Our results indicate the involvement of a non-nitrergic, non-adrenergic, apamin-sensitive transmitter which is inhibited by MRS2179, suggesting a possible role for purines.
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PMID:Investigation of the role of adrenergic and non-nitrergic, non-adrenergic neurotransmission in the sheep isolated internal anal sphincter. 1925 55

STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.
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PMID:Nitric oxide synthase mediates the ability of darbepoetin alpha to improve the cognitive performance of STOP null mice. 2232 5

VPAC2 receptors sensitive to vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), PAC1 receptors sensitive to PACAP, and nitric oxide (NO) generation by NO synthase (NOS) are all implicated in cutaneous active vasodilation (AVD) through incompletely defined mechanisms. We hypothesized that VPAC2/PAC1 receptor activation and NO are synergistic and interdependent in AVD and tested our hypothesis by examining the effects of VPAC2/PAC1 receptor blockade with and without NOS inhibition during heat stress. The VPAC2/PAC1 antagonist, pituitary adenylate cyclase activating peptide 6-38 (PACAP6-38) and the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME) were administered by intradermal microdialysis. PACAP6-38, l-NAME, a combination of PACAP6-38 and l-NAME, or Ringer's solution alone were perfused at four separate sites. Skin blood flow was monitored by laser-Doppler flowmetry at each site. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres, and cutaneous vascular conductance (CVC) calculated (CVC = laser-Doppler flowmetry/mean arterial pressure). The protocol began with a 5- to 10-min baseline period without antagonist perfusion, followed by perfusion of PACAP6-38, l-NAME, or combined PACAP6-38 and l-NAME at the different sites in normothermia (45 min), followed by 3 min of whole body cooling. Whole body heating was then performed to induce heat stress and activate AVD. Finally, 58 mM sodium nitroprusside were perfused at all sites to effect maximal vasodilation for normalization of blood flow data. No significant differences in CVC (normalized to maximum) were found among Ringer's PACAP6-38, l-NAME, or combined antagonist sites during normothermia (P > 0.05 among sites) or cold stress (P > 0.05 among sites). CVC responses at all treated sites were attenuated during AVD (P < 0.05 vs. Ringer's). Attenuation was greater at l-NAME and combined PACAP6-38- and l-NAME-treated sites than at PACAP6-38 sites (P > 0.05). Because responses did not differ between l-NAME and combined treatment sites (P > 0.05), we conclude that VPAC2/PAC1 receptors require NO in series to effect AVD.
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PMID:Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans. 2296 Dec 70


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