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)

Endothelium-derived relaxing factor (EDRF) is a potent endogenous vasodilator that has been indirectly suggested to play a role in isoflurane-mediated vasodilation. To examine directly the possible role of EDRF in isoflurane-mediated vasodilation, isolated rat thoracic aortic rings were suspended for isometric tension measurements, equilibrated to a resting tension of 2 g, and constricted with a 50% maximal concentration (EC50) dose of phenylephrine or KCl. Three groups of rings were studied: endothelium-intact, endothelium-denuded, and endothelium-intact rings treated with nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of EDRF synthase. Isoflurane was then added at 1, 2, and 3% in a cumulative manner, allowing 10 min for each concentration to equilibrate. Indomethacin was present in all experiments to prevent the formation of vasoactive prostanoid metabolites. Since EDRF causes vascular relaxation by stimulating soluble guanylyl cyclase and increasing cyclic GMP, the effect of isoflurane on vascular ring cyclic GMP content was determined as an additional indicator of EDRF-mediated dilation. Rings with intact and denuded endothelium were isolated as described above, constricted with phenylephrine, and challenged with methacholine (positive control) or 1, 2, or 3% isoflurane. After 8 min exposure, the rings were flash-frozen in dry-ice-cooled acetone and homogenized in 1 N HCl for subsequent analysis of cyclic GMP content by radioimmunoassay. Isoflurane caused dose-dependent vasodilation of both KCl- and phenylephrine-constricted rings. In the phenylephrine group, at 2% and 3% isoflurane, endothelium-denuded and L-NAME-treated rings relaxed to a greater extent than endothelium-intact rings (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoflurane does not vasodilate rat thoracic aortic rings by endothelium-derived relaxing factor or other cyclic GMP-mediated mechanisms. 131 21

1. The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperaemic response to acid back-diffusion through a disrupted gastric mucosal barrier was examined. The experiments were carried out on anaesthetized rats in which acid back-diffusion was elicited by gastric perfusion with dilute ethanol in 0.15 M HCl and gastric mucosal blood flow (MBF) was measured by the hydrogen gas clearance technique. 2. Indomethacin (28 mumols kg-1, s.c.), an inhibitor of the formation of cyclo-oxygenase products including prostacyclin, failed to alter mean arterial blood pressure (MAP), basal MBF and the hyperaemic response to acid back-diffusion in urethane-anaesthetized rats. 3. NG-nitro-L-arginine methyl ester (L-NAME; 13 and 43 mumols kg-1, i.v.), an inhibitor of endothelium-derived NO formation, increased MAP in a dose-dependent manner. Whilst basal MBF in urethane-anaesthetized rats was not changed, the increase in MBF caused by gastric perfusion with dilute ethanol in acid was dose-dependently depressed by L-NAME. The loss of H+ ions from the gastric lumen, an indirect measure of acid back-diffusion, was significantly enhanced by 43 mumols kg-1 L-NAME. In contrast, D-NAME (13 and 43 mumols kg-1) was without effect on MAP, basal and stimulated MBF, and acid back-diffusion. 4. Unlike in urethane-anaesthetized rats, L-NAME led to a significant reduction of basal MBF in phenobarbitone-anaesthetized rats. MAP in the phenobarbitone-anaesthetized rats was significantly higher than in urethane-anaesthetized rats, and the hypertensive effect of L-NAME under phenobarbitone anaesthesia was significantly smaller than under urethane anaesthesia.5. The rise in MBF brought about by acid back-diffusion was blocked by L-NAME administered to phenobarbitone-anaesthetized rats. Infusion of L-arginine (120 pmol kg -1 min- ', i.v.) led to a partial, but significant, reversal of the effects of L-NAME on MAP and the hyperaemia due to acid back-diffusion.6. These findings indicate that endothelium-derived NO plays an important mediator role in the gastric mucosal vasodilatation caused by back-diffusion whilst vasodilator prostanoids such as prostacyclin are not involved.
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PMID:Participation of endothelium-derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back-diffusion. 162 57

1. Acid back-diffusion through a disrupted gastric mucosal barrier is known to increase gastric mucosal blood flow via a neural mechanism. The present study examined how the acid-evoked change in the gastric microcirculation compares with blood flow changes in the left gastric artery, one of the major arteries supplying the stomach, and whether the dilator mediators in the left gastric artery are identical to those in the gastric mucosa. 2. The experiments were performed on rats anaesthetized with urethane. Blood flow in the left gastric artery was measured by the ultrasonic transit time shift technique, and blood flow in the gastric mucosa was assessed by the hydrogen gas clearance method. 3. Gastric acid back-diffusion evoked by perfusion of the stomach with 15% ethanol in 0.15 M HCl increased blood flow in the left gastric artery by a factor of 4.7, which was significantly larger than the 2.9-fold increase in blood flow through the gastric mucosa. Blood pressure and heart rate were not altered appreciably. 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67580. 5. The calcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) had no effect on gastric blood flow but prevented the dilator action of CGRP and inhibited the acid-evoked hyperaemia in the gastric mucosa to a larger degree than the hyperaemia in the left gastric artery. 6. Blockade of nitric oxide synthesis by N omega-nitro-L-arginine methyl ester (L-NAME) caused constriction of the left gastric artery and the gastric mucosal microvessels. The acid-evoked vasodilatation in the gastric mucosa was blocked by L-NAME, whereas the dilator response in the left gastric artery was not significantly depressed. 7. The data show that the gastric hyperaemic response to acid back-diffusion results from dilatation of mucosal microvessels and extramural arteries. The dilator mechanisms, however, differ between the two vascular beds. CGRP and nitric oxide are important vasodilator mediators in the gastric mucosa but are of less relevance in the left gastric artery.
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PMID:Vascular bed-dependent roles of the peptide CGRP and nitric oxide in acid-evoked hyperaemia of the rat stomach. 753 14

The protective action of mild irritants has been established. However, the mechanisms as to how they antagonize the injurious action produced by the subsequent challenge with an ulcerogenic stimulus are still unclear. The present study examined the different protective mechanisms of an oral administration of the three mild irritants, 20% ethanol, 0.3 mol/L HCl or 5% NaCl against the gastric injurious actions of absolute ethanol in rats. In an attempt to clarify the pathways and mediators involved in the adaptive cytoprotection, [D-Pro2, D-Trp7,9]-substance P (substance P antagonist), Nw-nitro-L-arginine methyl ester (L-NAME), indomethacin, capsaicin, lidocaine, atropine or hexamethonium was given. The protective action of 20% ethanol but not the other two mild irritants, was antagonized by L-NAME, indomethacin and capsaicin, which are the inhibitors of nitric oxide (NO) and prostaglandins (PG) synthesis, and afferent sensory neuron blocker, respectively. Substance P antagonist, lidocaine or atropine given alone, prevented mucosal damage; however, only substance P antagonist enhanced the anti-lesion action of 20% ethanol, while atropine and lidocaine increased the protective effect of NaCl and HCl. The three mild irritants increased the residual gastric secretion. Only 20% ethanol and 5% NaCl but not 0.3% HCl significantly increased the basal adherent mucus and also attenuated the mucus depletion by absolute ethanol. It is concluded that the cytoprotective action of either ethanol or NaCl seems to be mediated through the increase of residual gastric secretion and adherent mucus. In the ethanol-treated group, these actions could act through the afferent sensory fibres, with NO and PG as the possible mediators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The differential mechanisms of mild irritants on adaptive cytoprotection. 753 52

1. The interaction between endogenous nitric oxide (NO) and factors from the rat submandibular salivary gland such as epidermal growth factor (EGF) on gastric mucosal integrity in the rat has been investigated. 2. Bolus administration of the NO synthase inhibitor, NG nitro-L-arginine methyl ester (L-NAME; 6.25-50 mg kg-1, i.v.) to animals treated intraluminally with 0.15 N HCl resulted in a significant increase in the area of mucosal haemorrhagic damage at doses 12.5 and 50 mg kg-1. Concurrent administration of indomethacin (5 mg kg-1, i.v.) resulted in a significant haemorrhagic mucosal damage in response to L-NAME (12.5-50 mg kg-1). Administration of the highest dose of L-NAME resulted in an increase in histological damage to the rat gastric mucosa. 3. When compared to control animals, the extent of damage produced by L-NAME or L-NAME in combination with indomethacin was significantly exacerbated in rats which had been sialoadenectomized (SALX) by removal of the submandibular salivary glands. The mucosal damage in SALX rats was ameliorated by treatment with EGF (5 and 10 micrograms kg-1, i.v.). 4. L-NAME administration resulted in a small reduction of gastric mucosal blood flow as assessed by laser Doppler flowmetry (LDF). The reduction in LDF by 25 and 50 mg kg-1 L-NAME was significantly greater in SALX rats than in rats with intact salivary glands. Pretreatment of SALX rats with indomethacin did not augment this large decrease in LDF suggesting that endogenous prostanoids do not interact with NO and salivary factors in regulating mucosal microcirculation. 5. Mucosal NO biosynthesis as assessed by ['4C]-citrulline formation was reduced in SALX rats when compared to control animals. Pretreatment of SALX animals with parenterally-administered EGF(10 microg kg-1) was associated with an increase in [14C]-citrulline formation in the gastric mucosa to levels observed in control SALX rats.6. These data suggest that factors which originate from the salivary gland such as EGF interact with NO in the maintenance of mucosal integrity. The effects may be mediated at least in part by changes in gastric mucosal blood flow. Salivary glands and EGF may mediate these effects to some extent via changes in mucosal NO biosynthesis.
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PMID:Interaction of nitric oxide and salivary gland epidermal growth factor in the modulation of rat gastric mucosal integrity. 769 80

We examined the cytoprotective effect of L-arginine on gastric damage induced by 0.6 N HCl in rats and investigated whether the mechanism of this action is related to the nitric oxide (NO)-mediated protection. The animals were given 0.6 N HCl by gavage and killed 1 hr later. L-Arginine (100, 300 and 750 mg/kg) given p.o. 30 min before HCl treatment prevented these lesions in a dose-dependent manner, but had no effect when given i.v. (200 mg/kg). Similar effects were observed by D-arginine but not by an equimolar dose of mannitol. This effect of L-arginine (p.o.) was attenuated significantly by prior administration of indomethacin (5 mg/kg, s.c.) but not by NG-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg, i.v.), the NO synthase inhibitor. Both L- and D-arginine produced a reduction in potential difference (PD), inhibition of gastric motility, and increases of luminal pH and mucosal blood flow when they were given intragastrically. Indomethacin significantly mitigated these changes induced by L-arginine except PD reduction, while L-NAME showed significant inhibition only against the increased pH response. We conclude that L-arginine given p.o. exhibits gastric cytoprotection against HCl-induced damage in rats, probably by acting as a mild irritant. The mechanism of this action may appear through "adaptive cytoprotection" mediated by endogenous prostaglandins and does not involve the NO-mediated protective pathway.
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PMID:Cytoprotective action of L-arginine against HCl-induced gastric injury in rats: involvement of nitric oxide? 843 69

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.
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PMID:Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin. 869 42

We investigated the effect of hyperthyroidism on the responses of small mesenteric resistance arteries to several contractile and dilator agents. Hyperthyroidism was established by feeding rats for 28 days with 5 mg/kg L-thyroxine-containing rat chow. This treatment produced a stable hyperthyroid state, as indicated by the increased serum T4 levels (236 +/- 7 vs. 60 +/- 2; T4-treated vs. control). Preparations of small mesenteric arteries were mounted in an isometric wire myograph. Subsequently, concentration-effect curves were determined for K+, Ca2+, methoxamine, phenylephrine, 5-hydroxytryptamine (5-HT), 9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha (U46619), methacholine and nitroprusside. Our results indicate that hyperthyroidism does not induce major changes in the sensitivity of isolated resistance vessels to K+, Ca+, the alpha-adrenoceptor agonist, methacholine and nitroprusside. Furthermore, neither the affinity of alpha-receptors for methoxamine, nor the alpha-receptor reserve was influenced by the hyperthyroid state of the animal. A clearly sensitizing influence of hyperthyroidism was found for the vasoconstrictor effects of both 5-HT (6.57 +/- 0.04 vs. 6.29 +/- 0.06; hyperthyroid vs. control) and the thromboxane A2 receptor agonist U46619 (6.78 +/- 0.13 vs. 6.30 +/- 0.09; hyperthyroid vs. control). Sensitization to both 5-HT and U46619 was abolished in the presence of N omega-nitro-L-arginine methylester HCl (L-NAME, 0.1 mM). 5-HT-induced contractions in vessels from hyperthyroid rats were diminished by prior incubation with indomethacin (10 microM). The present results indicate that during hyperthyroidism resistance vessels are sensitized to both 5-HT and U46619. This sensitization involves the nitric oxide/L-arginine pathway and probably also certain steps in the cyclooxygenase pathway.
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PMID:The influence of hyperthyroidism on pharmacologically induced contractions of isolated resistance arteries. 874 Nov 71

We investigated the HCO3- stimulatory mechanism of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the anesthetized rat duodenum and examined whether L-NAME protects against mepirizole-induced duodenal damage. The proximal duodenal loop was perfused with saline and HCO3- secretion was measured at pH 7.0 using a pH-stat with added HCl (10 mM). L-NAME (1-5 mg/kg, i.v.) increased HCO3- secretion in a dose-dependent manner, with concomitant elevation in arterial blood pressure and an apparent decrease in heart rate. These changes were mimicked by another NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg, i.v.) but not by NG-nitro-D-arginine methyl ester (D-NAME), and were all antagonized by co-administration of L-arginine but not by D-arginine (200 mg/kg, i.v.). The HCO3- stimulatory effect of L-NAME was also inhibited by vagotomy and pretreatment with atropine (1 mg/kg, s.c.) or indomethacin (5 mg/kg, s.c.). Vagotomy and atropine did not affect blood pressure response, but both inhibited the decrease of heart rate caused by L-NAME, whereas indomethacin did not affect either of these changes. In addition, L-NAME increased HCO3- secretion in the presence of mepirizole (200 mg/kg, s.c.) and prevented duodenal lesions caused by this agent. These results suggest that L-NAME stimulates duodenal HCO3- secretion in association with the inhibition of endogenous NO production, mediated by neural reflex through vagal efferent nerves, resulting from the pressor response to this agent, and may protect the duodenal mucosa against acid-related damage.
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PMID:Effect of NG-nitro-L-arginine methyl ester, the nitric oxide synthase inhibitor, on duodenal alkaline secretion and mepirizole-induced duodenal lesions in rats. 877 93

Conditions such as hyperalgesia can occur days or months after the noxious insult. Substance P (SP) is released in response to noxious stimuli. Given the long-term effects of the N-terminus of SP on putative nociceptive transmitters, we investigated changes in formalin-induced nociception following an accumulation of SP N-terminal metabolites in mice. Pre-treatment with the N-terminal metabolite of SP, SP(1-7), was without effect when injected intrathecally (i.t.) 5 or 30 min before formalin. However, at 24 h, SP(1-7) increased behaviors during Phase 1, indicating hyperalgesia, and attenuated Phase 2 responses, consistent with antinociception. The nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester HCl (L-NAME), blocked both hyperalgesic and antinociceptive effects when co-injected with SP(1-7). Consistent with a NO-mediated pathway, L-arginine (L-arg), the N-terminal amino acid of SP and precursor to NO, mimicked the antinociceptive effect of SP(1-7) on Phase 2. The hyperalgesic effect of SP(1-7) in Phase 1, which was not mimicked by L-arg, was prevented by D-SP(1-7), a SP(1-7) antagonist. Thus, SP(1-7) modulates nociception via two distinct NO-mediated pathways. When injected for 7 days, tolerance developed to the antinociceptive effect of SP(1-7) on Phase 2, but not to the hyperalgesic effect on Phase 1. Intraperitoneally injected SP(1-7) also produced hyperalgesia during Phase 1, to which tolerance developed following seven daily injections. Together, these data support the hypothesis that an accumulation of SP N-terminal metabolites, either peripherally or within the spinal cord area, is sufficient for long-term modulation of multiple types of nociception with hyperalgesic responses being most persistent.
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PMID:Nitric oxide mediates long-term hyperalgesic and antinociceptive effects of the N-terminus of substance P in the formalin assay in mice. 895 39


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