UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.
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PMID:Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. 768 6

1. This study investigates the role of tumour necrosis factor (TNF) in the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in a rat model of endotoxin shock. 2. In anaesthetized rats, pretreatment with a monoclonal antibody for TNF (TNFab; 20 mg kg-1, s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg-1, i.v.). For instance, endotoxaemia for 180 min resulted in a fall in MAP from 114 +/- 6 (control) to 84 +/- 5 mmHg (P < 0.01; n = 7). In contrast, animals pretreated with TNFab prior to LPS injection maintained significantly higher MAP when compared to LPS-control (MAP at 180 min; 118 +/- 3 mmHg; P < 0.01, n = 5). 3. Three hours of endotoxaemia was also associated with a significant reduction of the contractile effects of noradrenaline (NA) (10(-8)-10(-6) M) on the thoracic aorta ex vivo. This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with NG-nitro-L-arginine methyl ester (L-NAME, 20 min, 3 x 10(-4) M). Pretreatment of rats with TNFab (20 mg kg-1; at 16 h prior to LPS) significantly (P < 0.05) attenuated the LPS-induced hyporeactivity of rat aortic rings ex vivo. L-NAME did not enhance the contractions of aortic rings obtained from TNFab pretreated LPS-rats. 4. At 180 min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 +/- 0.57 pmol citrulline mg-1 min-1, n = 8). TNFab pretreatment significantly attenuated this induction of NOS in response to LPS by 37 +/- 6% (n = 5; P<0.05).5. We conclude that the formation of endogenous TNF contributes to the induction of the calcium in dependent isoform of NOS in response to LPS in vivo. Thus, the beneficial effects of agents which inhibit either the release or the action of TNF in circulatory shock may be, in part, due to inhibition of NOS induction.
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PMID:Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. 769 76

We investigated the relationships between vascular endothelium and parathyroid function. Blood pressure (BP), circulating endothelins (ETs) and atrial natriuretic peptide (ANP), and BP responses to parathyroid hormone (PTH) and NG-nitro-L-arginine methyl ester (L-NAME) were measured in parathyroidectomized (PTx), PTx and fed a Ca2+ enriched diet (PTx-HCa) and sham SHR.22 weeks after surgery, BP was significantly decreased in PTx and PTx-HCa, plasma ETs levels were increased, whereas ANP levels were decreased. In anesthetized rats, BP increase induced by L-NAME was greater in PTx-HCa than in sham group, indicating increased endogenous nitric oxide release in hypoparathyroid rats. The hypotensive response to PTH remained unchanged. These data demonstrate that endothelium is activated in long-term hypoparathyroid SHR, reflecting an adaptative response to decreased BP.
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PMID:Endothelium is a target organ of parathyroid secretions in genetic hypertensive rats. 772 86

A long-term study to identify age-dependent alterations in vascular reactivity in obese Zucker rats, a model for non-insulin-dependent diabetes mellitus, was carried out. On aortic rings of 12-week-old obese Zucker rats, but not in older animals (36 and 52 weeks), the following different effects in comparison to the lean rat control group were observed: (i) a significantly enhanced maximal relaxation to acetylcholine and A23187, which was abolished by the nitric oxide-synthase inhibitor L-nitro-arginine methyl ester (L-NAME); relaxation of aortic rings to the endothelium-independent vasodilator nitroglycerin was similar; (ii) more pronounced maximal 5-hydroxytryptamine-induced-contractions in the presence of L-NAME, and (iii) a more pronounced reduction in phenylephrine-induced contractions by verapamil. These results are suggestive of an altered calcium metabolism in the first weeks of development in the obese rat strain, which is probably responsible for the hypotension seen in this early time period.
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PMID:Age-related changes in vascular reactivity in genetically diabetic rats. 779 11

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.
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PMID:cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. 783 30

To determine the influences of both PO2 and the presence of the endothelium on contractile responses of the human umbilical artery (HUA), the effects of a series of vasoconstrictors were compared in ring preparations with and without endothelium at low (2.5% O2, PO2 < 55 mmHg (1 mmHg = 133.3 Pa)) and high PO2 (95% O2, PO2 > 600 mmHg). The results demonstrate the following. (i) 5-Hydroxytryptamine (5-HT) and endothelin-1 (ET-1) contracted the HUA at either low or high PO2. At low PO2, removal of the endothelium significantly reduced receptor-mediated responses. (ii) The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM) did not modulate 5-HT-initiated contractions at either level of PO2. (iii) alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT) and 5-carboxamidotryptamine (5-CT), relatively selective 5-HT1C/5-HT2 and 5-HT1-like receptor agonists, respectively, elicited contractions in the HUA, and the responses were reduced at low PO2 but unaffected by removal of the endothelium. (iv) Responses of the HUA to high potassium (hK+) were unaffected by either changes in PO2 or removal of the endothelium. (v) The 5-HT2 receptor antagonist ketanserin at low concentration (10 nM) inhibited contractile responses to 5-HT in an apparently competitive manner. However, with 100 nM ketanserin and at low PO2, inhibition became noncompetitive. Removal of the endothelium did not influence the action of ketanserin. (vi) Regardless of PO2, the Ca2+ channel antagonist nifedipine (1 microM) significantly inhibited 5-HT- and ET-1-mediated contractions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The endothelium contributes to the contractile responses of the human umbilical artery to 5-hydroxytryptamine and endothelin-1 under low but not high PO2 conditions. 788 82

The effects of chronic therapy with the angiotensin-converting enzyme (ACE) inhibitor trandolapril and/or Ca2+ antagonist verapamil on endothelial and vascular smooth muscle (VSM) function were studied in spontaneously hypertensive, stroke-prone rats (SHRSP). Dosages decreasing systolic blood pressure (SBP) by 20% were administered orally (p.o.) by gavage as monotherapy or combination therapy for 8 weeks, beginning at age 6 weeks. Combination therapy dosages were the same as those used in monotherapy (trandolapril 0.7 mg/kg/day verapamil 20 mg/kg/day) in one group; the second group received only half the monotherapy dosage. The study was placebo-controlled and performed in parallel groups. Isometric tension was measured in aortic rings suspended in organ chambers (95% C2/5% CO2; 37 degrees C). SBP decreased in all groups, as compared with placebo [30-47 mm Hg, analysis of variance (ANOVA), p < 0.05], but decrease was more pronounced in rats receiving high-dose combination (76 mm Hg, ANOVA, p < 0.05). In norepinephrine (NE)-contracted rings, endothelium-dependent relaxation to acetylcholine (ACh) was augmented similarly with all forms of therapy (maximal relaxations 89-94%) as compared with placebo (64 +/- 6%, p < 0.05). In contrast, the response to sodium nitroprusside (SNP) was similar in all groups (NS). In quiescent rings, ACh elicited endothelium-dependent contractions (in the presence of N omega-monomethyl-L-arginine, L-NAME) that were not affected by therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelial dysfunction in aorta of the spontaneously hypertensive, stroke-prone rat: effects of therapy with verapamil and trandolapril alone and in combination. 789 83

1. A study has been made of the modulation of calcium-activated potassium channels in cultured neurones of avian ciliary ganglia by sodium nitroprusside and L-arginine. 2. Sodium nitroprusside (100 microM) reduced the net outward current by 22 +/- 1% at 4.8 ms (mean +/- s.e. mean) and 25 +/- 1% at 350 ms during a test depolarization to +40 mV from a holding potential of -40 mV. The outward current remained reduced for the duration of the recording following a single application of sodium nitroprusside. These effects did not occur if the influx of calcium ions was first blocked with Cd2+ (500 microM). Application of ferrocyanide (100 microM) reduced the net outward current by only 6 +/- 3% at 350 ms during a test depolarization to +40 mV. 3. L-Arginine (270 microM) reduced the net outward current on average by 19 +/- 2% at 4.8 ms and 22 +/- 2% at 350 ms during a test depolarization to +40 mV. The current remained in this reduced state for the duration of the recording following a single application of L-arginine. These effects were reduced to 11 +/- 1% at 4.8 ms and 11 +/- 2% at 350 ms in the presence of N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM). 4. In order to alleviate the dependence of calcium-activated potassium channels (Ik(Ca)) on the inward flux of calcium ions, the patch-clamp pipettes were filled with a solution containing 100 microM CaCl2, and the Ca2+ in the bathing solution was replaced with EGTA. Under these conditions sodium nitroprusside reduced the total outward current during a depolarizing pulse of + 40 mV by 9 +/_ 1% at 4.8 ms and by 36 +/- 3% at 350 ms. L-Arginine (270 microM) reduced this current under the same conditions by 9 +/- 1% at 4.8 ms and by 35 +/- 2% at 350 ms.5. Calcium-activated potassium currents were sensitive to apamin (50 nM), as this reduced the outward current by 23 +/- 3% at 350 ms when a high calcium-containing pipette was used during a depolarizing command to + 40 mV. L-Arginine still decreased the outward current in the presence of apamin(50 nM), by 5 +/- 1% at 4.8 ms and by 19 +/- 2% at 350 ms, indicating that L-arginine could reduce an apamin-insensitive Ik(Ca)6. Calcium-activated potassium currents were also sensitive to charybdotoxin (10 nM), as this reduced the outward current by 34 +/- 4% at 350 ms when a high calcium-containing pipette was used during a depolarizing command to + 40 mV. L-Arginine still decreased the outward current in the presence of charybdotoxin, by 6 +/- 1% at 4.8 ms and 12 +/- 4% at 350 ms, showing that L-arginine could reduce a charybdotoxin-insensitive Ik(Ca).7. The present results indicate that NO-synthase in ciliary ganglia can modulate Ik(Ca) by a method which is independent of the action of NO on the calcium channels. The Ik(ca) is decreased significantly at 4.8 ms into a depolarizing pulse, at a time that would decrease the rate of repolarization of the action potential. Ik(Ca) is also reduced at longer times (350 ms), indicating an affect on the inactivating process.
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PMID:Nitric oxide modulation of calcium-activated potassium channels in postganglionic neurones of avian cultured ciliary ganglia. 790 46

Cholinergic modulation of heart rate in isolated spontaneously beating single cells from the rabbit sino-atrial node was investigated by measuring transmembrane ionic currents using the nystatin-perforated patch whole-cell voltage-clamp technique. Carbamylcholine (CCh), a stable analogue of acetylcholine (ACh), significantly inhibited L-type calcium currents (Ica(L) which had been augmented by beta-adrenergic stimulation. In addition, CCh activated a potassium outward current (IK(ACh)). Both effects were blocked by atropine. The possible involvement of nitric oxide (NO) in these responses was evaluated by inhibiting NO synthesis. In the presence of NG-monomethyl-L-arginine (L-NMMA, 100 microM) or nitro-L-arginine methyl ester (L-NAME, 1 mM), two specific inhibitors of nitric oxide synthase (NOS), CCh no longer inhibited ICa(L). IK(ACh) could still be activated. Co-incubation of cells in L-NAME or in L-NMMA with arginine (the endogenous substrate of NOS) restored the CCh-induced attenuation of ICa(L), indicating that L-NAME or L-NMMA did not interfere directly with the muscarinic action of CCh on ICa(L). Effects of the NO-releasing agent molsidomine (SIN-1) on CCh-induced changes in ICa(L) were also investigated. After ICa(L) had been augmented by beta-adrenergic stimulation, SIN-1 (0.1 mM) inhibited ICa(L); however, SIN-1 had no further inhibitory effect after a maximal CCh concentration had been applied. These findings suggest that NO generation is an obligatory process in cholinergic inhibition of ICa(L) in mammalian cardiac pacemaker tissue.
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PMID:An obligatory role for nitric oxide in autonomic control of mammalian heart rate. 791 69

The purpose of this study was to evaluate potential mechanisms of ischemia-evoked amino acid transmitter release. Changes in extracellular levels of transmitter amino acids and lactic acid dehydrogenase (LDH) in rat cerebral cortex during and following four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked release of glutamate, aspartate and gamma-amino-butyric acid (GABA) was compared in control vs. drug-treated animals. Tetrodotoxin and antagonists of glutamate receptors (DNQX, MK-801, and AP-3) depressed the initial rate of increase in extracellular glutamate and aspartate without altering the total amount of these amino acids collected in the cortical superfusates. Cobalt, a calcium channel antagonist, failed to alter efflux. Acidic amino acid transport inhibitors (dihydrokainate, L-trans-PDC) depressed the rate of onset of glutamate and aspartate release and dihydrokainate depressed total release by 44%. PD 81723, an allosteric enhancer at the A1 adenosine receptor, depressed glutamate efflux, as did L-NAME, an inhibitor of nitric oxide synthase. Extracellular increases in GABA levels were depressed by tetrodotoxin and L-trans-PDC. The GABA transport inhibitor, nipecotic acid, increased the initial rate of onset of GABA release. Increases in LDH levels in the extracellular fluid became apparent during the period of ischemia and continued to increase during the subsequent 90 min of reperfusion. These results suggest that ischemia evokes a release of neurotransmitter amino acids that is only partially dependent upon Ca2+ influx activation or the reversal of amino acid transporters. Nonselective mechanisms, resulting from the disruption of plasma membrane integrity, may contribute significantly to the total ischemia-evoked release of excitatory amino acids.
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PMID:Characterization of glutamate, aspartate, and GABA release from ischemic rat cerebral cortex. 791 62

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