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. The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 micrograms kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 microgram kg-1 NA. 5. Infusion of sodium nitroprusside (30 micrograms kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1). 6. These results demonstrate that the restoration of vascular responsiveness to NA in LPS-treated anaesthetized rats by inhibitors of the L-arginine/nitric oxide pathway is stereospecific and reversible. Furthermore, the experiments involving indomethacin suggest that although cyclo-oxygenase products of arachidonic acid may contribute to the development of LPS-induced hyporeactivity, the effect of L-NAME is unlikely to involve inhibition of the cyclo-oxygenase pathway. Comparison of NA responsiveness during vasopressin and L-NMMA/L-NAME-induced hypertension shows that increasing the blood pressure may modify LPS-induced hyporeactivity, but cannot account for the complete restoration of responses to NA by L-NMMA and L-NAME. These observations suggest that activation of nitric oxide formation from L-arginine makes a direct contribution to the production of vascular hyporeactivity by LPS in vivo.
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PMID:The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. 190 34

The role of the L-arginine-NO pathway on the formation of PGE2 by human cultured astroglial cells incubated with NMDA has been investigated. Preincubation of T 67 astroglial cell line with NMDA (10-600 microM) produced a significant dose-dependent increase of both nitrite (the breakdown product of NO), PGE2 and cGMP levels in cell supernatant. This effect was inhibited by coincubation of cells with L-NAME (20-300 microM), an inhibitor of NO synthase showing that the release of PGE2 subsequent to NMDA receptor stimulation was driven by NO. The release of PGE2 but not elevation of nitrite and cGMP levels was affected by indomethacin (10 microM), an inhibitor of cyclooxygenase. The inhibitory effect of L-NAME on PGE2 release by NMDA-pretreated astroglial cells was reverted by arachidonic acid, showing that the effect of NO on PGE2 release occurred at the cyclo-oxygenase level. Thus, the present experiments demonstrate that the release of PGE2 by astroglial cells pretreated with NMDA is driven by activation of the L-arginine-NO pathway, and this may be relevant in the pathophysiological mechanisms where glutamatergic neurotransmission is involved.
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PMID:NMDA-dependent prostaglandin E2 release by human cultured astroglial cells is driven by nitric oxide. 748 43

The actions of NO synthase inhibitors and indomethacin, a cyclooxygenase inhibitor, on the nonadrenergic noncholinergic (NANC) mechanical responses of cat distal colon were studied in vitro using muscle strips orientated in the axis of the longitudinal muscle layer with pelvic nerves attached. Electrical field stimulation (EFS) or pelvic nerve stimulation (PNS) caused inhibition of spontaneous contractions followed by off-contractions. Indomethacin (10-30 microM) caused concentration-dependent reductions in amplitude and duration of EFS- and PNS-evoked off-contractions but not latency. The NO synthase inhibitors, N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA) (each at 100 microM) significantly reduced latency, amplitude, and duration of off-contractions evoked by EFS and PNS. This inhibition was partially reversed by L-arginine (120 microM) but not by D-arginine. Incubation of colonic strips with alpha-chymotrypsin (2 U/ml) decreased latency, amplitude, and duration of NANC off-contractions. L-NNA reduced amplitude, duration, and latency of off-contractions in preparations pretreated with alpha-chymotrypsin. Hydroquinone (10-30 microM), a generator of superoxide anions, caused significant depression of amplitude, duration, and latency of off-contractions which was completely reversed by superoxide dismutase (200 U/ml). These data suggest that the components of NANC off-contractions evoked by EFS and PNS involve peptides, NO, and prostaglandins.
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PMID:A nitric oxide and prostaglandin-dependent component of NANC off-contractions in cat colon. 750 99

We wanted to assess the respective roles of arachidonic acid products and nitric oxide in the modulation of pulmonary hypertension in chronically hypoxic rats. In isolated blood-perfused lungs, the effects of arachidonic acid before and after treatment with the cyclooxygenase inhibitor, meclofenamate, were compared in control (C) rats and rats exposed for two weeks to 10% oxygen (chronic hypoxia CH). Arachidonic acid caused mixed dilator and constrictor effects during both normoxia and hypoxia; dilatation was more prominent in chronically hypoxic rats. Meclofenamate abolished both dilator and constrictor actions of arachidonic acid; it raised baseline, normoxic pulmonary artery pressure, in chronically hypoxic but not control rats, which suggests that dilator products of arachidonic acid are released in the pulmonary hypertension of chronic hypoxia and attenuate pulmonary artery pressure. As shown previously, the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) raised pressure in chronically hypoxic but not control rats. Meclofenamate and L-NAME given in sequence both raised pulmonary artery pressure in chronically hypoxic rats and the combined rise was substantial (+13 mmHg). We conclude that, in the conditions of our experiment, both nitric oxide and dilator prostanoids are released in hypoxic pulmonary hypertension in rats. Thus, two synthetic processes, both possibly endothelial dependent, may modulate hypoxic pulmonary hypertension.
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PMID:Attenuation of chronic hypoxic pulmonary hypertension in rats by cyclooxygenase products and by nitric oxide. 750 94

The effects of endothelin-1 (ET-1), an ET(A)/ETB-receptor agonist, and IRL 1620, a potent and selective ETB-receptor agonist, were assessed on left circumflex coronary artery diameter (sonomicrometry) and flow (electromagnetic flow probe) in pentobarbital-anesthetized dogs. Intracoronary (i.c.) bolus injections of ET-1 (80 pmol/dose) caused large, sustained coronary diameter decreases (281 +/- 39 microns) and transient flow increases (5.6 +/- 2.6 ml/min), followed by transient (10.0 +/- 1.9 ml/min) and then sustained flow reductions (6.6 +/- 2.5 ml/min) before terminating in ventricular fibrillation after two to five doses (max delta s; n = 4 dogs). IRL 1620 boluses (5-2,000 pmol/dose i.c.; max delta s; n = 3) also dose-dependently and transiently increased (16.8 +/- 1.4 ml/min; 200 pmol), then transiently decreased (12.8 +/- 1.5 ml/min; 1,600 pmol) flow but had minimal effects on diameter (delta = -23 +/- 4 microns; 2,000 pmol). Doses of IRL 1620 beyond 400 pmol were accompanied by a slowly responding, sustained decrease in baseline flow (-9.2 +/- 2.7 ml/min) and baseline diameter (232 +/- 150 microns). In a separate group of dogs (n = 5), IRL 1620 (400 pmol i.c.) was evaluated before and after sequential inhibition of cyclooxygenase (indomethacin; 10 mg/kg i.v.) and then nitric oxide synthase (N omega-nitro-L-arginine methyl ester, L-NAME; 50 mg/kg i.v.). Indomethacin alone did not affect the flow increase to IRL 1620 (11.0 +/- 2.0 versus 11.8 +/- 1.8 ml/min) but blunted the flow decrease by 30 +/- 6% (10.6 +/- 1.4 versus 7.1 +/- 0.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential responsiveness of conduit and resistance coronary arteries to endothelin A and B receptor stimulation in anesthetized dogs. 750 56

Mechanisms underlying production of vascular free radicals are unclear. We hypothesized that changes in blood flow might serve as a physiological stimulus for endothelial free radical release. Intact isolated aortas from 45 rabbits were perfused with the spin trap alpha-phenyl-N-tert-butylnitrone (PBN, 20 mmol/L) and formed radical adducts detected by electron paramagnetic resonance spectroscopy (EPR). Sequential perfusion at 2, 7.5, and 12 mL/min changed cumulative vascular PBN radical adduct yields, respectively, from 3.2 +/- 0.9 to 4.1 +/- 0.7 (P < .05) and 7.0 +/- 1.5 (P < .005) pmol/mg with endothelium and from 3.6 +/- 1.6 to 3.8 +/- 1.4 and 2.2 +/- 0.8 pmol/mg without endothelium (P = NS). In endothelialized aortas, superoxide dismutase (SOD) completely blocked flow-induced free radical production, whereas inactivated SOD, indomethacin, and the nitric oxide synthetase antagonist nitro-L-arginine methyl ester (L-NAME) had no effect; relaxations to acetylcholine remained unchanged with higher flows. To assess the role of flow on in vivo radical production, femoral arterial plasma levels of the ascorbyl radical, a stable ascorbate oxidation product, were measured by direct EPR in 56 other rabbits. Ascorbyl levels were assessed at baseline (30.2 +/- 0.7 nmol/L) and at peak-induced iliac flow changes. Flow increases from 25% to 100% due to saline injections through an extracorporeal aortic loop induced significant dose-dependent increases in ascorbyl levels (n = 5). In addition, after papaverine bolus injections, flow increased by 114 +/- 8% versus baseline, and ascorbyl levels increased by 5.4 +/- 0.7 nmol/L (n = 31, P < .001); similar results occurred with adenosine, isoproterenol, or hyperemia after 30-second occlusions (P < .05, n = 4 or 5 in each group). Active SOD completely blocked papaverine-induced ascorbyl radical increase, despite preserved flow response (delta ascorbyl = 0.02 +/- 1.6 nmol/L, P = NS); inactivated SOD, catalase, indomethacin, and L-NAME had no effect. Blood flow decreases of 65% to 100% due to phenylephrine or 60-second balloon occlusions were accompanied by an average decrease of 4.4 nmol/L (P < .05) in ascorbyl levels. No change in ascorbyl signal was observed when rabbit blood alone was submitted to in vitro flow increases through a tubing circuit. Thus, increases in blood flow trigger vascular free radical generation; such a response seems to involve endothelium-derived superoxide radicals unrelated to cyclooxygenase or nitric oxide synthetase activities. This mechanism may contribute to explain vascular free radical generation in physiological or pathological circumstances.
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PMID:Vascular free radical release. Ex vivo and in vivo evidence for a flow-dependent endothelial mechanism. 751 Oct 72

Left lung autotransplantation (LLA) increased the pulmonary vasoconstriction evoked by phenylephrine and attenuated the vasodilatation caused by acetylcholine or bradykinin in conscious dogs. To study the mechanisms responsible for these changes, pulmonary arterial rings were isolated from right (control) and left (LLA) lower lobes of dogs 1-26 mo after LLA and were suspended for isometric tension recording. Compared with control rings from the same anatomic location, contractions to phenylephrine were increased after LLA in rings with or without endothelium. In arterial rings contracted to 50% of their maximal response to phenylephrine, acetylcholine, bradykinin, and calcium ionophore caused endothelium-dependent relaxations that were reduced in LLA compared with control rings. In arterial rings from control and LLA lungs, relaxations to acetylcholine were not altered by inhibition of cyclooxygenase (indomethacin) but were reduced after inhibition of NO synthase [N omega-nitro-L-arginine methyl ester (L-NAME)]. After L-NAME, there was no longer any significant difference in acetylcholine-induced relaxation between arterial rings from control and LLA lungs. Relaxation to SIN-1, a NO donor, was similar in arterial rings (without endothelium) from control and LLA lungs. The results suggest that LLA causes an increased sensitivity of vascular smooth muscle to alpha 1-adrenergic activation and endothelial dysfunction that is mediated by a selective reduction in the activity of endothelium-derived relaxing factor/NO.
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PMID:Endothelial and vascular smooth muscle responses are altered after left lung autotransplantation. 751 88

Photoactivation of intravascular dyes with high doses of light is a technique used clinically to treat tumors. This procedure results in arteriolar constriction, mast cell degranulation, platelet thrombus formation, and, ultimately, microvascular stasis. In vivo microscopy was utilized in the current study to examine if the endothelial release of prostaglandins and nitric oxide could participate in the microvascular effects of photoactivation. Diameter changes and thrombus formation of arterioles and venules of the cremaster muscle of male Sprague-Dawley rats were quantitated during continuous light activation of intravascular fluorescein isothiocyanate conjugated to bovine serum albumin. Vasoconstriction and thrombus development were assessed separately, using the relationships between the width of the red blood cell column, the inner wall diameter, and the thickness of the plasma layer. Venular photoactivation resulted in thrombus growth which reached 30% of the maximum size by 16.8 +/- 3.71 min and a subsequent growth rate of 6.2 +/- 1.64 microns/min. In arterioles, 30% thrombus growth occurred at 14.0 +/- 2.02 min with a growth rate of 3.0 +/- 0.57 microns/min. Continuous arteriolar photoactivation led to a vasoconstriction of 34.4 +/- 6.87% of the initial vessel diameter. Thirty percent of the maximal constriction occurred after 10.6 +/- 1.26 min of photoactivation. Constriction proceeded at a rate of 3.8 +/- 1.32 microns/min. Topically applied mefenamic acid (a cyclooxygenase inhibitor) and Nw-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) each enhanced both the arteriolar and the venular thrombus growth due to photoactivation. Photoactivation-induced arteriolar constriction was augmented by L-NAME and inhibited by mefenamic acid. These data suggest that the photoactivation of intravascular dyes is accompanied both by the release of nitric oxide, which inhibits thrombus development and arteriolar constriction, and by the release of cyclooxygenase products, which inhibit thrombus growth and induce vasoconstriction. Rats treated with busulfan to induce thrombocytopenia exhibited a 90% decrease in circulating platelets. In these animals, photoactivation caused significantly delayed thrombus growth in arterioles and venules, while arteriolar constriction remained unaltered, suggesting that the vasoconstrictor prostanoid is not of platelet origin.
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PMID:Involvement of nitric oxide and cyclooxygenase products in photoactivation-induced microvascular occlusion. 751 91

The contribution of the renin-angiotensin system (RAS) and various endogenous vasoconstrictors on the pressor response to acute N omega-nitro-L-arginine methyl ester (L-NAME) administration (200 micrograms/kg/min) was assessed in anesthetized Wistar rats. Activity of the endogenous RAS was suppressed either by chronic treatment by a nonpeptide angiotensin II (AII) receptor antagonist (losartan) or an angiotensin-converting enzyme inhibitor (ACEI: enalapril), DOCA-salt pretreatment (without previous uninephrectomy), and binephrectomy (36-40 hours before experiments). We also studied the influence of chronic dietary sodium restriction. The role of alpha 1-adrenoceptor activity, endothelin (ET), and eicosanoids was evaluated in rats pretreated by prazosin, phosphoramidon (a nonspecific blocker of the conversion of big ET to ET), indomethacin, and the thromboxane A2 (TXA2) prostaglandin H2 (PGH2)-receptor antagonist SQ 29548, respectively. Finally, we tested the influence of the calcium channel blocker nicardipine on the vasopressor effect of L-NAME. In nonpretreated animals, L-NAME infusion induced an increase in mean arterial pressure (MAP) of 38 +/- 4 mm Hg. Chronic suppression of the RAS by losartan, enalapril, or DOCA did not alter the response to L-NAME, but the effect of L-NAME was moderately blunted in binephrectomized rats. Moderate attenuation (approximately 25%) and to a similar extent of the pressor effect of L-NAME was afforded by the low-sodium diet, phosphoramidon, SQ 29548, and indomethacin, whereas nicardipine markedly blunted by 74% the effect of L-NAME. We conclude that the acute pressor effect of L-NAME is mediated (at least in part) by cyclooxygenase-dependent products (mainly TXA2) and ET, but not by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous vasoactive systems and the pressor effect of acute N omega-nitro-L-arginine methyl ester administration. 752 59

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.
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PMID:Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia. 753 38


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