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Owen L. Woodman - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic neurogenic vasodilatation is mediated by nitric oxide in the dog hindlimb
Cardiovascular research, 1994Co-Authors: Kit E. Loke, Christopher G. Sobey, Gregory J. Dusting, Owen L. WoodmanAbstract:Objective: The aim was to investigate the role of nitric oxide (NO) in cholinergic neurogenic vasodilatation in the dog hindlimb using the NO synthase inhibitor, N-nitro-L-arginine (Nola), and the NO precursor, L-arginine. Methods: 20 dogs were anaesthetised with thiopentone and α chloralose and experiments were performed in the presence of noradrenergic neurone blockade with guanethidine (15 mg·kg−1 subcutaneously). Using stereotaxic procedures, specific sites in the hypothalamus were electrically stimulated (HS) to produce depressor and hindlimb vasodilator responses. In each experiment, responses to intra-arterial (ia) injections of acetylcholine and glyceryl trinitrate produced increases in femoral blood flow similar to those caused by HS. Results: Vasodilator responses to HS and acetylcholine but not glyceryl trinitrate were reduced by the muscarinic receptor antagonists tropicamide (3-12 mg ia) or atropine (0.5 mg·kg−1 intravenously, iv). Administration of Nola (5-15 mg·kg−1 ia) significantly attenuated the HS induced decrease in arterial pressure [ΔAP: control = −21(SEM 3) mm Hg v Nola treated = −9(3) mm Hg, p< 0.005] and the increase in femoral blood flow [ΔFBF: control = 43(7) ml·min−1 v Nola treated = 17(4) ml·min−1, p< 0.005]. Nola also significantly inhibited femoral vasodilator responses to acetylcholine [ΔFBF: control = 47(6) ml·min−1 v Nola treated = 35(6) ml·min−1, p < 0.05] whereas responses to glyceryl trinitrate were enhanced [FBF: control = 54(9) ml·min−1 v Nola treated = 69(9) ml·min−1, p< 0.005]. In addition L-arginine (150-300 mg·kg−1 iv), but not D-arginine (150 mg·kg−1 iv), reversed the inhibitory effect of Nola on HS induced dilator responses [ΔFBF: Nola treated = 14(4) ml·min−1 v L-arginine treated = 35(8) ml·min−1, n = 8; greater than Nola treated, p
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INVOLVEMENT OF NITRIC OXIDE IN CORONARY VASCULAR RESPONSES TO 5‐HYDROXYTRYPTAMINE IN THE ANAESTHETIZED GREYHOUND
Clinical and experimental pharmacology & physiology, 1994Co-Authors: Owen L. Woodman, Gregory J. DustingAbstract:1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1-1.0 micrograms/kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine (Nola; 5 mg/kg i.c.) in nine anaesthetized greyhounds. Before administration of Nola, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of Nola significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of Nola, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before Nola treatment. 3. The response to Nola suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.
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Baroreceptor reflexes and vascular reactivity during inhibition of nitric oxide synthesis in conscious rabbits.
European journal of pharmacology, 1992Co-Authors: Gregory J. Dusting, Owen L. WoodmanAbstract:The effect of the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (Nola) on vascular reactivity and the baroreceptor heart rate reflex was examined in chronically instrumented conscious rabbits. Nola (15 mg/kg i.v.) significantly increased mean arterial pressure and hindlimb vascular resistance and decreased heart rate. Increases and decreases in arterial pressure were produced by the intravenous injection of phenylephrine and sodium nitroprusside respectively and the values obtained relating mean arterial blood pressure to heart rate were fitted to a sigmoid curve. Nola significantly reduced the lower plateau of the arterial pressure--heart rate curve but did not significantly affect baroreceptor sensitivity. Depressor and hindlimb vasodilator responses to acetylcholine were significantly impaired by Nola whereas responses to sodium nitroprusside were significantly enhanced. The pressor and hindlimb vasoconstrictor responses to phenylephrine were significantly enhanced in the presence of Nola. We conclude that the bradycardia produced by Nola does not result from a change in baroreceptor sensitivity. The continuous generation of NO appears to be important in regulating basal vascular resistance and in modulating vascular reactivity to both vasodilator and vasoconstrictor agents.
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INHIBITION OF NITRIC OXIDE SYNTHASE SPECIFICALLY ENHANCES ADRENERGIC VASOCONSTRICTION IN RABBITS
Clinical and experimental pharmacology & physiology, 1992Co-Authors: Gregory J. Dusting, Owen L. WoodmanAbstract:1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (Nola) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of Nola (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of Nola. In contrast, Nola significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of Nola, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, Nola (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. Nola enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, Nola causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, Nola enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.
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Mechanism of the hypertension produced by inhibition of nitric oxide biosynthesis in rats
Journal of Cardiovascular Pharmacology, 1991Co-Authors: Maria Zambetis, Gregory J. Dusting, S. Rajanayagam, Owen L. WoodmanAbstract:We have examined the effects of inhibition of nitric oxide (NO) biosynthesis on the blood pressure (BP) of anesthetized rats using N-nitro-L-arginine (Nola). Infusion of Nola (5, 15, or 60 mg/kg) caused a rise in BP of up to 155 mm Hg could be prevented (but not reversed) by administration of L-arginine (300 and 600 mg/kg, i.v.). In addition, Nola(5-60 mg/kg) reduced the duration of the depressor response to acetylcholine (1 μg/kg), but not that of sodium nitroprusside (10 μg/kg).
Gregory J. Dusting - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic neurogenic vasodilatation is mediated by nitric oxide in the dog hindlimb
Cardiovascular research, 1994Co-Authors: Kit E. Loke, Christopher G. Sobey, Gregory J. Dusting, Owen L. WoodmanAbstract:Objective: The aim was to investigate the role of nitric oxide (NO) in cholinergic neurogenic vasodilatation in the dog hindlimb using the NO synthase inhibitor, N-nitro-L-arginine (Nola), and the NO precursor, L-arginine. Methods: 20 dogs were anaesthetised with thiopentone and α chloralose and experiments were performed in the presence of noradrenergic neurone blockade with guanethidine (15 mg·kg−1 subcutaneously). Using stereotaxic procedures, specific sites in the hypothalamus were electrically stimulated (HS) to produce depressor and hindlimb vasodilator responses. In each experiment, responses to intra-arterial (ia) injections of acetylcholine and glyceryl trinitrate produced increases in femoral blood flow similar to those caused by HS. Results: Vasodilator responses to HS and acetylcholine but not glyceryl trinitrate were reduced by the muscarinic receptor antagonists tropicamide (3-12 mg ia) or atropine (0.5 mg·kg−1 intravenously, iv). Administration of Nola (5-15 mg·kg−1 ia) significantly attenuated the HS induced decrease in arterial pressure [ΔAP: control = −21(SEM 3) mm Hg v Nola treated = −9(3) mm Hg, p< 0.005] and the increase in femoral blood flow [ΔFBF: control = 43(7) ml·min−1 v Nola treated = 17(4) ml·min−1, p< 0.005]. Nola also significantly inhibited femoral vasodilator responses to acetylcholine [ΔFBF: control = 47(6) ml·min−1 v Nola treated = 35(6) ml·min−1, p < 0.05] whereas responses to glyceryl trinitrate were enhanced [FBF: control = 54(9) ml·min−1 v Nola treated = 69(9) ml·min−1, p< 0.005]. In addition L-arginine (150-300 mg·kg−1 iv), but not D-arginine (150 mg·kg−1 iv), reversed the inhibitory effect of Nola on HS induced dilator responses [ΔFBF: Nola treated = 14(4) ml·min−1 v L-arginine treated = 35(8) ml·min−1, n = 8; greater than Nola treated, p
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INVOLVEMENT OF NITRIC OXIDE IN CORONARY VASCULAR RESPONSES TO 5‐HYDROXYTRYPTAMINE IN THE ANAESTHETIZED GREYHOUND
Clinical and experimental pharmacology & physiology, 1994Co-Authors: Owen L. Woodman, Gregory J. DustingAbstract:1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1-1.0 micrograms/kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine (Nola; 5 mg/kg i.c.) in nine anaesthetized greyhounds. Before administration of Nola, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of Nola significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of Nola, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before Nola treatment. 3. The response to Nola suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.
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Baroreceptor reflexes and vascular reactivity during inhibition of nitric oxide synthesis in conscious rabbits.
European journal of pharmacology, 1992Co-Authors: Gregory J. Dusting, Owen L. WoodmanAbstract:The effect of the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (Nola) on vascular reactivity and the baroreceptor heart rate reflex was examined in chronically instrumented conscious rabbits. Nola (15 mg/kg i.v.) significantly increased mean arterial pressure and hindlimb vascular resistance and decreased heart rate. Increases and decreases in arterial pressure were produced by the intravenous injection of phenylephrine and sodium nitroprusside respectively and the values obtained relating mean arterial blood pressure to heart rate were fitted to a sigmoid curve. Nola significantly reduced the lower plateau of the arterial pressure--heart rate curve but did not significantly affect baroreceptor sensitivity. Depressor and hindlimb vasodilator responses to acetylcholine were significantly impaired by Nola whereas responses to sodium nitroprusside were significantly enhanced. The pressor and hindlimb vasoconstrictor responses to phenylephrine were significantly enhanced in the presence of Nola. We conclude that the bradycardia produced by Nola does not result from a change in baroreceptor sensitivity. The continuous generation of NO appears to be important in regulating basal vascular resistance and in modulating vascular reactivity to both vasodilator and vasoconstrictor agents.
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INHIBITION OF NITRIC OXIDE SYNTHASE SPECIFICALLY ENHANCES ADRENERGIC VASOCONSTRICTION IN RABBITS
Clinical and experimental pharmacology & physiology, 1992Co-Authors: Gregory J. Dusting, Owen L. WoodmanAbstract:1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (Nola) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of Nola (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of Nola. In contrast, Nola significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of Nola, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, Nola (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. Nola enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, Nola causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, Nola enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.
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Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats.
Clinical and experimental pharmacology & physiology, 1992Co-Authors: Gregory J. Dusting, Judith A. WhitworthAbstract:1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (Nola) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. Nola administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving Nola than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; Nola + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since Nola increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and Nola administration.
Gary Stacey - One of the best experts on this subject based on the ideXlab platform.
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A Two-Component Regulator Mediates Population-Density-Dependent Expression of the Bradyrhizobium japonicum Nodulation Genes
Journal of bacteriology, 2002Co-Authors: John T. Loh, D. Lohar, Brett Andersen, Gary StaceyAbstract:Bradyrhizobium japonicum nod gene expression was previously shown to be population density dependent. Induction of the nod genes is highest at low culture density and repressed at high population densities. This repression involves both Nola and NodD2 and is mediated by an extracellular factor found in B. japonicum conditioned medium. Nola and NodD2 expression is maximal at high population densities. We demonstrate here that a response regulator, encoded by nwsB, is required for the full expression of the B. japonicum nodYABC operon. In addition, NwsB is also required for the population-density-dependent expression of both Nola and nodD2. Expression of Nola and nodD2 in the nwsB mutant remained at a basal level, even at high culture densities. The nwsB defect could be complemented by overexpression of a second response regulator, NodW. Consistent with the fact that Nola and NodD2 repress nod gene expression, the expression of a nodY-lacZ fusion in the nwsB mutant was unaffected by culture density. In plant assays with GUS fusions, nodules infected with the wild type showed no nodY-GUS expression. In contrast, nodY-GUS expression was not repressed in nodules infected with the nwsB mutant. Nodule competition assays between the wild type and the nwsB mutant revealed that the addition of conditioned medium resulted in a competitive advantage for the nwsB mutant.
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EXPRESSION OF THE BRADYRHIZOBIUM JAPONICUM Nola GENE IN RESPONSE TO CHEMICALLY DISTINCT SOYBEAN INDUCERS
Nitrogen Fixation: From Molecules to Crop Productivity, 2002Co-Authors: John T. Loh, Sérvio Túlio Alves Cassini, Fernando F. Oliveira, Gary StaceyAbstract:Two inducers of the Bradyrhizobium japonicum Nola gene have been characterized by using NolalacZ fusions. These inducers were isolated from extracts of 5-day old etiolated soybean seedlings. The first is peptide-like and may act only on the Nola P1 promoter. The second is chitinase sensitive and induces expression of Nola from the P2 promoter. B. japonicum strains treated with both compounds nodulated soybean plants to a higher level than with untreated B. japonicum strains. 2. Results and Conclusions I: Nola is induced by two chemically distinct compounds. Soybean seedling extracts (SSGE) were fractionated by reverse phase HPLC over a C-18 column (Phenomenex). Bound samples were then eluted with a methanol solvent gradient and analyzed for Nola inducing activity (Loh,J et al 1999). Fractions collected at 40 and 55 minutes, indicated as INDUCER-1 (IND-1) and INDUCER-2 (IND-2), were able to induce expression of B.japonicum Nola-lacZ fusions. II: IND-1 and IND-2 are sensitive to proteinase K and chitinase treatment, respectively. Purified active fractions (IND-1 and IND-2) were assayed for proteinase and chitinase sensitivity. Results showed a strong sensitivity of IND-1 to proteinase K, indicating its possible protein-like nature. Conversely, the sensitivity of IND-2 to chitinase suggests a chitin-like structure for IND-2. III: IND-1 and IND-2 act separately on the P1 and P2 promoters. To analyze the role of IND-1 and IND-2 on Nola expression, both compounds were compared by its ability to induce the and lacZ-fusions. As previously mentioned, expression of occurs from the P1 promoter, while is expressed from the P2 promoter (Loh et al, 1999). The results showed a higher activity of Nola 1,2,3 strains with both Ind-1 and Ind-2. IV: Effect on nodulation of soybean cultivars. Fractions of SSGE from soybean cultivar UFV-16 were applied to a silica gel column and eluted sequentially with ethanol, methanol, ethyl acetate and chloroform. The eluted fractions were evaluated for activity using a fusion (Garcia et al, 1996). Active group fractions termed G2 (chitin-like) and G10 (peptide-like) were tested for their effect on nodulation with growth pouches using B. japonicum strains that were either untreated or pretreated with G2 or G10. The results indicate that pretreatment of B. japonicum cells with both G2 and G10 increase the capacity of B. japonicum to nodulate soybean plants.
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The Bradyrhizobium japonicum Nola gene encodes three functionally distinct proteins
Journal of bacteriology, 1999Co-Authors: John T. Loh, Minviluz G. Stacey, Michael J. Sadowsky, Gary StaceyAbstract:Examination of Nola revealed that Nola can be uniquely translated from three ATG start codons. Translation from the first ATG (ATG1) predicts a protein (Nola1) having an N-terminal, helix-turn-helix DNA-binding motif similar to the DNA-binding domains of the MerR-type regulatory proteins. Translation from ATG2 and ATG3 would give the N-terminally truncated proteins Nola2 and Nola3, respectively, lacking the DNA-binding domain. Consistent with this, immunoblot analyses of Bradyrhizobium japonicum extracts with a polyclonal antiserum to Nola revealed three distinct polypeptides whose molecular weights were consistent with translation of Nola from the three ATG initiation sites. Site-directed mutagenesis was used to produce derivatives of Nola in which ATG start sites were sequentially deleted. Immunoblots revealed a corresponding absence of the polypeptide whose ATG start site was removed. Translational fusions of the Nola mutants to a promoterless lacZ yielded functional fusion proteins in both Escherichia coli and B. japonicum. Expression of Nola is inducible upon addition of extracts from 5-day-old etiolated soybean seedlings but is not inducible by genistein, a known inducer of the B. japonicum nod genes. The expression of both Nola2 and Nola3 requires the presence of Nola1. Nola1 or Nola3 is required for the genotype-specific nodulation of soybean genotype PI 377578.
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Phenotypic characterization and regulation of the Nola gene of Bradyrhizobium japonicum.
Molecular plant-microbe interactions : MPMI, 1996Co-Authors: M Garcia, J Dunlap, John T. Loh, Gary StaceyAbstract:Two Bradyrhizobium japonicum Nola mutants were constructed and used to test the functional role of Nola in nodulation. Contrary to the previous hypothesis that Nola acts as a repressor of nod gene transcription, the expression of a nodD1-lacZ or nodY-lacZ fusion in the Nola mutant strains was similar to that found in the wild type. However, Nola does appear to act as a transcriptional regulatory protein since it is required for its own expression, as well as that of nodD2. Expression of NodD2 from a constitutive promoter led to a significant reduction in nodC-lacZ activity. Therefore, the repression of nod gene expression by Nola is likely an indirect effect, perhaps mediated by other genes (e.g., nodD2) that are regulated by Nola. When inoculated onto soybean roots, the Nola mutant strains showed only a slight delay in nodulation as compared to the wild type. However, the mutant strains were grossly defective in nodulation and nitrogen fixation on cowpea plants. Microscopic examination of soybean nodules induced by the Nola mutant strains showed developmental and morphological characteristics similar to nodules formed by the wild type with only a slight delay in bacteroid maturation. In contrast, cowpea nodules induced by the Nola mutant strains contained fewer infected cells and bacteroids were not found in a typical symbiosome structure. These results indicate that Nola is a transcriptional activator required for the expression of genes that play a role not only in the early stages of infection, but also during the later stages of bacteroid development and maintenance.
M.j. Whiting - One of the best experts on this subject based on the ideXlab platform.
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ENDOTOXIN ALTERS THE SYSTEMIC DISPOSITION OF NITRIC OXIDE SYNTHASE INHIBITORS IN THE AWAKE SHEEP
Clinical and experimental pharmacology & physiology, 1997Co-Authors: A.j. Rutten, Andrew D. Bersten, M.j. WhitingAbstract:SUMMARY 1. We evaluated the haemodynamic effects and systemic disposition of the nitric oxide synthase (NOS) inhibitor NL-nitro-L-arginine (Nola) after intravenous (i.v.) administration of two different doses (5 and 20 mg/kg) in awake healthy sheep and awake sheep given a continuous i.v. infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i.v., for 18 h). In addition, we determined the systemic disposition of another NOS inhibitor, NL-nitro-L-arginine methylester (L-NAME; 20 mg/kg, i.v.) in awake healthy sheep only. 2. ArL-Nitro-L-arginine produced a dose-dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose-dependent increase in mean arterial pressure (MAP) and peripheral vascular resistance (PVR) when compared to baseline. In endotoxic sheep Nola produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP). 3. In healthy sheep there was a dose-related increase in total body clearance (CI) of Nola. The CI increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose. The infusion of endotoxin caused an increase in CI of Nola to 0.040 and 0.047 L/min, respectively, and a decrease in plasma slow half-life (t1/2 from 825 to 546 min and from 780 to 453 min, respectively. 4. NL-Nitro-L-arginine methylester was rapidly cleared from the plasma with a slow half-life of approximately 7.5 min and there was a simultaneous appearance of Nola in the plasma. 5. These results support the view that nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in CI of Nola with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical studies.
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Determination of NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester in plasma by high-performance liquid chromatography.
Journal of chromatography. B Biomedical applications, 1994Co-Authors: M.j. Whiting, A.j. Rutten, P. Williams, Andrew D. BerstenAbstract:Abstract An HPLC method has been developed for the measurement of the nitric oxide synthase inhibitors, N G -nitro- l -arginine ( l -Nola) and N G -nitro- l -arginine methyl ester ( l -NAME), in sheep plasma. Using an ion-exchange HPLC column (JWAS 150, 100 × 3.9 mm I.D., Millipore-Waters, Australia) and post-column ninhydrin detection, l -Nola was separated from valine and other plasma amino acids. When added to sheep plasma, good recovery (mean 102%) and precision (mean coefficient of variation 2.7%) in the measurement of l -Nola was obtained over the range 2–50 mg/l. l -NAME was unstable in sheep plasma at 37°C, and was converted to l -Nola with a half-life of 250 min. This method will permit pharmacokinetic parameters to be determined for these potential drugs, and will allow plasma drug concentrations to be correlated with the pharmacodynamic effects of these compounds.
Judith A. Whitworth - One of the best experts on this subject based on the ideXlab platform.
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Role of nitric oxide in adrenocorticotrophin-induced hypertension: L-arginine effects reversed by N-nitro-L-arginine.
Clinical and experimental pharmacology & physiology, 2000Co-Authors: Cheng Wen, Judith A. WhitworthAbstract:1. L-arginine prevents adrenocorticotrophin (ACTH)-induced hypertension in the rat. To confirm that this effect is mediated through the nitric oxide (NO) system, we examined whether N-nitro-L-arginine (Nola) could reverse the L-arginine-induced blockade of ACTH-induced hypertension. 2. Blood pressure and metabolic parameters were examined in sham-, ACTH-, L-arginine + sham-, Nola + sham-, ACTH + L-arginine- and ACTH + L-arginine + Nola-treated Sprague-Dawley rats (n = 40). 3. Adrenocorticotrophin treatment increased systolic blood pressure (SBP), water intake and urine output and decreased bodyweight. N-Nitro-L-arginine alone increased SBP without affecting metabolic variables. L-Arginine alone did not affect blood pressure. The SBP was lower in L-arginine + ACTH- than ACTH-treated rats (P < 0.001), but was higher following ACTH + L-arginine + Nola than ACTH + L-arginine (P < 0.05). 4. N-Nitro-L-arginine reversed the blood pressure-lowering effect of L-arginine in ACTH-induced hypertension in the rat, supporting the notion that NO plays a role in the hypertension.
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Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats.
Clinical and experimental pharmacology & physiology, 1992Co-Authors: Gregory J. Dusting, Judith A. WhitworthAbstract:1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (Nola) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. Nola administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving Nola than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; Nola + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since Nola increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and Nola administration.