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1.
Article in Russian | MEDLINE | ID: mdl-25464764

ABSTRACT

In Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, it was shown that presentation to rats during exploratory activity of a tone previously pared with footshock inhibited the exploration and prevented the exploration-induced increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. Intra-accumbal infusions of 20 µM bicuculline, a GABA(A)-receptor antagonist, firstly, partially restored the exploration-induced increase of extracellular citrulline levels in this brain area, which was inhibited by presentation of the tone, previously paired with foot-shock and, secondly, prevented the inhibition of exploratory behavior produced by this sound signal of danger. The data obtained indicate for the first time that signals of danger inhibit exploratory behavior and exploration-induced activation of the accumbal nitrergic system via GABA(A)-receptor mechanisms.


Subject(s)
Citrulline/metabolism , Fear/psychology , Nitric Oxide/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Bicuculline/administration & dosage , Citrulline/drug effects , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Fear/drug effects , GABA Antagonists/administration & dosage , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Rats
2.
Diabet Med ; 29(10): e365-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22803961

ABSTRACT

AIM: Endothelial dysfunction is defined by reduced bioavailability of nitric oxide and has been shown to be associated with cardiovascular risk. The global arginine bioavailability ratio and the arginine to ornithine ratio have recently been shown to be associated with cardiovascular outcome in patients with coronary artery disease. The aim of our study was to investigate the impact of a multifactorial risk factor intervention in subjects with Type 2 diabetes on these two potential new cardiovascular surrogate parameters. METHODS: In a single-centre and prospective study, we investigated 41 patients with Type 2 diabetes not reaching treatment targets according to current local diabetes guidelines in two out of three of the following measurements: HbA(1c) LDL cholesterol 2.6 or blood pressure. Within 3 months, therapy was intensified according to current guidelines aiming to reach the treatment targets. At baseline and 3 months, arginine, ornithine and citrulline were chromatographically determined after pre-column-derivatization followed by fluorescent detection, and arginine bioavailability ratios were calculated. RESULTS: Intensified risk factor management significantly improved the global arginine bioavailability ratio (0.33 ± 0.12 at baseline vs. 0.38 ± 0.14 after 3 months; P = 0.018). A significant improvement was only seen in patients with short diabetes duration (< 5 years), whereas in patients with longer diabetes duration improvement did not reach statistical significance. CONCLUSION: In patients with Type 2 diabetes, intensified risk factor management improves arginine bioavailability ratios. Duration of diabetes seems to be an important factor influencing the capacity of the global arginine bioavailability ratio improvement.


Subject(s)
Anticholesteremic Agents/administration & dosage , Arginine/pharmacokinetics , Citrulline/blood , Coronary Artery Disease/blood , Coronary Artery Disease/prevention & control , Diabetes Mellitus, Type 2/blood , Diabetic Angiopathies/blood , Ornithine/blood , Aged , Arginine/analogs & derivatives , Arginine/metabolism , Biological Availability , Blood Pressure/drug effects , Cholesterol, LDL/blood , Citrulline/drug effects , Diabetes Mellitus, Type 2/prevention & control , Diabetic Angiopathies/prevention & control , Female , Humans , Male , Middle Aged , Nitric Oxide Synthase/metabolism , Ornithine/drug effects , Prospective Studies , Risk Factors , Time Factors
3.
Ross Fiziol Zh Im I M Sechenova ; 98(3): 318-24, 2012 Mar.
Article in Russian | MEDLINE | ID: mdl-22645940

ABSTRACT

In Sprague-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis it was shown that the infusion into the n. accumbens of the D2-receptor antagonist raclopride (20, 100 microM) did not affect extracellular level ofcitrulline (an NO co-product) in this brain area. The intraaccumbal infusion of NMDA, an NMDA receptor agonist (100 microM) caused a rise of the extracellular citrulline level in this brain area. This rise was prevented by intraaccumbal infusion of 0.5 mM 7-nitroindazole, a neuronal NO-synthase inhibitor, and it was significantly reduced by the infusion of raclopride (20, 100 microM) into this brain area. The data obtained suggest that the D2-receptors of the n. accumbens are implicated in the regulation of neuronal NO-synthase activity induced by local NMDA receptor stimulation.


Subject(s)
Brain/metabolism , Citrulline/biosynthesis , Dopamine D2 Receptor Antagonists , Neurons/metabolism , Nucleus Accumbens/metabolism , Animals , Citrulline/drug effects , Indazoles/administration & dosage , N-Methylaspartate/administration & dosage , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/antagonists & inhibitors , Raclopride/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/drug effects , Signal Transduction
4.
J Physiol Biochem ; 67(1): 105-13, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20960085

ABSTRACT

To understand their role in epilepsy, the nitric oxide synthetase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite (NOx), thiobarbituric acid reactive substances (TBARS), and total antioxidant status (TAS), were estimated in different regions of brain in rats subjected to experimental epilepsy induced by subcutaneous administration of kainic acid (KA). The short-term (acute) group animals were killed after 2 h and the long term (chronic) group animals were killed after 5 days of single injection of KA (15 mg/kg body weight). After decapitation of rats, the brain regions were separated and in their homogenates, the concentration of NOx, TBARS and TAS and the activities of NOS, AS, AL, arginase and glutamine synthetase were assayed by colorimetric methods. The results of the study demonstrated the increased activity of NOS and formation of NO in acute and chronic groups epilepsy. The activities of AS and AL were increased and indicate the effective recycling of citrulline to arginine. The activity of glutamine synthetase was decreased in acute and chronic groups of epilepsy compared to control group and indicate the modulation of its activity by NO in epilepsy. The activity of arginase was not changed in acute group; however it was decreased in chronic group and may favor increased production of NO in this condition. The concentration TBARS were increased and TAS decreased in acute and chronic groups of epilepsy and supports the oxidative stress in epilepsy.


Subject(s)
Brain/metabolism , Citrulline/metabolism , Epilepsy/metabolism , Glutamate-Ammonia Ligase/metabolism , Nitric Oxide/metabolism , Oxidative Stress , Animals , Antioxidants/metabolism , Arginase/metabolism , Argininosuccinate Lyase/metabolism , Argininosuccinate Synthase/metabolism , Brain Stem/metabolism , Cerebellum/metabolism , Cerebral Cortex/drug effects , Citrulline/drug effects , Disease Models, Animal , Epilepsy/chemically induced , Kainic Acid , Male , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/metabolism , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/metabolism
5.
Neurosci Res ; 53(2): 116-22, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16009439

ABSTRACT

Nitric oxide (NO) is involved in many pathophysiological processes in the brain. NO is synthesized from arginine by nitric oxide synthase (NOS) enzymes. Citrulline formed as a by-product of the NOS reaction, can be recycled to arginine by successive actions of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) via the citrulline-NO cycle. Hyperammonemia is known to cause poorly understood perturbations of the citrulline-NO cycle. To understand the role of citrulline-NO cycle in hyperammonemia, NOS, ASS, ASL and arginase activities, as well as nitrate/nitrite (NOx), arginine, ornithine, citrulline, glutamine, glutamate and GABA were estimated in cerebral cortex (CC), cerebellum (CB) and brain stem (BS) of rats subjected to acute ammonia toxicity. NOx concentration and NOS activity were found to increase in all the regions of brain in acute ammonia toxicity. The activities of ASS and ASL showed an increasing trend whereas the arginase was not changed. The results of this study clearly demonstrated the increased formation of NO, suggesting the involvement of NO in the pathophysiology of acute ammonia toxicity. The increased activities of ASS and ASL suggest the increased and effective recycling of citrulline to arginine in acute ammonia toxicity, making NO production more effective and contributing to its toxic effects.


Subject(s)
Ammonia/toxicity , Arginase/drug effects , Brain/drug effects , Citrulline/drug effects , Nitric Oxide/metabolism , Amino Acids/drug effects , Amino Acids/metabolism , Animals , Arginase/metabolism , Argininosuccinate Lyase/drug effects , Argininosuccinate Lyase/metabolism , Argininosuccinate Synthase/drug effects , Argininosuccinate Synthase/metabolism , Brain/enzymology , Citrulline/metabolism , Male , Nitrates/metabolism , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase/metabolism , Nitrites/metabolism , Rats , Rats, Sprague-Dawley , gamma-Aminobutyric Acid/drug effects , gamma-Aminobutyric Acid/metabolism
6.
Biol Res Nurs ; 6(4): 289-99, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15788738

ABSTRACT

The purpose of this study was to determine whether arginine supplementation enhances in vitro (neutrophil burst and mitogen-induced lymphocyte proliferation) and in vivo (delayed-type hypersensitivity [DTH] and serum nitric oxide) measures of immune function in nursing home elders with pressure ulcers. Twenty-six elders, 65 years of age or older, with one or more pressure ulcers, were randomized to receive 8.5 g of arginine or an isonitrogenous supplement for 4 weeks. Immune function studies and serum arginine, ornithine, citrulline, and nitric oxide were measured at baseline, 4 weeks postsupplementation (Week 4) and after a 6-week washout (Week 10). At Week 4, serum ornithine increased (p = .01) and arginine trended to increase (p = .055), but there was no increase in citrulline or nitric oxide with arginine supplementation. There were no differences in neutrophil burst or DTH responses between groups. Whole blood mitogen-induced proliferation decreased significantly at Week 10 in the isonitrogenous but not in the arginine-supplemented group. There is mounting concern that arginine supplementation during an inflammatory state could be detrimental due to overwhelming nitric oxide production. A key finding of this study is that arginine supplementation did not increase serum nitric oxide levels over that observed in elders with pressure ulcers given an isonitrogenous supplement.


Subject(s)
Arginine/therapeutic use , Dietary Supplements/statistics & numerical data , Nitric Oxide/blood , Pressure Ulcer/drug therapy , Administration, Oral , Aged , Arginine/blood , Arginine/pharmacology , Citrulline/blood , Citrulline/drug effects , Drug Monitoring , Female , Florida , Geriatric Assessment , Humans , Inflammation , Lymphocyte Activation/drug effects , Male , Mitogens , Neutrophil Activation/drug effects , Nursing Homes , Nutrition Assessment , Nutritional Status , Ornithine/blood , Ornithine/drug effects , Pressure Ulcer/blood , Pressure Ulcer/immunology , Respiratory Burst/drug effects , Time Factors
7.
Eur J Pharmacol ; 436(1-2): 53-6, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11834246

ABSTRACT

Nitric oxide (NO) and serotonin (5-hydroxytryptamine; 5-HT) are important neuromodulators that are involved in a myriad of biochemical reactions. In this work, we describe a novel model co-culture system to study the interactions between NO and 5-HT. NO derived from cytokine stimulated Bv2 microglial cells depleted 5-HT from RBL-2H3 cells. Reduction of 5-HT content by NO derived from the NO donor S-nitroso-N-acetylpenicillamine (SNAP) was concentration-dependent, independent of intracellular Ca(2+) and inhibited by reduced glutathione (GSH). Collectively, these data indicate that this cell co-culture system is a viable model to study the mechanisms of interaction between nitrergic and serotonergic pathways.


Subject(s)
Microglia/metabolism , Nitric Oxide/metabolism , Penicillamine/analogs & derivatives , Serotonin/metabolism , Animals , Calcium/metabolism , Cell Line , Citrulline/drug effects , Citrulline/metabolism , Coculture Techniques , Dose-Response Relationship, Drug , Glutathione/pharmacology , Leukemia/metabolism , Leukemia/pathology , Microglia/cytology , Penicillamine/pharmacology , Rats , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism
8.
Eur J Pharmacol ; 428(2): 261-7, 2001 Oct 05.
Article in English | MEDLINE | ID: mdl-11675044

ABSTRACT

In the present study, the effect of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methylester (L-NAME), on the antishock actions of oxotremorine was investigated in rats subjected to hemorrhagic shock under urethane anesthesia. L-citrulline production in the AV3V region, as an indicator of nitric oxide (NO) synthesis, was assayed by high-performance liquid chromatography (HPLC) with fluorescent detection throughout the experiment. The rats were pretreated with either intravenous (i.v.) physiological saline or L-NAME (2.5 mg/kg) before bleeding. L-NAME potentiated the reversal of hypotension by oxotremorine (25 microg/kg, i.v.). However, oxotremorine either alone or in combination with L-NAME did not produce any significant change in 60-min survival rate at this low dose. Analysis of microdialysis samples collected from the AV3V region showed that L-citrulline concentration increased during bleeding and that this increase was abolished by L-NAME pretreatment. These results may suggest that nitric oxide production contributes to hypotension in rats bled to shock since nitric oxide levels in the AV3V region increased in response to bleeding and nitric oxide synthase (NOS) inhibition abolished this increase and potentiated the oxotremorine-induced reversal of hypotension.


Subject(s)
Nitric Oxide/physiology , Oxotremorine/pharmacology , Shock, Hemorrhagic/prevention & control , Animals , Blood Pressure/drug effects , Cerebral Ventricles/drug effects , Cerebral Ventricles/metabolism , Citrulline/drug effects , Citrulline/metabolism , Enzyme Inhibitors/pharmacology , Female , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Oxotremorine/therapeutic use , Rats , Rats, Sprague-Dawley , Shock, Hemorrhagic/mortality , Shock, Hemorrhagic/physiopathology , Survival Rate , Time Factors
10.
Pharmacology ; 62(1): 10-6, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11150917

ABSTRACT

Nitric oxide synthase (NOS) catalyzes nitric oxide (NO) formation from L-arginine in the presence of molecular oxygen and NADPH. NO is involved in the regulation of microvasculature. Isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) have been widely used as vasodilators to treat acute myocardial ischemia, their biological effects being due to the release of NO. In this investigation, the effects of ISDN and GTN on NOS activity in the presence or absence of oxyhemoglobin under hypoxia and normoxia were studied. The apparent K(m) values for molecular oxygen were 21.6 +/- 1.5 and 9.4 +/- 1.3 micromol/l for nNOS and eNOS, respectively. ISDN liberated NO in a concentration- and pH-dependent manner, but no differences between hypoxia and normoxia were observed. The NO release from ISDN was also measured directly by an electron spin resonance spectral method with N-(dithiocarboxy)sarcosine-Fe complex as a NO-trapping agent. ISDN increased nNOS and eNOS activities in the presence of 30 micromol/l oxyhemoglobin under hypoxia, while it did not affect nNOS and eNOS activities under normoxia. In the absence of oxyhemoglobin, ISDN inhibited nNOS and eNOS activities under both hypoxic and normoxic experimental conditions. The rate of oxygen release from oxyhemoglobin under hypoxia was increased 3 times in the presence of 1 mmol/l ISDN. In contrast to ISDN, GTN could not release NO spontaneously, and it also did not affect nNOS and eNOS activities in the absence or presence of 30 micromol/l oxyhemoglobin under both hypoxic and normoxic conditions. These results indicated that the NO release from ISDN is different from that of GTN, and the increase of NOS activity by ISDN in the presence of oxyhemoglobin under hypoxia is ascribed to the increase in molecular oxygen concentration.


Subject(s)
Isosorbide Dinitrate/pharmacology , Nitric Oxide Synthase/drug effects , Oxygen/pharmacology , Animals , Citrulline/drug effects , Citrulline/metabolism , Dose-Response Relationship, Drug , Hydrogen-Ion Concentration , Kinetics , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Nitroglycerin/pharmacology , Oxyhemoglobins/pharmacology , Swine
11.
Eur J Pharmacol ; 403(1-2): 67-74, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10969145

ABSTRACT

A number of studies suggest the involvement of glutamate in central hyperalgesia through NMDA receptors in animal models of inflammation. Most studies analyze glutamate effects at the spinal cord level. In this work, the effects of morphine, dizocilpine and riluzole on the hyperalgesia induced by carrageenan administration in the rat paw model were investigated. The effects of morphine and riluzole on the release of glutamate and aspartate and on the concentrations of citrulline and arginine in dialysates of the ventral posterolateral nucleus of the thalamus were also examined. All three drugs decreased hyperalgesia when administered prior to carrageenan injection. Morphine decreased the glutamate concentration in dialysates of the ventral posterolateral nucleus but did not affect the concentrations of the other amino acids. The effect of morphine was observed in the absence of painful stimulation and when pressure applied to the rat paw induced a nociceptive reaction. Riluzole decreased the concentrations of glutamate and aspartate and those of citrulline and arginine in the presence or absence of painful stimulation. These experiments suggest that morphine and riluzole attenuate the hyperalgesia induced by injection of carrageenan in the rat hind paw, at least partly, by decreasing glutamate release in the ventral posterolateral thalamic nucleus.


Subject(s)
Dizocilpine Maleate/pharmacology , Hyperalgesia/prevention & control , Morphine/pharmacology , Riluzole/pharmacology , Thalamic Nuclei/drug effects , Analysis of Variance , Animals , Arginine/drug effects , Arginine/metabolism , Aspartic Acid/drug effects , Aspartic Acid/metabolism , Carrageenan/adverse effects , Citrulline/drug effects , Citrulline/metabolism , Dialysis Solutions/chemistry , Dose-Response Relationship, Drug , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Hindlimb , Hyperalgesia/chemically induced , Male , Microdialysis , Neuroprotective Agents/pharmacology , Rats , Rats, Wistar , Thalamic Nuclei/chemistry
12.
Rev Esp Cardiol ; 53(2): 205-11, 2000 Feb.
Article in Spanish | MEDLINE | ID: mdl-10734753

ABSTRACT

INTRODUCTION AND AIMS: The thrombotic process is a multicellular phenomenon in which not only platelets are involved but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal reduced platelet aggregation by stimulating nitric oxide (NO) production by neutrophils. The aim of the present study was to evaluate whether the in vivo treatment with triflusal could also modify the ability of neutrophils to produce NO. Furthermore, the role of NO released by neutrophils on platelet aggregation and secretion was also tested. METHODS: The study was performed in 12 healthy volunteers of 32 +/- 6 years of age. The volunteers were treated with triflusal (600 mg/day) for 5 days and platelets and neutrophils were isolated before and after treatment. The ability of neutrophils to produce NO and the capacity of inhibiting platelet aggregation and secretion of transforming growth factor-beta (TGF-beta) were assessed. RESULTS: After the treatment with triflusal we obtained the following results: a) an increase in NO production by neutrophils; b) potentiation of the inhibition of platelet aggregation by neutrophils, an effect that was reverted by incubating neutrophils with an L-arginine antagonist, L-NAME, and c) the presence of neutrophils reduced the release of TGF-beta by platelets measured as index of platelet secretion by a NO-independent mechanism. CONCLUSIONS: Triflusal (600 mg/day/5 days) stimulated NO production by neutrophils. After the treatment with triflusal, neutrophils inhibited both platelet aggregation and secretion. The antiaggregating effect of neutrophils was an NO-dependent mechanism while the inhibition of platelet secretion mediated by neutrophils after the treatment with triflusal was an NO-independent mechanism.


Subject(s)
Blood Platelets/drug effects , Blood Platelets/metabolism , Nitric Oxide/physiology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Salicylates/pharmacology , Adult , Citrulline/blood , Citrulline/drug effects , Cyclic GMP/blood , Cyclic GMP/pharmacology , Guanosine Monophosphate/blood , Humans , Neutrophils/drug effects , Neutrophils/metabolism , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/drug effects
13.
Mol Pharmacol ; 55(2): 304-8, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9927622

ABSTRACT

Binding of idazoxan (IDA) to imidazoline receptors of the I2 subtype in astrocytes influences astroglial gene expression as evidenced by increased expression of glial fibrillary acidic protein and mRNA. To determine whether IDA affected glial inflammatory gene expression, we tested the effects of IDA on astroglial nitric oxide synthase type-2 (NOS-2) expression. NOS-2 was induced in primary rat astrocytes and C6 glioma cells by incubation with 1 microgram/ml lipopolysaccharide (LPS) plus three cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma) or three cytokines alone. Cells were incubated with 1-100 microM IDA, and at 24 h NOS-2 expression assessed. In astrocytes and C6 cells, preincubation with IDA dose-dependently inhibited nitrite accumulation (IC50 approximately 25 microM), accompanied by a reduction in NOS-2 protein levels and L-citrulline synthesis activity in cell lysates. IDA also inhibited nitrite production in LPS stimulated RAW 264.7 macrophages. In astrocytes, but not C6 cells, longer preincubation times with IDA yielded significantly greater suppression, and maximal suppression (>90%) was achieved after a 8 h preincubation in 100 microM IDA. The degree of inhibition was diminished whether IDA was added after LPS plus cytokine mixture. In contrast to NE, continuous incubation with IDA was required to achieve suppression. IDA reduced induction of NOS-2 protein levels, steady state NOS-2 mRNA levels, and activity of a NOS-2 promoter construct stably transfected in C6 cells. These results show that IDA inhibits NOS-2 activity and protein expression in glial cells and macrophages, and suggest that this occurs by decreasing transcription from the NOS-2 promoter.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Astrocytes/drug effects , Idazoxan/pharmacology , Nitric Oxide Synthase/genetics , Adrenergic alpha-Agonists/pharmacology , Animals , Animals, Newborn , Arginine/drug effects , Arginine/metabolism , Astrocytes/cytology , Astrocytes/enzymology , Cell Line , Cell-Free System/drug effects , Cell-Free System/enzymology , Chloramphenicol O-Acetyltransferase/drug effects , Chloramphenicol O-Acetyltransferase/genetics , Chloramphenicol O-Acetyltransferase/metabolism , Citrulline/drug effects , Citrulline/metabolism , Cytokines/pharmacology , Dose-Response Relationship, Drug , Gene Expression Regulation, Enzymologic/drug effects , Lipopolysaccharides/pharmacology , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I , Nitrites/metabolism , Norepinephrine/pharmacology , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , RNA, Messenger/drug effects , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/drug effects , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Time Factors , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/enzymology
14.
Thromb Res ; 88(2): 229-35, 1997 Oct 15.
Article in English | MEDLINE | ID: mdl-9361375

ABSTRACT

Nitric Oxide (NO) inhibits platelet aggregation via activation of an intraplatelet soluble guanylate cyclase which induces an increase in cyclic GMP (1). It has been also demonstrated that platelets contain a constitutive, calcium-dependent, NO synthase which is activated by collagen-induced platelet aggregation. This leads to a NO synthesis from L-Arginine (L-Arg), which in turn increases cyclic GMP and down-regulates platelet aggregation (2). In vitro administration of supraphysiological concentrations of L-Arg enhances platelet cyclic GMP levels by increasing NO production and reduces platelet aggregation. This effect is reversed by pre-incubation with NO-synthase inhibitors (3). These results indicate that the L-Arg: NO pathway plays an important role in the modulation of human platelet aggregation (4). In vivo L-Arg, when administered i.v., induces hypotension (5) and vasodilatation (6,7) in humans, and when orally supplemented reduces platelet aggregability both in hypercholesterolemic rabbits and healthy men (8,9).


Subject(s)
Arginine/pharmacology , Nitric Oxide/blood , Platelet Aggregation/drug effects , Adenosine Diphosphate/pharmacology , Adult , Arginine/administration & dosage , Arginine/blood , Blood Pressure/drug effects , Citrulline/blood , Citrulline/drug effects , Collagen/pharmacology , Diastole , Female , Humans , Infusions, Intravenous , Nitrites/blood , Placebos , Systole , Time Factors
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