11 results on '"Levi, R"'
Search Results
2. Alkyl chain homologs of platelet-activating factor and their effects on the mammalian heart
- Author
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Arturo Genovese, Roberto Levi, R. Neal Pinckard, Levi, R, Genovese, Arturo, and Pinckard, Rn
- Subjects
Male ,Alkylation ,Stereochemistry ,Guinea Pigs ,Biophysics ,Phospholipid ,Pharmacology ,In Vitro Techniques ,Biochemistry ,Guinea pig ,chemistry.chemical_compound ,Structure-Activity Relationship ,Coronary Circulation ,Structure–activity relationship ,Potency ,Animals ,Platelet ,Platelet Activating Factor ,Receptor ,Molecular Biology ,Platelet-activating factor ,food and beverages ,Biological activity ,Heart ,Cell Biology ,Coronary Vessels ,Myocardial Contraction ,chemistry ,Vasoconstriction ,lipids (amino acids, peptides, and proteins) - Abstract
Platelet-activating factor (PAF; AGEPC) is a potent negative inotropic and coronary-vasoconstricting agent. Minor structural alterations in the PAF molecule are known to greatly affect its biological activity; thus, we have investigated the effects of selected synthetic saturated and unsaturated alkyl chain PAF homologs on the isolated guinea pig heart. The rank order of potency for the negative inotropic effect was C16:0- greater than C18:1- greater than beef-heart AGEPC greater than C15:0- greater than C18:0- greater than C14:0-AGEPC; the rank order for the coronary-vasoconstricting effect was C16:0- approximately C18:1- approximately beef-heart AGEPC greater than C15:0- greater than C18:0- approximately C14:0-AGEPC. With the exception of C16:0- and C18:1-AGEPC, the relative potencies for the cardiac and coronary effects of the alkyl chain AGEPC homologs did not correlate well with their relative potencies in stimulating rabbit platelets and human neutrophils. The differences in the rank order of potency for these AGEPC homologs suggest the presence of species and/or target cell PAF receptor heterogeneity.
- Published
- 1989
3. Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3-receptors.
- Author
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Koyama M, Heerdt PM, and Levi R
- Subjects
- Adrenergic alpha-Agonists metabolism, Animals, Arrhythmias, Cardiac pathology, Electrocardiography, Female, Humans, Mice, Mice, Transgenic, Myocardial Ischemia, Myocardial Reperfusion Injury pathology, Norepinephrine metabolism, Receptors, Histamine H3 genetics, Arrhythmias, Cardiac metabolism, Myocardial Reperfusion Injury metabolism, Receptors, Histamine H3 metabolism
- Abstract
We had previously reported that activation of histamine H(3)-receptors (H(3)R) on cardiac adrenergic nerve terminals decreases norepinephrine (NE) overflow from ischemic hearts and alleviates reperfusion arrhythmias. Thus, we used transgenic mice lacking H(3)R (H(3)R(-/-)) to investigate whether ischemic arrhythmias might be more severe in H(3)R(-/-) hearts than in hearts with intact H(3)R (H(3)R(+/+)). We report a greater incidence and longer duration of ventricular fibrillation (VF) in H(3)R(-/-) hearts subjected to ischemia. VF duration was linearly correlated with NE overflow, suggesting a possible cause-effect relationship between magnitude of NE release and severity of reperfusion arrhythmias. Thus, our findings strengthen a protective antiarrhythmic role of H(3)R in myocardial ischemia. Since malignant tachyarrhythmias cause sudden death in ischemic heart disease, attenuation of NE release by selective H(3)R agonists may represent a new approach in the prevention and treatment of ischemic arrhythmias.
- Published
- 2003
- Full Text
- View/download PDF
4. Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis.
- Author
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Pomerantz KB, Hajjar DP, Levi R, and Gross SS
- Subjects
- Animals, Aorta, Thoracic drug effects, Cells, Cultured, Escherichia coli, Foam Cells physiology, Humans, Kinetics, Lipopolysaccharides pharmacology, Lipoproteins, LDL blood, Lipoproteins, LDL isolation & purification, Lipoproteins, LDL pharmacology, Muscle, Smooth, Vascular drug effects, Rats, Recombinant Proteins pharmacology, Tumor Necrosis Factor-alpha pharmacology, Aorta, Thoracic metabolism, Cholesterol pharmacology, Cytokines pharmacology, Interferon-gamma pharmacology, Muscle, Smooth, Vascular metabolism, Nitric Oxide metabolism
- Abstract
Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.
- Published
- 1993
- Full Text
- View/download PDF
5. Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages.
- Author
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Gross SS, Jaffe EA, Levi R, and Kilbourn RG
- Subjects
- Animals, Biopterins metabolism, Brain, Cells, Cultured, Cycloheximide pharmacology, Endothelium, Vascular drug effects, Interferon-gamma pharmacology, Kinetics, Mice, Nitric Oxide Synthase, Pteridines pharmacology, Recombinant Proteins pharmacology, Tumor Necrosis Factor-alpha pharmacology, Amino Acid Oxidoreductases metabolism, Arginine analogs & derivatives, Arginine pharmacology, Biopterins analogs & derivatives, Calmodulin pharmacology, Cytokines pharmacology, Endothelium, Vascular enzymology, Isoenzymes metabolism, Macrophage Activation, Macrophages enzymology, Nitric Oxide metabolism, Pterins
- Abstract
We have previously reported that cultured murine brain endothelial cells (MBE) produce large quantities of nitric oxide (NO) after activation with interferon-gamma in combination with any of several immunoactivators including: bacterial endotoxin, tumor necrosis factor and interleukin-1. Since endothelial cells are the first example of a cell-type which may possess both a constitutive and an inducible type of NO synthase, it was of interest to compare the requirements of these two enzyme activities. Induction of NO synthesis in MBE by cytokines was abolished by the protein synthesis inhibitor, cycloheximide, and by 2,4-diamino-6-hydroxypyridine (DAHP), a selective inhibitor of GTP cyclohydrolase I, the rate-limiting enzyme for de novo synthesis of tetrahydrobiopterin (THB). In the presence of DAHP, NO synthesis was restored by sepiapterin (SEP), a substrate for the alternative pathway of THB synthesis occurring via pterin salvage. Moreover, SEP increased NO synthesis to greater than 150% of control values, suggesting that THB availability is rate-limiting for NO synthesis by cytokine-induced MBE. Methotrexate, an inhibitor of the pterin salvage pathway of THB synthesis, completely reversed the stimulation of NO synthesis by sepiapterin. Thus, cytokine-induced MBE NO synthase appears to have an absolute requirement for THB as cofactor. In additional studies we found that NO synthesis by cytokine-activated MBE was inhibited by NG-monosubstituted arginine analogs with a rank-order of potency NH2 greater than CH3 greater than NO2, in contrast with the rank-order of NO2 greater than NH2 greater than CH3 previously described for inhibition of the constitutive endothelial cell enzyme. Using a kinetic assay for NO synthase activity, based on oxidation of myoglobin heme-iron, we have found that these rank orders of potency also apply to cytosol preparations of cytokine-induced and untreated endothelial cells, respectively. Further differences between constitutive and cytokine-induced NO synthase were observed with regard to calmodulin requirements. Whereas constitutive NO synthase was potently inhibited by the calmodulin antagonists mellitin and trifluoperazine, cytokine-induced NO synthase was unaffected. In summary, NO synthesis by cytokine-activated MBE is THB-dependent, calmodulin-independent and inhibited by NG-substituted arginine analogs with a rank-order profile distinct from that for untreated endothelial cells but identical to that for cytokine-activated macrophages.
- Published
- 1991
- Full Text
- View/download PDF
6. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.
- Author
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Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, and Lodato RF
- Subjects
- Animals, Arginine pharmacology, Blood Pressure, Cytokines pharmacology, Dogs, Female, Hypertension chemically induced, Kinetics, Male, Shock, Septic drug therapy, Vascular Resistance drug effects, omega-N-Methylarginine, Arginine analogs & derivatives, Endotoxins pharmacology, Nitric Oxide metabolism, Shock, Septic chemically induced
- Abstract
Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.
- Published
- 1990
- Full Text
- View/download PDF
7. Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine.
- Author
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Gross SS, Stuehr DJ, Aisaka K, Jaffe EA, Levi R, and Griffith OW
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Blood Pressure drug effects, Cattle, Cells, Cultured, Endothelium, Vascular enzymology, Endothelium, Vascular metabolism, Guinea Pigs, Macrophages enzymology, Macrophages metabolism, Mice, Nitric Oxide antagonists & inhibitors, Nitroarginine, omega-N-Methylarginine, Endothelium, Vascular drug effects, Macrophages drug effects, Nitric Oxide metabolism
- Abstract
Many cell types are known to synthesize nitric oxide (NO.) from L-arginine. There appear to be at least two forms of NO. synthase: an inducible, tetrahydrobiopterin- and flavin-dependent activity exemplified by the macrophage enzyme and a constitutive, Ca+(+)-dependent activity exemplified by the endothelial cell enzyme. L-NG-methylarginine inhibits NO. synthesis by both cell types. We now report that L-NG-aminoarginine and L-NG-nitroarginine are about 100-fold more potent than NG-methylarginine in blocking endothelial cell NO. synthesis. In contrast, NG-aminoarginine and NG-methylarginine are about equipotent with macrophages whereas NG-nitroarginine is much less potent. Since macrophage and endothelial cell NO. synthesis are differentially sensitive to the inhibitors, the panel of inhibitors can be used in complex biological systems to determine if macrophage-like or endothelial-like cells are the predominant source of NO.. Indeed, all three inhibitors elicit a strong pressor response in the anesthetized guinea pig, a result consistent with the view that endothelial cells continually produce vasodilatory NO(.).
- Published
- 1990
- Full Text
- View/download PDF
8. L-arginine availability determines the duration of acetylcholine-induced systemic vasodilation in vivo.
- Author
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Aisaka K, Gross SS, Griffith OW, and Levi R
- Subjects
- Animals, Arginine analogs & derivatives, Biological Availability, Blood Pressure drug effects, Depression, Chemical, Guinea Pigs, Male, Nitric Oxide metabolism, Time Factors, omega-N-Methylarginine, Acetylcholine pharmacology, Arginine metabolism, Vasodilation drug effects
- Abstract
In vitro studies have shown that acetylcholine-induced vasorelaxation is mediated by endothelium-derived relaxing factor/nitric oxide (EDRF/NO). EDRF/NO is synthesized from L-arginine by an enzymatic pathway that is inhibited by L-NG-methylarginine. To assess whether EDRF/NO also mediates the vasodilating action of acetylcholine in vivo, we have investigated the effect of L-arginine and L-NG-methylarginine on the hypotensive response to acetylcholine in the anesthetized guinea pig. L-arginine prolonged the duration of the depressor response to acetylcholine and L-NG-methylarginine decreased it. However, neither L-arginine nor L-NG-methylarginine modified the magnitude of acetylcholine's hypotensive effect unless the blood pressure was previously elevated by infusion with norepinephrine. Thus, de novo synthesis of nitric oxide from L-arginine contributes importantly, but not exclusively, to acetylcholine's hypotensive effect in the guinea pig. Furthermore, the concentration of circulating L-arginine may influence the duration and magnitude of acetylcholine-induced depressor responses under normotensive and hypertensive conditions.
- Published
- 1989
- Full Text
- View/download PDF
9. Alkyl chain homologs of platelet-activating factor and their effects on the mammalian heart.
- Author
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Levi R, Genovese A, and Pinckard RN
- Subjects
- Alkylation, Animals, Coronary Circulation drug effects, Coronary Vessels drug effects, Coronary Vessels physiology, Guinea Pigs, Heart physiology, In Vitro Techniques, Male, Myocardial Contraction drug effects, Structure-Activity Relationship, Vasoconstriction drug effects, Heart drug effects, Platelet Activating Factor pharmacology
- Abstract
Platelet-activating factor (PAF; AGEPC) is a potent negative inotropic and coronary-vasoconstricting agent. Minor structural alterations in the PAF molecule are known to greatly affect its biological activity; thus, we have investigated the effects of selected synthetic saturated and unsaturated alkyl chain PAF homologs on the isolated guinea pig heart. The rank order of potency for the negative inotropic effect was C16:0- greater than C18:1- greater than beef-heart AGEPC greater than C15:0- greater than C18:0- greater than C14:0-AGEPC; the rank order for the coronary-vasoconstricting effect was C16:0- approximately C18:1- approximately beef-heart AGEPC greater than C15:0- greater than C18:0- approximately C14:0-AGEPC. With the exception of C16:0- and C18:1-AGEPC, the relative potencies for the cardiac and coronary effects of the alkyl chain AGEPC homologs did not correlate well with their relative potencies in stimulating rabbit platelets and human neutrophils. The differences in the rank order of potency for these AGEPC homologs suggest the presence of species and/or target cell PAF receptor heterogeneity.
- Published
- 1989
- Full Text
- View/download PDF
10. Synthesis of nitrogen oxides from L-arginine by macrophage cytosol: requirement for inducible and constitutive components.
- Author
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Stuehr DJ, Kwon NS, Gross SS, Thiel BA, Levi R, and Nathan CF
- Subjects
- Animals, Cytosol metabolism, Free Radicals, In Vitro Techniques, Macrophage Activation, Mice, Mice, Inbred C3H, NADP metabolism, Temperature, Arginine metabolism, Macrophages metabolism, Nitrogen Oxides biosynthesis
- Abstract
Cytosols prepared from murine peritoneal macrophages and the RAW 264 macrophage cell line catalyzed conversion of L-arginine to the labile vaso-relaxant nitric oxide and its accumulating endproducts, nitrite and nitrate. This activity required previous exposure of the cells to interferon-gamma and bacterial lipopolysaccharide. Nitrogen oxide synthetase activity was characterized further using nitrite + nitrate production as an indicator of the synthesis of all three nitrogen oxides. Nitrogen oxide synthetase activity was heat-sensitive, NADPH-dependent, and exhibited substrate stereospecificity. The nitrite + nitrate formation was proportional to time and concentration of cytosol. However, dilution decreased the specific activity, suggesting a cofactor requirement in addition to NADPH. Specific activity was restored by addition of cytosol from non-activated macrophages, which itself did not make nitric oxide. Both high and low molecular weight fractions of control macrophage cytosol were required to restore activity of cytosol from activated macrophages that had been either diluted or partially purified. Thus, the enzymatic system involved in nitric oxide synthesis by murine macrophages consists of at least one inducible and two constitutive components.
- Published
- 1989
- Full Text
- View/download PDF
11. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?
- Author
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Aisaka K, Gross SS, Griffith OW, and Levi R
- Subjects
- Angiotensin II administration & dosage, Animals, Arginine administration & dosage, Guinea Pigs, Heart Rate drug effects, Injections, Intravenous, Male, Nitric Oxide biosynthesis, Norepinephrine administration & dosage, Premedication, omega-N-Methylarginine, Arginine analogs & derivatives, Blood Pressure drug effects, Endothelium, Vascular physiology, Nitric Oxide physiology, Vasoconstrictor Agents administration & dosage
- Abstract
Nitric oxide is a major endothelium-derived vascular smooth muscle relaxing factor; its synthesis from L-arginine is selectively inhibited by L-NG-methylarginine. To assess whether basal nitric oxide release contributes to blood pressure regulation in vivo, we have investigated the cardiovascular effects of L-NG-methylarginine in the anesthetized guinea pig. L-NG-methylarginine (0.1-10 mg/kg, i.v. bolus) elicited a sustained, dose-dependent, increase in arterial pressure and a moderate bradycardia. L-arginine (30 mg/kg i.v.) prevented or reversed the pressor effect of L-NG-methylarginine, while atropine (2 mg/kg) abolished the associated bradycardia. In contrast, L-arginine did not attenuate the pressor effect of norepinephrine or angiotensin. Our findings suggest that basal nitric oxide production is sufficient to modulate peripheral vascular resistance; hence nitric oxide may play a role in arterial pressure homeostasis.
- Published
- 1989
- Full Text
- View/download PDF
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