Showing papers on "Agmatine published in 1997"
TL;DR: It is suggested that agmatine prevents naloxone-precipitated abstinence syndrome in morphine dependent rats; thus, this drug may be beneficial in the treatment of opioid dependence.
109 citations
TL;DR: Agmatine concentrations in rat brain were proportioned similarly to the regional distribution of imidazoline-1 receptors, and the accuracy of the isocratic method compared favorably with a gradient HPLC protocol, originally developed for bacterial agmatine, which was modified for use with tissues.
93 citations
TL;DR: The activity of arginine decarboxylase (ADC), a key enzyme in plant polyamine biosynthesis, was manipulated in two generations of transgenic tobacco plants and overaccumulation of agmatine in the transgenic plants did not affect morphological development.
Abstract: The activity of arginine decarboxylase (ADC), a key enzyme in plant polyamine biosynthesis, was manipulated in two generations of transgenic tobacco plants. Second-generation transgenic plants overexpressing an oat ADC cDNA contained high levels of oat ADC transcript relative to tobacco ADC, possessed elevated ADC enzyme activity and accumulated 10-20-fold more agmatine, the direct product of ADC. In the presence of high levels of the precursor agmatine, no increase in the levels of the polyamines putrescine, spermidine and spermine was detected in the transgenic plants. Similarly, the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase were unchanged. No diversion of polyamine metabolism into the hydroxycinnamic acid-polyamine conjugate pool or into the tobacco alkaloid nicotine was detected. Activity of the catabolic enzyme diamine oxidase was the same in transgenic and control plants. The elevated ADC activity and agmatine production were subjected to a metabolic/physical block preventing increased, i.e. deregulated, polyamine accumulation. Overaccumulation of agmatine in the transgenic plants did not affect morphological development.
89 citations
TL;DR: Current evidence is consistent with an hypothesis that agmatine meets many criteria for a neurotransmitter-neuromodulator, but its role in normal brain function has not yet been established because of the absence of agents that selectively affect its biosynthesis or degradation.
Abstract: Publisher Summary Current evidence is consistent with a hypothesis that agmatine meets many criteria for a neurotransmitter-neuromodulator. It is synthesized, stored, and released in brain; is contained in neurons and axon terminals with a heterogeneous distribution; interacts with cell-specific receptors; and elicits biological actions within the central nervous system. Immunocytochemically, agmatine has been localized in brain and adrenal using polyclonal antibodies. While in untreated brain agmatine-like immunoreactivity (-LI) is detected in only a few perikarya, after pretreatment with intracerebroventricular (i.c.v.) colchicine, it can be seen in the cytoplasm of many neurons throughout the brain. These are most heavily concentrated in hypothalamus, neocortex, and periaquaductal regions of midbrain. By electron microscopy agmatine-LI can be detected in dense-core vesicles in axon terminals in the nucleus tractus solatarii and in the hilus of the hippocampal formation. Hence, its storage site is such that would be expected of a neurotransmitter candidate. Agmatine binds with high affinity to α2-adrenergic receptors of all subclasses and to the imidazoline receptors of the I1 and I2 subclasses. The fact that amines are present in brain and it binds to α2-adrenergic receptors and IRs raised the question of whether agmatine might, like other bioamines, have biological actions in its own right, possibly as a neurotransmitter-neuromodulator.
67 citations
01 Jan 1997
TL;DR: The results suggest that agmatine can bind to a cell surface imidazoline receptor on endothelial cells and can stimulate nitric oxide production by increasing cytosolic calcium, a vasodilatory substance.
Abstract: Agmatine is a product of arginine decarboxylation. Systemic infusion of agmatine into rats causes hypotension. This effect could be due either to a central action of agmatine (a clonidine displacing substance), or to a direct effect of agmatine on cells of blood vessel walls, which induces them to cause vasodilatation, or both. In this study, we examined the effects of agmatine on endothelial cell function by using cultured bovine pulmonary artery endothelial cells. Agmatine stimulated nitrite production three-fold above basal nitrite formation by endothelial cells. The increased nitrite production by agmatine was inhibited by idazoxan but not by yohimbine. Agmatine displaced [3H]-idazoxan from endothelial cell membranes and was found to induce transients in the cytosolic calcium of endothelial cells. The transients could be downregulated by repeated exposure to agmatine but were not affected by pretreatment with norepinephrine. These results suggest that agmatine can bind to a cell surface imidazoline receptor on endothelial cells and can stimulate nitric oxide production by increasing cytosolic calcium. Therefore, agmatine appears to act directly on endothelial cells to increase the synthesis of nitric oxide, a vasodilatory substance.
58 citations
TL;DR: Agmatine exerts effects on glomerular ultrafiltration via a constitutive NOS-dependent mechanism, and this does not require the participation of alpha 2-adrenoreceptors.
Abstract: Arginine decarboxylase is present in the kidney and metabolizes the amino acid, arginine, to agmatine. Agmatine increases filtration rate in single nephrons (J. J. Lortie, W. F. Novotny, O. W. Peterson, V. Vallon, K. Malvey, M. Mendonca, J. Satriano, P. Insel, S. C. Thomson, and R. C. Blantz. J. Clin. Invest. 97:413-420, 1996). Experiments were conducted to determine whether exogenously administered agmatine exerts these effects via interaction with nitric oxide synthase (NOS) and whether this interaction depends upon alpha 2-adrenergic receptors. Agmatine microperfused (1 microM) into the urinary space of surface glomeruli of the rat increased nephron filtration rate from 33 +/- 4 to 40 +/- 5 nl/min with complete recovery within 10 min. When NG-monomethyl-L-arginine (L-NMMA), a nonselective NOS inhibitor, was systemically infused, agmatine no longer increased single-nephron glomerular filtration rate (SNGFR). BHT-933, an alpha 2-adrenergic agonist, did not increase SNGFR and was unaffected by concurrent L-NMMA. In vitro incubation of freshly harvested glomeruli with agmatine resulted in significant increases in the generation of cGMP, effects similar to carbachol, and blocked by nitro-L-arginine methyl ester (L-NAME) but not yohimbine, an alpha 2-adrenergic antagonist. Agmatine exerts effects on glomerular ultrafiltration via a constitutive NOS-dependent mechanism, and this does not require the participation of alpha 2-adrenoreceptors.
53 citations
TL;DR: It is concluded that noradrenoceptor release in human atrial appendages and pulmonary arteries preincubated with [3H]‐noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone is inhibited, and presynaptic imidazoline receptors appear to be characterized in rabbit aorta.
Abstract: 1
In segments of human right atrial appendages and pulmonary arteries preincubated with [3H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [3H]-noradrenaline release was investigated.
2
In human atrial appendages, the guanidines aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynaptic imidazoline receptors, inhibited electrically-evoked [3H]-noradrenaline release. The inhibition was not affected by blockade of α2-adrenoceptors with 1 μM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 μM; apparent pA2 against aganodine and DTG: 5.55 and 5.21, respectively).
3
In the presence of 1 μM rauwolscine, [3H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory effects of 100 μM idazoxan and 30 μM cirazoline were abolished by 30 μM rauwolscine.
4
In the atrial appendages, the rank order of potency of all guanidines and imidazolines for their inhibitory effect on electrically-evoked [3H]-noradrenaline release in the presence of 1 μM rauwolscine was: aganodineBDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline]>DTGclonidine>cirazoline>idazoxan (BDF 6143 and clonidine were previously studied under identical conditions). This potency order corresponded to that previously determined at the presynaptic imidazoline receptors in the rabbit aorta.
5
When, in the experiments in the human pulmonary artery, rauwolscine was absent from the superfusion fluid, the concentration-response curve for BDF 6143 (a mixed α2-adrenoceptor antagonist/imidazoline receptor agonist) for its facilitatory effect on electrically-evoked [3H]-noradrenaline release was bell-shaped. In the presence of 1 μM rauwolscine, BDF 6143 and cirazoline concentration-dependently inhibited the evoked [3H]-noradrenaline release.
6
In human atrial appendages, non-adrenoceptor [3H]-idazoxan binding sites were identified and characterized. The binding of [3H]-idazoxan was specific, reversible, saturable and of high affinity (KD: 25.5 nM). The specific binding of [3H]-idazoxan (defined by cirazoline 0.1 mM) to membranes of human atrial appendages was concentration-dependently inhibited by several imidazolines and guanidines, but not by rauwolscine and agmatine. In most cases, the competition curves were best fitted to a two-site model.
7
The rank order of affinity for the high affinity site (in a few cases for the only detectable site; cirazoline=idazoxan>BDF 6143>DTGclonidine) is compatible with the pharmacological properties of I2-imidazoline binding sites, but is clearly different from the rank order of potency for inhibiting evoked noradrenaline release from sympathetic nerves in the same tissue.
8
It is concluded that noradrenaline release in the human atrium and, less well established, in the pulmonary artery is inhibited via presynaptic imidazoline receptors. These presynaptic imidazoline receptors appear to be related to those previously characterized in rabbit aorta and pulmonary artery, but differ clearly from I1 and I2 imidazoline binding sites.
British Journal of Pharmacology (1997) 122, 43–50; doi:10.1038/sj.bjp.0701343
38 citations
TL;DR: In spinalised animals, agmatine caused a generalised increase in background firing which in animals with a non-inflamed paw was significantly reduced after atipamezole, and there was no significant change in evoked responses once corrected for background activity.
33 citations
TL;DR: It is concluded that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways.
Abstract: Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for 3 H-idazoxan and an imidazoline receptor–binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of 3 H-thymidine (IC 50 : 5 and 70 μmol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560±440 disintegrations per minute norepinephrine versus 3345±220 norepinephrine and idazoxan), angiotensin II (7680±335 disintegrations per minute angiotensin II versus 3769±450 angiotensin II and idazoxan), or platelet-derived growth factor (IC 50 : 3 μmol/L for idazoxan and 40 μmol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.
31 citations
TL;DR: Rat RT6 proteins, and perhaps mouse Rt6, identify a set of immunoregulatory T lymphocytes, and mRt6.1 is an NAD:arginine ADP-ribosyltransferase capable of catalyzing a multiple turnover, stereospecific Sn2-like reaction.
26 citations
TL;DR: Results show that agmatine produces bradycardia as does moxonidine and clonidine but does not mimic or block the hypotensive responses to these agents, which does not support the hypothesis that ag matine is an endogenous ligand for IR.
TL;DR: Arginine decarboxylase (EC 4.1.19) was purified from soybean, Glycine max, hypocotyls by a procedure which includes ammonium sulfate fractionation, acetone precipitation, gel filtration chromatography, and affinity chromatography.
Abstract: Arginine decarboxylase (EC 4.1.1.19) was purified from soybean, Glycine max, hypocotyls by a procedure which includes ammonium sulfate fractionation, acetone precipitation, gel filtration chromatography, and affinity chromatography. Using this procedure, ADC was purified to one band in non-denaturing PAGE. The purified ADC has an M(r) of 240 kDa based on gel filtration chromatography and is a trimer of identical subunits which has an estimated M(r) of 74 kDa based on SDS-PAGE. ADC is active between 30 and 50 degrees C and has a Km value of 46.1 microM. ADC is very sensitive to agmatine or putrescine but not to spermidine or spermine. In the presence of 0.5 mM agmatine (or putrescine), the enzyme activity was inhibited by 70%. However, at the same concentration of spermidine (or spermine), the enzyme activity was inhibited by only 10-20%.
Journal Article•
TL;DR: The effects of moxonidine in mediating inhibition of intestinal motility and enhancing fluid transport are attributed predominantly to interaction with alpha-2 adrenoceptors.
Abstract: The aims of this study were to examine how the imidazoline (I) 1 / alpha -2 receptor agonist moxonidine and the putative endogenous imidazoline receptor agonist agmatine might affect intestinal motility and fluid transport. The effects of moxonidine were compared with those of UK 14,304, a highly selective alpha -2 adrenoceptor agonist with very low affinity for I 1 receptors. Moxonidine and UK 14,304 inhibited the peristaltic reflex in the isolated rat ileum. The inhibitory effects were antagonized by the selective alpha -2 adrenoceptor antagonist yohimbine and the I 1 / alpha -2 antagonist efaroxan and almost completely blocked by the irreversible alpha -2 adrenoceptor antagonist EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), whichhas a low affinity for imidazoline receptors. Yohimbine (3 μM) and efaroxan (0.01 and 1 μM) caused parallel rightward shifts to the concentration-response curves of moxonidine and UK 14,304, yielding p K B values corresponding to those at alpha -2 binding sites. Moxonidine induced dose-dependent proabsorptive effects in the jejunum and ileum and also reversed the secretory phase of the vasoactive intestinal peptide-induced responses. The degree of antagonism by yohimbine and efaroxan was similar against moxonidine and UK 14,304 on the proabsorptive and antisecretory effects. We conclude that the effects of moxonidine in mediating inhibition of intestinal motility and enhancing fluid transport are attributed predominantly to interaction with alpha -2 adrenoceptors. Agmatine had no effect on peristalsis but significantly decreased the rate of fluid absorption from the jejunum and ileum, an effect in contrast to moxonidine. A physiological role for agmatine in the regulation of intestinal transport remains to be clarified.
TL;DR: Results suggest that like glutamic acid-112, histidine-44 plays an essential role in toxicity, and a tentative model, which explains NAD+ catalysis and the transfer of the ADP-ribosyl moiety to a target amino acid, is proposed.
Abstract: We examined the role in toxicity of histidine-44 of the A subunit of Escherichia coli enterotoxin, which is located in the active site cavity close to glutamic acid-112. Although amino acid substitution of histidine-44 usually renders a mutant toxin unstable to trypsin, one mutant, alanine-44 (His44Ala) was found to be stable. His44Ala did not show any agmatine:ADP-ribosyltransferase activity in the presence or absence of recombinant ADP-ribosylation factor. It showed no diarrheal or rabbit skin permeability activity and was a competitor in enterotoxin-ADP-ribosyltransferase assays containing recombinant ADP-ribosylation factor. These results suggest that like glutamic acid-112, histidine-44 plays an essential role in toxicity. A tentative model, which explains NAD+ catalysis and the transfer of the ADP-ribosyl moiety to a target amino acid, is proposed for histidine-44 and glutamic acid-112.
Patent•
25 Sep 1997
TL;DR: In this article, an arginine derivative or agmatine derivative was administered to the cells in condition such as cancer or hypertrophy to reduce polyamine levels intracellularly.
Abstract: The present invention provides a method of reducing polyamine levels intracellularly by administering an arginine derivative to a mammal. The present invention also provides a pharmacological composition comprising agmatine in a physiologically acceptable buffer. Accordingly, the present invention also provides a method of treating conditions resulting from abnormally elevated intracellular polyamine levels by administering an arginine derivative or agmatine to the cells in condition such as cancer or hypertrophy. The present invention further provides a method of regulating inducible nitric oxide synthase while maintaining constitutive nitric oxide synthase, by administering agmatine or an arginine derivative to a mammal. The present invention further provides a method of treating septic shock in a mammal, by administering a composition comprising agmatine or an arginine derivative to a mammal. In addition, the present invention provides a method of treating conditions resulting from excessive inducible nitric oxide production, including treatment of septic shock, arthritis, glomerulonephritis, angiogenesis in tumors, transplantation and tissue graft rejection, neurodegeneration, stroke, ischemic injury, chronic inflammation and diabetes.
TL;DR: An anti-idazoxan RIA is a sensitive, selective and clinically applicable RIA for measuring ir-CDS, which represents a family of endogenous ligands for imidazoline receptors including ir- CDS and agmatine.
TL;DR: Control of polyamine levels is important because they are a potential hazard for human health and also because of their effects on aminopeptidase activity.
Abstract: The effects of polyamines (agmatine, cadaverine, putrescine, spermidine and spermine) on the activity of the main aminopeptidases (AP I and AP II) from Lactobacillus sake were determined. Concentrations in the range of 1 mM caused 6–25% inhibition of AP I except for spermine (45% inhibition). Higher polyamine levels (5–10 mM), except for putrescine, exerted a stronger inhibition (20–60%) on AP I. Agmatine and putrescine also reduced AP II activity (6–25%) at concentrations of 0.1–10 mM while cadaverine did not have a notable effect. Spermidine and spermine stimulated (15–70%) the activity of AP II at concentrations >1 mM. Thus, control of polyamine levels is important because they are a potential hazard for human health and also because of their effects on aminopeptidase activity.
Journal Article•
TL;DR: Agmatine (AGM) is decarboxylated arginine found in bovine brain which binds to imidazoline receptors which differs substantially from earlier discovered clonidine displacing substance (CDS) and ir-CDS.
Abstract: Agmatine (AGM) is decarboxylated arginine found in bovine brain which binds to imidazoline receptors. It differs substantially from earlier discovered clonidine displacing substance (CDS) and ir-CDS. AGM is synthetized in brain from arginine decarboxylase, and metabolized by diamine oxidase. It is widely and unequally distributed in peripheral tissues and in the brain. AGM interacts with both I-1 and I-2 imidazoline receptors as well as with alpha 2-adrenoreceptors. AGM can regulate cardiovascular functions and can modulate some processes in the central nervous system.
01 Jan 1997
TL;DR: This chapter summarizes available information on the synthesis of L-arginine and various pathways of its utilization: arginase-catalyzed synthesis of urea and ornithine, production of agmatine through L- arginine metabolism by arginine decarboxylase, and nitric oxide synthase-Catalyzed conversion of L to citrulline and NO.
Abstract: In addition to its role in the synthesis of proteins, the amino acid L-arginine is essential for the synthesis of urea, creatine, nitric oxide, agmatine, and polyamines and influences the release of hormones and the synthesis of pyrimidine bases [1]. Arginine was identified and isolated from proteins more than a century ago [23]. It was not until the 1930s that its prominent role in normal metabolism began to unfold. This chapter summarizes available information on the synthesis of L-arginine and various pathways of its utilization: arginase-catalyzed synthesis of urea and ornithine, production of agmatine through L-arginine metabolism by arginine decarboxylase, and nitric oxide synthase-catalyzed conversion of L-arginine to citrulline and NO.