Agmatine ; administration & dosage ; pharmacology ; Analgesia ; methods ; Animals ; Injections, Spinal ; Male ; Morphine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects

This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning.
Agmatine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Chlorpromazine/toxicity ; Oxidative Stress/*drug effects ; Prosencephalon/*drug effects ; Rats ; Rats, Wistar

This study is to explore a behavioral and pathological model for depression in mice, and evaluate the anti-depressant-like effect of agmatine. Neonatal Kunming mice were treated with fluoxetine (10 mg x kg(-1), ip, qd) for 17 d (between day 4 and 21 after birth), and then the mice were normally housed till being adult (about 10 weeks after birth). The behaviors of the mice were measured by using open-field test, novelty suppressed feeding test and tail-suspension test. Hippocampal adenylate cyclase (AC) activity was measured by radioimmunoassay. Neonatal exposure to fluoxetine induced a "depression-like" behaviors in the adult mice, shown as the decreased locomotor activity, increased feeding latency and immobility time in the open-field test, novelty suppressed feeding test, and tail-suspension test, respectively. Chronic agmatine treatment (10 mg x kg(-1), ig, bid) for 3 weeks significantly increased the locomotor activity, and decreased the feeding latency in the neonatal fluoxetine exposed mice. Furthermore, single treatment with agmatine (40 mg x kg(-1), ig) also decreased the immobility time in the tail-suspension test, and increased the hippocampal AC activity in the mice. These results indicate that neonatal exposure to fluoxetine induces depressive-like behaviors in the adult mice. Agmatine reverses these behaviors, which may be closely related to the enhancement of the hippocampal AC activity.
Agmatine ; pharmacology ; Animals ; Antidepressive Agents ; pharmacology ; Depressive Disorder ; chemically induced ; Disease Models, Animal ; Female ; Fluoxetine ; administration & dosage ; adverse effects ; Male ; Mice ; Mice, Inbred Strains

The present study was to investigate the effects of agmatine (Agm) on free intracellular calcium concentration ([Ca(2+)]( i )) of isolated rat ventricular myocytes. [Ca(2+)]( i ) was measured by confocal microscopy in single rat ventricular myocytes which were dissociated by enzymatic dissociation method and loaded with Fluo 3-AM. The changes in [Ca(2+)]( i ) were represented by fluorescence intensity (FI) or relative fluorescence intensity (F/F(0)%). The results showed that the control level of FI value of single rat ventricular myocytes was 128.8+/-13.8 and 119.6+/-13.6 in the presence of normal Tyrode's solution containing Ca(2+) 1.0 mmol/L and Ca(2+)-free Tyrode's solution, respectively. There was no difference between these two groups (P>0.05). Agm 0.1, 1, and 10 mmol/L significantly reduced the [Ca(2+)]( i ) in both extracellular solutions in a concentration-dependent manner. The similar effect of Agm on [Ca(2+)]( i ) was also observed in the presence of EGTA 3 mmol/L. KCl 60 mmol/L, PE 30 micromol/L, and Bay-K-8644 10 micromol/L, all these substances induced [Ca(2+)]( i ) elevations in ventricular myocytes. Agm (0.1, 1, and 10 mmol/L) markedly inhibited the increase in [Ca(2+)]( i ) induced by KCl, phenylephrine (PE), and Bay-K-8644. When Ca(2+) waves were produced by increasing extracellular Ca(2+) concentration from 1 to 10 mmol/L, 1 mmol/L Agm could block the propagating waves of elevated [Ca(2+)]( i ), and reduce the velocity and duration of propagating waves. These results suggest that Agm possesses an inhibitory effects on [Ca(2+)]( i ) via blocking voltage-dependent Ca(2+) channel, and possibly by alleviating calcium release from SR in single isolated rat ventricular myocytes.
Agmatine ; pharmacology ; Animals ; Calcium ; metabolism ; Calcium Channels ; drug effects ; Cells, Cultured ; Female ; Heart Ventricles ; cytology ; Male ; Myocytes, Cardiac ; cytology ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley

The cardiac electrophysiological effects of genistein (GST) were examined in guinea pig papillary muscle using intracellular microelectrode technique. The results obtained are as follows. (1) Duration of action potential (APD) in normal papillary muscles was decreased by GST (10 100 micromol/L) in a concentration-dependent manner. (2) In partially depolarized papillary muscles, 50 micromol/L GST not only reduced APD, but also decreased the amplitude of action potential, overshoot and maximal velocity of phase 0 depolarization. (3) Pretreatment with N( )-nitro-L-arginine (L-NNA, 5 mmol/L) failed to affect the above effects of GST (50 micromol/L)on papillary muscles. (4) 17beta-estradiol (E(2), 5 micromol/L) or GST (10 micromol/L) alone did not affect action potential, while GST combined with E(2) at the same doses shortened APD significantly. All these results indicate that the effects of GST on papillary muscles are likely due to a decrease of calcium inflow which is not mediated by NO and that GST has a facilitative or synergetic action with E(2).
Action Potentials ; drug effects ; Agmatine ; pharmacology ; Animals ; Dose-Response Relationship, Drug ; Drug Synergism ; Electrophysiology ; Estradiol ; pharmacology ; Estrogens, Non-Steroidal ; pharmacology ; Female ; Genistein ; pharmacology ; Guinea Pigs ; Isoflavones ; Male ; Papillary Muscles ; drug effects ; physiology ; Phytoestrogens ; Plant Preparations

In order to search for novel inhibitors of Na+/H+ exchanger isoform-1 (NHE-1), nine feruloylagmatine analogues were designed and synthesized from ferulic acid and agmatine. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR and mass spectra, among which compounds 5f-5i were novel compounds. The results of preliminary pharmacological test showed that some of the compounds possessed strong NHE-1 inhibitory activity, among which compounds 5a, 5b and 6c were more potent than cariporide in NHE-1 inhibition.
Agmatine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Cardiotonic Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Design ; Female ; Male ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Sodium-Hydrogen Exchangers ; antagonists & inhibitors ; Structure-Activity Relationship

This study is to explore the possible mechanisms of the antidepressant-like effect of agmatine. By using two traditional "behavior despair" model, tail suspension test and forced swimming test, we examined the effects of some monoamine receptor antagonists (including beta-adrenergic receptor antagonist propranolol, beta-adrenergic receptor antagonist/5-HT1A/1B receptor antagonist pindolol, alpha2-adrenergic receptor antagonists yohimbine and idazoxan and 5-HT3 receptor antagonist tropisetron) on the antidepressant-like action of agmatine in mice. Activity of adenylate cyclase (AC) in the synapse membrane from rat frontal cortex was determined by radioimmunoassay. Single dose of agmatine (5-40 mg x kg(-1), ig) dose-dependently decrease the immobility time in tail suspension test in mice, indicating an antidepressant-like effect. The effect of agmatine (40 mg x kg(-1), ig) was antagonized by co-administration of beta-adrenergic receptor antagonist/5-HT1A/1B receptor antagonist pindolol (20 mg x kg(-1), ip), alpha2-adrenergic receptor antagonists yohimbine (5-10 mg x kg(-1), ip) or idazoxan (4 mg x kg(-1), ip), but not beta-adrenergic receptor antagonist propranolol (5-20 mg x kg(-1), ip) and 5-HT3 receptor antagonist tropisetron (5-40 mg x kg(-1), ip). Agmatine (5-40 mg x kg(-1), ig) also dose-dependently decrease the immobility time in forced swimming test in mice. The effect of agmatine (40 mg x kg(-1), ig) was also antagonized by pindolol (20 mg x kg(-1), ip), yohimbine (5-10 mg x kg(-1), ip), or idazoxan (4 mg x kg(-1), ip). Incubation of agmatine (0.1-6.4 micromol x L(-1)) with the synaptic membrane extracted from rat frontal cortex activated the AC in a dose-dependent manner in vitro. While the effect of agmatine (6.4 micromol x L(-1)) was dose-dependently antagonized by pindolol (1 micromol x L(-1)) or yohimbine (0.25-1 micromol x L(-1)). Chronic treatment with agmatine (10 mg x kg(-1), ig, bid, 2 w) or fluoxetine (10 mg x kg(-1), ig, bid, 2 w) increased the basic activity, as well as the Gpp (NH)p (1-100 micromol x L(-1)) stimulated AC activity in rat prefrontal cortex. These results indicate that regulation on 5-HT1A/1B and alpha2 receptors, and activation AC in the frontal cortex is one of the important mechanisms involving in agmatine's antidepressant-like action.
Adenylyl Cyclases ; metabolism ; Adrenergic alpha-Antagonists ; pharmacology ; Adrenergic beta-Antagonists ; pharmacology ; Agmatine ; administration & dosage ; pharmacology ; Animals ; Antidepressive Agents ; administration & dosage ; pharmacology ; Behavior, Animal ; drug effects ; Depression ; metabolism ; physiopathology ; Dose-Response Relationship, Drug ; Fenclonine ; pharmacology ; Idazoxan ; pharmacology ; Male ; Mice ; Pindolol ; pharmacology ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Biogenic Amine ; antagonists & inhibitors ; Serotonin 5-HT1 Receptor Antagonists ; Swimming ; Synapses ; enzymology ; Yohimbine ; pharmacology

AIMTo determine the effect of agmatine on the proliferation of PASMCs induced by serum.

METHODSPrimary culture of rat PASMCs was prepared from adult male Wistar rat pulmonary artery by the method of tissue block anchorage. PASMCs were divided into two groups: control group and agmatine administration group. The activity of LDH in the medium was measured by chromatometry. The 3H-TdR incorporation was measured by liquid scintillometry. The cell cycle was measured by flow cytometry. The PCNA content was measured by image analysis.

RESULTSAgmatine did not exert significant effect on the activity of LDH in the medium. Agmatine significantly decreased the 3H-TdR incorporation and PCNA content of PASMCs. Agmatine significantly decreased the cell ratio of G2/M phase and increased the cell ratio of G0/G1 phase. With the increment of the concentration of agmatine, 3H-TdR incorporation was significantly decreased correspondingly.

CONCLUSIONAgmatine has no significant cytotoxic effect on PASMCs. Agmatine can dose-dependently inhibit the proliferation of rat PASMCs induced by serum.

Agmatine ; pharmacology ; Animals ; Cell Proliferation ; drug effects ; Cells, Cultured ; Male ; Muscle, Smooth, Vascular ; cytology ; drug effects ; Myocytes, Smooth Muscle ; cytology ; drug effects ; Pulmonary Artery ; cytology ; Rats ; Rats, Wistar ; Serum

The effects of agmatine (Agm) on the discharges of neurons in CA1 area of hippocampal slices were examined by using extracellular recording technique. The results are as follows. (1) In response to the application of Agm (0.1-1.0 micromol/L) into the superfusate for 2 min, the spontaneous discharge rates (SDR) of 38/47 (80.9%) neurons were decreased significantly in a dose-dependent manner, while that of 9/47 (19.1%) neurons showed no change in discharge rate; (2) pretreatment with L-glutamate (L-Glu, 0.2 mmol/L) led to a marked increase in SDR of 9/12 (75%) neurons in an epileptiform pattern and that of 2/12 (25%) neurons were not affected, then after Agm (1.0 micromol/L) was applied into the superfusate for 2 min, the epileptiform discharges were suppressed significantly; (3) in 7 neurons, perfusion of the selective L-type calcium channel agonist, Bay K-8644 (0.1 micromol/L), induced an increase in the SDR of 6/7 (85.7%) neurons, while that of 1/7 (14.3%) neuron showed no change, and the discharges were also decreased by application of Agm (1.0 micromol/L) into the superfusate; and (4) application of NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) into the superfusate 5 min later also significantly increased the SDR in all 13 (100%) neurons; then Agm (1.0 micromol/L) applied into the superfusate inhibited the discharges of 11/13 (84.6%) neurons, while those of 2/13 (15.4%) neurons were not affected. These results suggest that agmatine can inhibit the spontaneous discharges and L-glutamate-, Bay K-8644- and L-NAME-induced discharges of hippocampal CA1 neurons. These inhibitory effects of agmatine may be related to the blockade of NMDA receptors and a reduction in calcium influx in hippocampal neurons
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; pharmacology ; Agmatine ; pharmacology ; Animals ; Calcium Channel Agonists ; pharmacology ; Dose-Response Relationship, Drug ; Electrophysiology ; Female ; Glutamic Acid ; pharmacology ; Hippocampus ; physiology ; Male ; Neurons ; physiology ; Nitric Oxide Synthase ; antagonists & inhibitors ; Nitroarginine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors

The aim of this study was to investigate the effects of agmatine (Agm) on the electrical activity of neurons in subfornical organ (SFO) slices using extracellular recording technique. The results are as follows. (1) In response to the application of Agm (1.0 micromol/L) into the superfusate for 2 min, the discharge rate of 24/28 (85.7%) subfornical neurons was decreased significantly, while the discharge rate of 4/28 (14.3%) neurons were not affected. (2) Pretreatment with L-glutamate (0.3 mmol/L) led to a marked increase in the discharge rate of 19/24 (79.2%) subfornical neurons in an epileptiform pattern and the activity of the remaining 5/24 (20.8%) neurons was unaffected. By application of Agm (1.0 micromol/L) into the superfusate for 2 min, the epileptiform dicharge of 15/19 (78.9%) neurons was suppressed significantly, while that of the other 4 (21.1%) neurons was not inhibited. (3) In 12 neurons, perfusion of the selective L-type calcium channel agonist, Bay K-8644 (0.1 micromol/L), induced a significant increase in the discharge rate of 10/12 (83.3%) neurons, while the other 2 (16.7%) neurons showed no change. The increased discharge of 8/10 (80%) neurons was reduced by application of Agm (1.0 micromol/L) into the superfusate and that of 2/10 (20%) neurons was not affected. (4) Application of nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) into the superfusate also significantly increased the discharge rate of 6/9 (66.7%) neurons, and that of 3/9 (33.3%) neurons had no response. Agm (1.0 micromol/L) applied into the superfusate reduced the increased discharge of all 6/6 (100%) neurons. These results suggest that Agm can inhibit the spontaneous discharge, and L-glutamate, Bay K-8644- or L-NAME-induced discharge of neurons in SFO. These inhibitory effects of Agm may be related to the blockade of NMDA receptors and reduction in calcium influx in SFO neurons.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; pharmacology ; Action Potentials ; drug effects ; Agmatine ; pharmacology ; Animals ; Calcium Channel Agonists ; pharmacology ; Female ; Glutamic Acid ; pharmacology ; Hippocampus ; physiology ; Male ; Neurons ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Drug ; agonists ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Subfornical Organ ; drug effects ; physiology