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2.
Psychopharmacology (Berl) ; 238(7): 2043-2044, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34115156

ABSTRACT

With respect to Guo's inspiring article (Guo et al. 2021), we would like to suggest several corrections about some of the figures. We felt obliged to write this erratum letter as these incompatibilities may cause confusion for the readers.


Subject(s)
Depressive Disorder, Major/metabolism , Receptors, sigma/metabolism , Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacology , Animals , Ligands , Locomotion/drug effects , Locomotion/physiology , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Rats , Sigma-1 Receptor
3.
Turk Neurosurg ; 30(6): 871-884, 2020.
Article in English | MEDLINE | ID: mdl-32705669

ABSTRACT

AIM: To evaluate the possible neuroprotective effects of ketamine and dantrolene on the hippocampal apoptosis and spatial learning in rats exposed to repeated electroconvulsive seizures (ECS) as a model of status epilepticus (SE). MATERIAL AND METHODS: Twenty-four rats were assigned to 4 groups. 1st Group was Sham. 2nd Group was ECS: ECS was induced by ear electrodes via electrical stimulation. The same ECS protocol was applied to the 3th and 4th Groups which received ketamine (40 mg/kg s.c.) or dantrolene (5 mg/kg i.p.) 1 h before each ECS, respectively. Following 30 days of recovery, the cognitive status of the animals was evaluated via Morris Water Maze (MWM). The same experimental protocol was repeated 14 days afterward to evaluate the retention of the memory. Hippocampal apoptosis was examined in corresponding experimental groups. RESULTS: All the animals in four groups learned the task with no significant difference between groups in MWM. The ECS+ketamine group showed memory impairment 14 days afterward. ECS+dantrolene group was not different from controls. ECS caused long term apoptotic processes in dentate gyrus (DG) and non-apoptotic neuronal injury in CA1 and CA2. CONCLUSION: Dantrolene and ketamine inhibited apoptosis and showed neuroprotective effects. Although ketamine and dantrolene inhibited ECS-induced apoptosis and non-apoptotic injury, they did not produce similar effects on memory retention. It will be warranted to evaluate cognitive dysfunction by taking into consideration the other factors in addition to apoptosis and neurodegenerative changes.


Subject(s)
Dantrolene/pharmacology , Hippocampus/drug effects , Ketamine/pharmacology , Neuroprotective Agents/pharmacology , Status Epilepticus/physiopathology , Animals , Apoptosis/drug effects , Disease Models, Animal , Electroshock/adverse effects , Hippocampus/pathology , Male , Maze Learning/drug effects , Rats
4.
Kidney Int ; 88(2): 311-20, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25993324

ABSTRACT

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 µM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.


Subject(s)
Diuresis/drug effects , Membrane Transport Proteins/metabolism , Sodium Chloride/urine , Thiourea/analogs & derivatives , Animals , Binding Sites , Disease Models, Animal , Diuretics/pharmacology , Dogs , Drug Evaluation, Preclinical , Female , Furosemide/pharmacology , Hypokalemia/chemically induced , Hyponatremia/etiology , Hyponatremia/prevention & control , Inappropriate ADH Syndrome/complications , Inappropriate ADH Syndrome/drug therapy , Inhibitory Concentration 50 , Madin Darby Canine Kidney Cells , Membrane Transport Proteins/chemistry , Molecular Structure , Osmolar Concentration , Rats , Rats, Wistar , Thiourea/blood , Thiourea/chemistry , Thiourea/pharmacology , Thiourea/therapeutic use , Time Factors , Urine/chemistry , Urea Transporters
5.
J Pediatr Surg ; 50(10): 1691-4, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25783399

ABSTRACT

In long-gap esophageal atresia surgeries, anastomoses can be tensioned by several traction methods in order to establish esophageal continuity. It is unclear whether the etiology of esophageal dysmotility after traction is related with esophageal atresia itself or tensioned esophagus. Therefore, we evaluated the effects of acute in vitro esophageal tension application on esophageal muscle contractility in rats. 26 Wistar rats weighing 250-300 g were included to the study. After diethyl ether anesthesia, proximal segment (PS) and distal segment (DS) of esophagus were removed and suspended in an isolated organ bath kept at 37°C, Krebs-Henseleit solution. Rats were enrolled into four groups including control group (CG, n=14) without tension, 5 g (5G, n=4), 15 g (15G, n=4) and 25 g (25G, n=4) tension groups. In all groups, contractile responses to electrical field stimulation (EFS), carbachol and KCl, and relaxation responses to serotonin were obtained. In CG, higher contractile responses were obtained in PS than DS after EFS. Both PS and DS showed higher contractile amplitudes in 5G with respect to that of CG, 15G and 25G (p<0.05). In 5G, contractile responses to carbachol were significantly increased in both PS and DS with respect to CG (p<0.05). However, contractile amplitudes in response to carbachol were decreased in PS when tension was increased to 15 g and 25 g. In DS, contractile responses in 15G and 25G were lower than 5G, and still higher than CG. Serotonin relaxation responses in PS were decreased when compared to CG at tension levels of 5 g, 15 g and 25 g (p<0.05). In DS, responses to serotonin were also decreased in tension groups. PS had higher contraction amplitudes than DS when contractile responses were obtained by high K(+) (p<0.05). Tension groups of both PS and DS showed increased contractions to high K(+) compared to CG (p<0.05). Increased esophageal tension led to increase in cholinergic responses of smooth muscles as well as in EFS-induced skeletal muscle responses. On the other hand, relaxation responses induced by serotonin decreased. These data indicate that esophageal tension increase impairs esophageal motility in both segments.


Subject(s)
Esophageal Atresia/surgery , Esophageal Motility Disorders/etiology , Esophagus/physiopathology , Muscle Contraction/physiology , Muscle, Smooth/physiopathology , Postoperative Complications/etiology , Traction/adverse effects , Animals , Esophageal Motility Disorders/physiopathology , In Vitro Techniques , Male , Postoperative Complications/physiopathology , Rats , Rats, Wistar
6.
J Pediatr Surg ; 48(9): 1954-61, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24074674

ABSTRACT

BACKGROUND/PURPOSE: The controversy in management of primary obstructed megaureter necessitates further elucidation of the underlying pathophysiology. We evaluated smooth muscle contractility, and cholinergic, adrenergic and serotonergic activity of rabbit distal ureters after ureterovesical junction (UVJ) obstruction. METHODS: Sham (SH) operation, partial obstruction (PO) and complete obstruction (CO) of the right UVJ were performed in rabbits. Three weeks later, distal ureters were isolated; spontaneous contractions (SC), contractile responses to electrical field stimulation (EFS), high KCl, carbachol, phenylephrine and serotonin were recorded. RESULTS: SC amplitudes increased in CO compared to PO and SH (p<0.001). SC frequency was higher in CO (p<0.05). EFS-induced contraction amplitudes were greater in CO than other groups (p<0.05). High KCl-induced contractions were greater in CO (p<0.001) and PO (p<0.01). Carbachol-induced contractility was enhanced in CO and PO (p<0.05). Contractile response to phenylephrine was greater in CO than other groups (p<0.05). Serotonin induced contractile responses in CO and PO, greater in CO (p<0.05). UVJ obstruction also increased spontaneous contractility in contralateral PO and CO ureters. CONCLUSIONS: UVJ obstruction increased spontaneous and neurotransmitter-induced contractions in an obstruction grade-dependent manner. Obstruction also altered contractility of the contralateral ureters. Our findings may serve to provide further understanding of the pathophysiology of megaureter.


Subject(s)
Muscle, Smooth/physiopathology , Ureteral Obstruction/physiopathology , Adrenergic Agonists/pharmacology , Adrenergic Fibers/physiology , Animals , Carbachol/pharmacology , Cholinergic Agonists/pharmacology , Cholinergic Fibers/physiology , Electric Stimulation , Female , Muscle Contraction/drug effects , Muscle Contraction/physiology , Peristalsis/drug effects , Peristalsis/physiology , Phenylephrine/pharmacology , Potassium Chloride/pharmacology , Rabbits , Random Allocation , Serotonin/pharmacology , Serotonin/physiology , Ureter/innervation
7.
Vasc Endovascular Surg ; 47(7): 540-5, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23873671

ABSTRACT

Ischemia-reperfusion (I/R) injury negatively affects the outcome of surgical interventions for amputated or severely traumatized extremities. This study aimed to evaluate the protective role of l-carnitine on the contractile properties of fast-twitch (extensor digitorum longus [EDL]) and slow-twitch (soleus [SOL]) skeletal muscles following I/R-induced injury in a rat model. Rats were divided into 4 groups (1) saline pretreatment, (2) l-carnitine pretreatment, (3) saline pretreatment and I/R, and (4) l-carnitine pretreatment and I/R. Twitch and tetanic contractions in the EDL and SOL muscles in each group were recorded. Additionally, a fatigue protocol was performed in these muscles. Twitch and tetanic contraction amplitudes were lower in the EDL and SOL muscles in which I/R was induced (P < .01). l-Carnitine pretreatment significantly increased tetanic contraction amplitude in the SOL muscles following I/R (P < .01) but not in the EDL muscles. l-Carnitine pretreatment did not alter the fatigue response in any of the muscles.


Subject(s)
Carnitine/pharmacology , Muscle Fibers, Slow-Twitch/drug effects , Muscle, Skeletal/blood supply , Muscle, Skeletal/drug effects , Reperfusion Injury/prevention & control , Animals , Cytoprotection , Disease Models, Animal , Electric Stimulation , Male , Muscle Contraction/drug effects , Muscle Fatigue/drug effects , Muscle Fibers, Fast-Twitch/drug effects , Muscle, Skeletal/physiopathology , Rats , Rats, Inbred F344 , Reperfusion Injury/physiopathology
8.
Ren Fail ; 34(2): 211-20, 2012.
Article in English | MEDLINE | ID: mdl-22229548

ABSTRACT

Rhabdomyolysis is an important cause of acute renal failure (ARF) and renal vasoconstriction is the main mechanism in the pathogenesis of ARF. Lipid peroxidation due to hydroxyl radical (.OH) formation and redox cycling of myoglobin also have a role. We investigated the disturbance in renal vascular reactivity to reveal the mechanisms leading to ARF. Female Wistar rats (n = 7) were injected with glycerol (10 mL/kg, 50% in saline) intramuscularly to induce rhabdomyolysis, and then the kidneys were isolated and perfused. We investigated acetylcholine (ACh)-induced endothelium-dependent and papaverine (PAP)-induced endothelium-independent vasodilation responses and renal nerve stimulation (RNS)-induced vasoconstrictions. These were also investigated both in rats which received either .OH scavenger, dimethylthiourea (DMTU: 500 mg/kg before glycerol injection and 125 mg/kg 8 h after glycerol injection, n = 7), or myoglobin redox cycling inhibitor, acetaminophen (ApAP: 100 mg/kg 2 h before glycerol injection and 100 mg/kg each 4 h, and 22 h after glycerol injection, n = 7). ACh-induced responses in glycerol group were decreased (p < 0.001), but PAP-induced vasodilation did not change. RNS-induced vasoconstriction in all kidneys was greater (p < 0.001) in glycerol group. DMTU restored both endothelium-dependent vasodilation and RNS-induced vasoconstriction. ApAP had no effect on vascular responses. Both DMTU and ApAP exerted a partial protective effect in renal histology without restoring serum creatinine and blood urea nitrogen (BUN) levels or creatinine clearance. This study showed that endothelial dysfunction and increased vasoconstriction developed during rhabdomyolysis. .OH plays an important role in the development of these vascular responses. These findings suggest that decreased endothelium-dependent vasodilation and augmented renal sympathetic tonus contribute to the development of renal vasoconstriction during rhabdomyolysis-induced ARF.


Subject(s)
Acute Kidney Injury/physiopathology , Endothelium, Vascular/physiopathology , Hydroxyl Radical , Kidney/innervation , Acetaminophen/pharmacology , Acute Kidney Injury/etiology , Animals , Electric Stimulation , Endothelium, Vascular/drug effects , Female , Free Radical Scavengers/pharmacology , In Vitro Techniques , Rats , Rats, Wistar , Rhabdomyolysis/complications , Thiourea/analogs & derivatives , Thiourea/pharmacology
9.
Pharmacology ; 84(4): 240-8, 2009.
Article in English | MEDLINE | ID: mdl-19776660

ABSTRACT

Congestive heart failure (CHF) is associated with exercise intolerance that cannot be entirely explained by hypoperfusion of the skeletal muscles. We studied the contractile properties of fast-twitch (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) skeletal muscles in doxorubicin-induced CHF in rats, and evaluated the defective steps of excitation-contraction coupling. Both types of muscles-obtained from CHF rats displayed significant reduction in twitch and tetanic contractions. Twitch half-relaxation times of CHF SOL muscles were prolonged while there was no significant difference in EDL muscles. High K(+) application induced lower contracture amplitudes in CHF muscles. Caffeine-induced contractures were significantly diminished in CHF SOL. Verapamil application depressed tetanic contractions in all preparations while depression was more pronounced in CHF SOL. Immunohistochemistry revealed reduced expression of sarcoplasmic reticulum Ca(2+)-ATPase-1 and -2 in CHF EDL and in CHF SOL, respectively. Sarcolemmal excitability and spontaneous neurotransmitter release were unaffected since resting membrane potential, action potential and miniature end-plate potentials were unaltered in CHF muscles. We conclude that CHF induces contractile impairment that occurs predominantly in rat slow-twitch skeletal muscles. Our results suggest that this muscle-type-specific effect of CHF is related to the defective intracellular Ca(2+) release and uptake mechanisms and reduced sarcolemmal-dihydropyridine-sensitive Ca(2+) channel activity.


Subject(s)
Heart Failure/physiopathology , Muscle Contraction/physiology , Muscle, Skeletal/physiopathology , Action Potentials/physiology , Animals , Caffeine/pharmacology , Disease Models, Animal , Doxorubicin , Heart Failure/chemically induced , Heart Failure/pathology , Male , Membrane Potentials/physiology , Miniature Postsynaptic Potentials/physiology , Muscle Contraction/drug effects , Muscle, Skeletal/drug effects , Potassium/pharmacology , Rats , Rats, Wistar , Sarcoplasmic Reticulum/metabolism , Sarcoplasmic Reticulum/physiology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Verapamil/pharmacology
10.
Indian J Pharmacol ; 41(5): 213-7, 2009 Oct.
Article in English | MEDLINE | ID: mdl-20177491

ABSTRACT

OBJECTIVES: The objective of this study was to investigate the effects of pentoxifylline (PTX), a drug that is mainly used for indications related to tissue hypoxia, on hypoxia-induced inhibition of skeletal muscle contractility and neuromuscular transmission in mice. We hypothesized that chronic PTX treatment alters skeletal muscle contractility and hypoxia-induced dysfunction. MATERIALS AND METHODS: Mice were treated with 50 mg/kg PTX or saline intraperitoneally for a week. Following ether anesthesia, diaphragm muscles were removed; isometric muscle contractions and action potentials were recorded. Time to reach neuromuscular blockade and the rate of recovery of muscle contractility were assessed during hypoxia and re-oxygenation. RESULTS: The PTX group displayed 90% greater twitch amplitudes (P < 0.01). Hypoxia depressed twitch contractions and caused neuromuscular blockade in both groups. However, neuromuscular blockade occurred earlier in PTX-treated animals (P < 0.05). Muscle contractures developed during hypoxia were more pronounced in the PTX group (P < 0.05). Re-oxygenation reduced contracture and indirect muscle contractions resumed. The rate of recovery of contractions was faster (P < 0.05) and the amplitude of contractions was greater (P < 0.01) in the PTX group. PTX treatment increased amplitude (P < 0.05) and shortened action potential (P < 0.05) without altering resting membrane potential, excitation threshold, and neurotransmitter release. CONCLUSION: Chronic PTX treatment increases diaphragm contractility, but amplifies hypoxia-induced contractile dysfunction in mice. These results may implicate important clinical consequences for clinical usage of PTX in hypoxia-related conditions.

11.
J Neurosci ; 28(40): 10151-66, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18829973

ABSTRACT

In a synapse, spontaneous and action-potential-driven neurotransmitter release is assumed to activate the same set of postsynaptic receptors. Here, we tested this assumption using (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), a well characterized use-dependent blocker of NMDA receptors. NMDA-receptor-mediated spontaneous miniature EPSCs (NMDA-mEPSCs) were substantially decreased by MK-801 within 2 min in a use-dependent manner. In contrast, MK-801 application at rest for 10 min did not significantly impair the subsequent NMDA-receptor-mediated evoked EPSCs (NMDA-eEPSCs). Brief stimulation in the presence of MK-801 significantly depressed evoked NMDA-eEPSCs but only mildly affected the spontaneous NMDA-mEPSCs detected on the same cell. Optical imaging of synaptic vesicle fusion showed that spontaneous and evoked release could occur at the same synapse albeit without correlation between their kinetics. In addition, modeling glutamate diffusion and NMDA receptor activation revealed that postsynaptic densities larger than approximately 0.2 microm(2) can accommodate two populations of NMDA receptors with nonoverlapping responsiveness. Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side.


Subject(s)
Glutamic Acid/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Animals, Newborn , Cells, Cultured , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Rats , Rats, Sprague-Dawley , Receptor Cross-Talk/drug effects , Receptor Cross-Talk/physiology , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
12.
Proc Natl Acad Sci U S A ; 105(27): 9391-6, 2008 Jul 08.
Article in English | MEDLINE | ID: mdl-18599438

ABSTRACT

Learning and memory depend on the activity-dependent structural plasticity of synapses and changes in neuronal gene expression. We show that deletion of the MEF2C transcription factor in the CNS of mice impairs hippocampal-dependent learning and memory. Unexpectedly, these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission. Conversely, neuronal expression of a superactivating form of MEF2C results in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. We conclude that MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory.


Subject(s)
Memory/physiology , Myogenic Regulatory Factors/metabolism , Synapses/metabolism , Transcription Factors/metabolism , Animals , Dendritic Spines/metabolism , Dentate Gyrus/metabolism , Dentate Gyrus/ultrastructure , Gene Deletion , Herpes Simplex Virus Protein Vmw65/metabolism , Long-Term Potentiation , MEF2 Transcription Factors , Mice , Mice, Transgenic , Mutation/genetics , Myogenic Regulatory Factors/genetics , Organ Specificity , Perforant Pathway/metabolism , Synapses/ultrastructure , Synaptic Transmission
13.
J Neurosci ; 27(2): 341-54, 2007 Jan 10.
Article in English | MEDLINE | ID: mdl-17215395

ABSTRACT

During short-term synaptic depression, neurotransmission rapidly decreases in response to repetitive action potential firing. Here, by blocking the vacuolar ATPase, alkalinizing the extracellular pH, or exposing hippocampal slices to pH buffers, we impaired neurotransmitter refilling, and electrophysiologically tested the role of vesicle reuse in synaptic depression. Under all conditions, synapses onto hippocampal CA1 pyramidal cells showed faster depression with increasing stimulation frequencies. At 20 Hz, compromising neurotransmitter refilling increased depression within 300 ms reaching completion within 2 s, suggesting a minimal contribution of reserve vesicles to neurotransmission. In contrast, at 1 Hz, depression emerged gradually and became significant within 100 s. Moreover, the depression induced by pH buffers was reversible with a similar frequency dependence, suggesting that the frequency-dependent increase in depression was caused by impairment of rapid synaptic vesicle reuse. These results indicate that synaptic vesicle trafficking impacts the kinetics of short-term synaptic plasticity at an extremely rapid time scale.


Subject(s)
Hippocampus/physiology , Long-Term Synaptic Depression/physiology , Synaptic Vesicles/physiology , Animals , Rats , Rats, Sprague-Dawley , Reaction Time/physiology , Synapses/physiology
14.
J Physiol ; 579(Pt 2): 413-29, 2007 Mar 01.
Article in English | MEDLINE | ID: mdl-17170046

ABSTRACT

Cholesterol is a prominent component of nerve terminals. To examine cholesterol's role in central neurotransmission, we treated hippocampal cultures with methyl-beta-cyclodextrin, which reversibly binds cholesterol, or mevastatin, an inhibitor of cholesterol biosynthesis, to deplete cholesterol. We also used hippocampal cultures from Niemann-Pick type C1-deficient mice defective in intracellular cholesterol trafficking. These conditions revealed an augmentation in spontaneous neurotransmission detected electrically and an increase in spontaneous vesicle endocytosis judged by horseradish peroxidase uptake after cholesterol depletion by methyl-beta-cyclodextrin. In contrast, responses evoked by action potentials and hypertonicity were severely impaired after the same treatments. The increase in spontaneous vesicle recycling and the decrease in evoked neurotransmission were reversible upon cholesterol addition. Cholesterol removal did not impact on the low level of evoked neurotransmission seen in the absence of synaptic vesicle SNARE protein synaptobrevin-2 whereas the increase in spontaneous fusion remained. These results suggest that synaptic cholesterol balances evoked and spontaneous neurotransmission by hindering spontaneous synaptic vesicle turnover and sustaining evoked exo-endocytosis.


Subject(s)
Cholesterol/physiology , Evoked Potentials/physiology , Hippocampus/physiology , Synaptic Vesicles/physiology , Animals , Cells, Cultured , Disease Models, Animal , Hippocampus/cytology , Hippocampus/drug effects , Intracellular Signaling Peptides and Proteins , Lovastatin/analogs & derivatives , Lovastatin/pharmacology , Mice , Mice, Knockout , Neuroglia/physiology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/physiopathology , Proteins/genetics , Proteins/physiology , Rats , Rats, Sprague-Dawley , Synaptic Transmission/physiology , Vesicle-Associated Membrane Protein 2/physiology , beta-Cyclodextrins/pharmacology
15.
Vascul Pharmacol ; 46(2): 129-36, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17064967

ABSTRACT

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.


Subject(s)
Arrhythmias, Cardiac/physiopathology , Endotoxemia/physiopathology , Glyburide/pharmacology , Myocardial Ischemia/physiopathology , Potassium Channel Blockers/pharmacology , Potassium Channels/metabolism , Action Potentials/drug effects , Adenosine Triphosphate/metabolism , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Blood Pressure/drug effects , Carbamates/pharmacology , Cyclohexanes/pharmacology , Disease Models, Animal , Drug Interactions , Endotoxemia/chemically induced , Endotoxemia/complications , Endotoxemia/metabolism , Heart Atria/drug effects , Heart Atria/metabolism , Heart Atria/physiopathology , Heart Conduction System/drug effects , Heart Conduction System/metabolism , Lipopolysaccharides/pharmacology , Male , Myocardial Ischemia/complications , Myocardial Ischemia/metabolism , Nateglinide , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Piperidines/pharmacology , Potassium Channels/drug effects , Rats , Rats, Sprague-Dawley , Tachycardia, Ventricular/metabolism , Tachycardia, Ventricular/physiopathology , Tetraethylammonium , Time Factors , Ventricular Fibrillation/metabolism , Ventricular Fibrillation/physiopathology , Ventricular Premature Complexes/metabolism , Ventricular Premature Complexes/physiopathology
16.
J Neurosci ; 25(47): 10922-9, 2005 Nov 23.
Article in English | MEDLINE | ID: mdl-16306405

ABSTRACT

Using electrophysiology and styryl dye imaging, we studied the effect of phorbol 12-myristate 13-acetate (PMA) on activity-dependent and spontaneous vesicle recycling. In electrophysiological experiments, we found that the PMA effect depended on the maturational state of the synapses. Spontaneous neurotransmitter release from nascent synapses without a functional readily releasable pool (RRP) was unresponsive to PMA application. In contrast, mature synapses responded robustly to PMA application, consistent with previous studies. Using styryl dye imaging, we found that there was a PMA-dependent increase in the size of the RRP when PMA was present before, during, or after activity-dependent dye uptake, suggesting that this effect involves an increase in the population of the RRP by vesicles recruited from the reserve pool. Additionally, we found that when PMA was present during spontaneous dye uptake, there was an increase in dye labeling, and these additional dye-loaded vesicles showed rapid destaining in response to strong stimulation and were also releasable by hypertonic sucrose. In contrast, these observations were not reproducible when PMA treatment was performed after spontaneous dye uptake and extracellular dye washout. Together, these findings suggest that the increased spontaneous neurotransmission in the presence of PMA was attributable to release of vesicles from the RRP rather than an effect of PMA on the spontaneously recycling pool. Thus, the phorbol esters selectively regulate the activity-dependent pool of vesicles, indicating that priming mechanisms that prepare vesicles for fusion, which are targeted by phorbol esters, are different for the spontaneous and evoked forms of fusion.


Subject(s)
Neurotransmitter Agents/metabolism , Synaptic Vesicles/drug effects , Synaptic Vesicles/physiology , Tetradecanoylphorbol Acetate/pharmacology , Animals , Cells, Cultured , Coloring Agents , Electrophysiology , Fluorescence , Hippocampus/cytology , Macrolides/pharmacology , Membrane Fusion/physiology , Neurotransmitter Agents/antagonists & inhibitors , Pyridinium Compounds , Quaternary Ammonium Compounds , Rats , Rats, Sprague-Dawley , Synaptic Vesicles/metabolism
17.
J Neurosci ; 25(36): 8209-16, 2005 Sep 07.
Article in English | MEDLINE | ID: mdl-16148228

ABSTRACT

Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+ entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.


Subject(s)
Cell Adhesion Molecules, Neuronal/physiology , Cerebral Cortex/physiology , Extracellular Matrix Proteins/physiology , Nerve Tissue Proteins/physiology , Neurons/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Serine Endopeptidases/physiology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Cerebral Cortex/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Female , Mice , Pregnancy , Rats , Rats, Sprague-Dawley , Reelin Protein , Signal Transduction/physiology , Synaptic Transmission/physiology
18.
Eur J Pharmacol ; 505(1-3): 177-86, 2004 Nov 28.
Article in English | MEDLINE | ID: mdl-15556151

ABSTRACT

We examined the contribution of nitric oxide (NO) on the contractile impairment in diaphragm muscles of endotoxemic rats. Force-frequency relationship was depressed 24 h after lipopolysaccharide administration. 7-Nitroindazole, aminoguanidine and 1H-[1,2,4]Oxadiazole (4,3-a)quinoxalin-1-one (ODQ) partially restored the contractile impairment, Nomega-Nitro-L-Arginine (L-NNA) was ineffective. K+ contractions were reduced by 50% in endotoxemic muscles, 7-nitroindazole partially recovered, while aminoguanidine and L-NNA were ineffective. Verapamil reduced contractility to a greater extent in endotoxemic muscles. Caffeine and ryanodine contractions were augmented during endotoxemia without NOS contribution. L-NNA, 7-nitroindazole, ODQ and hemoglobin did not affect, but aminoguanidine completely restored partially inhibited neurotransmission by d-tubocurarine. Endotoxemia did not change membrane potentials and neurotransmitter release but slightly increased excitability. At this stage of endotoxemia, (1) constitutive NOS appears to be the dominant isoform, (2) NO does not have a major role on contractile dysfunction and (3) impairment could be explained by altered sensitivity of the voltage sensor. (4) NO does not substantially modulate neuromuscular transmission in normal and endotoxemic rats.


Subject(s)
Endotoxemia/physiopathology , Muscle Contraction/physiology , Nitric Oxide/physiology , Animals , Caffeine/pharmacology , Diaphragm/drug effects , Diaphragm/physiopathology , Endotoxemia/chemically induced , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , In Vitro Techniques , Indazoles/pharmacology , Lipopolysaccharides/toxicity , Male , Muscle Contraction/drug effects , Neuromuscular Nondepolarizing Agents/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitroarginine/pharmacology , Oxadiazoles/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Wistar , Ryanodine/pharmacology , Tubocurarine/pharmacology , Vasodilator Agents/pharmacology , Verapamil/pharmacology
19.
J Pediatr Surg ; 38(11): 1628-32, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14614713

ABSTRACT

BACKGROUND/PURPOSE: Androgens are proposed to influence testicular descent through modulating sympathetic tone. An experimental study was undertaken to evaluate the effects of prenatal chemical sympathectomy on testicular location associated with the alterations in contractile properties of cremaster muscles in rats. METHODS: Time-mated pregnancies were started in 10 rats. Two groups, each receiving saline or 6-hydroxydopamine from day 15 to day 19 of intrauterine life were established. At 2 months of age, localization of testes were evaluated, cremaster muscles were removed, and contractile properties were studied. Twitch and tetanic contractions were recorded isometrically at 37 degrees C. Effects of verapamil, isoprenaline, and L-NNA were investigated. Results were compared through analysis of variance (ANOVA), and P values less than.05 were considered to be significant. RESULTS: Both testes of all male offspring in the control group (n = 19) were in the scrotum. Six offspring among 17 subjected to 6-hydroxydopamine had undescended testes. Treatment with 6-hydroxydopamine had no effect on force-frequency relationship of cremaster muscle strips. Cremaster muscles of rats exposed to 6-hydroxydopamine had lower sensitivity to voltage-sensitive Ca++ channel blockade by verapamil (3 x 10(4) mol/L; P <.05). These muscles displayed greater contractile response to isoprenaline (10(-5) mol/L; P <.05) but not to nitric oxide synthase inhibition by N(omega)-nitro-L-arginine. Alterations in contractile properties of the muscles did not differ according to localization of testes among rats subjected to 6-hydroxydopamine. CONCLUSIONS: Administration of 6-hydroxydopamine resulted in suprascrotally located testes. This localization has been associated with less exposure at sympathetic tonus. These findings support that sympathetic activity plays an important role in localization of testis.


Subject(s)
Cryptorchidism/chemically induced , Muscle, Smooth/drug effects , Oxidopamine/toxicity , Sympathectomy, Chemical/adverse effects , Sympatholytics/toxicity , Testis/embryology , Animals , Calcium Channel Blockers/pharmacology , Cryptorchidism/embryology , Enzyme Inhibitors/pharmacology , Female , Isoproterenol/pharmacology , Male , Muscle Contraction/drug effects , Muscle, Smooth/embryology , Nitroarginine/pharmacology , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Sympathomimetics/pharmacology , Verapamil/pharmacology
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