Injury or inflammation induces release of a range of inflammatory mediators. Bradykinin is one of the most important inflammatory mediators and plays a crucial role in mediating inflammatory pain. It is well known that multiple ion channels located in the nociceptors participate in pain sensation. Recent studies demonstrate an important role of bradykinin in regulating the function and expression of pain-related ion channels. This paper summarizes the recent advances in the understanding of the role of bradykinin in modulation of the channels and discusses future possibilities in the treatment of inflammatory pain.
Acid Sensing Ion Channels ; Animals ; Bradykinin ; pharmacology ; physiology ; Humans ; Inflammation ; complications ; Inflammation Mediators ; pharmacology ; physiology ; Ion Channels ; KCNQ Potassium Channels ; metabolism ; physiology ; Nerve Tissue Proteins ; metabolism ; Pain ; etiology ; metabolism ; physiopathology ; Receptors, AMPA ; metabolism ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Receptors, Purinergic P2X3 ; metabolism ; Sodium Channels ; metabolism ; TRPA1 Cation Channel ; TRPV Cation Channels ; metabolism ; physiology ; Transient Receptor Potential Channels ; metabolism ; physiology

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed prior to 1980 appear to act on sodium channels, gamma-amino butyric acid type A (GABA(A)) receptors or calcium channels. Benzodiazepines and barbiturates enhance GABA(A) receptormediated inhibition. Barbiturates increase the duration of chloride channel opening and at higher doses, they block voltage-dependent calcium channels presynaptically, decreasing excitatory amino acid (EAAs) transmission. Benzodiazepines also interact with the GABA(A) receptor complex and increase the frequency of chloride channel opening. Phenytoin, carbamazepine and possibly sodium valproate decrease high frequency repetitive firing of action potentials by enhancing sodium channel inactivation. At higher doses, PHT may block sodium channels presynaptically and decrease EAAs release. In addition to the action on sodium channel, CBZ interacts with adenosine receptor and decrease C-AMP, and block reuptake of norepinephrine. VPA shows diverse mechanisms including sodium channel blocking. It increases synaptosomal GABA by increasing production and decreasing break-down and interacts with T-type calcium channels preventing thalamocortical interaction necessary for absence. Ethosuximide and sodium valproate reduce a low threshold (T-type) calcium channel current. The mechanisms of action of newly developed AEDs are not fully established. Felbamate is broad-spectrum, and probably has multiple actions on sodium channels, interaction with GABA(A) receptors, and interaction with NM.D.A receptors. Gabapentin binds to a high affinity site on neuronal membranes in a restricted regional distribution of the CNS. This binding site may be related to a possible active transport process of gabapentin into neurons. However this has not proven and the mechanism of action of gabapentin remains uncertain. It is structurally related to GABA and its action of antiepileptic activity is suspected due to change of neuronal amino acids (interfere glutamate synthesis, block GABA uptake, and enhance GABA release). Lamotrigine, initially developed as an antifolate drug, decreases sustained high frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. It may also interact with GABA receptors but its primary antiepileptic action is on the sodium channel similar to the PHT and CBZ. Because of such a diverse mechanism of action, LTG is one of the wide spectrum AEDs. Oxcarbazepine's mechanism of action is not known ; however, its similarity in structure and clinical efficacy to that of carbamazepine suggests that its mechanism of action may involve inhibition of sustained high frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin is a "designer" drug as is developed rationally, and it reversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of VGB. Tiagabine is a potent blocker of GABA re-uptake by glia and neuron.
4-Aminobutyrate Transaminase ; Action Potentials ; Amino Acids ; Anticonvulsants* ; Barbiturates ; Benzodiazepines ; Binding Sites ; Biological Transport, Active ; Butyric Acid ; Calcium Channels ; Calcium Channels, T-Type ; Carbamazepine ; Chloride Channels ; Ethosuximide ; Excitatory Amino Acids ; Fires ; gamma-Aminobutyric Acid ; Glutamic Acid ; Ion Channels ; Membranes ; Neuroglia ; Neurons ; Neurotransmitter Agents ; Norepinephrine ; Phenytoin ; Receptors, GABA ; Receptors, GABA-A ; Receptors, Neurotransmitter ; Receptors, Purinergic P1 ; Sodium ; Sodium Channels ; Synapses ; Valproic Acid ; Vigabatrin

The mathematical models for simulation of cardiac sodium, potassium and calcium channel kinetics courses and currents were developed to simulate the properties of ionic currents and channel dynamic courses. With modifications of these models, it is possible to make them integrated for simulating the whole process of action potential, thus additional discussion on ionic mechanism could provide a theoretical foundation for further animal experiments and clinical applications.
Action Potentials ; Algorithms ; Calcium Channels ; physiology ; Computer Simulation ; Ion Channels ; physiology ; Membrane Potentials ; Models, Cardiovascular ; Myocytes, Cardiac ; physiology ; Potassium Channels ; physiology ; Sodium Channels ; physiology

Familial hypokalemic periodic paralysis (hypoPP) is a rare inherited channelopathy that often presents with episodic weakness accompanied by hypokalemia. Thus far, mutations in the gene encoding two ion channels (CACNL1A3, L-type calcium channel alpha-1 subunit and SCN4A, a sodium channel type IV alpha subunit) have been identified. Several cases of familial hypoPP in children have been reported in Koreans, but there are only a few cases with identified mutations. We report a 12-year-old boy and his affected mother with hypoPP who has a heterozygous G to A substitution at codon 1239 in exon 30 of the CACNL1A3 gene that causes a change from arginine to histidine (Arg1239His, CACNL1A3). This mutation is common among Caucasians; however, it has not yet been reported in Koreans. The patients were treated with oral acetazolamide and potassium replacement and were instructed to avoid precipitating factors. After the medication and lifestyle modification, the paralytic attacks significantly decreased.
Acetazolamide ; Arginine ; Calcium Channels, L-Type ; Channelopathies ; Child ; Codon ; Exons ; Histidine ; Humans ; Hypokalemia ; Hypokalemic Periodic Paralysis ; Ion Channels ; Life Style ; Mothers ; Potassium ; Precipitating Factors ; Sodium Channels

BACKGROUNDShensong Yangxin (SSYX) is one of the compound recipe of Chinese materia medica. This study was conducted to investigate the effects of SSYX on sodium current (I(Na)), L-type calcium current (I(Ca, L)), transient outward potassium current (I(to)), delayed rectifier current (I(K)), and inward rectifier potassium currents (I(K1)) in isolated ventricular myocytes.

METHODSWhole cell patch-clamp technique was used to study ion channel currents in enzymatically isolated guinea pig or rat ventricular myocytes.

RESULTSSSYX decreased peak I(Na) by (44.84 +/- 7.65)% from 27.21 +/- 5.35 to 14.88 +/- 2.75 pA/pF (n = 5, P < 0.05). The medicine significantly inhibited the I(Ca, L). At concentrations of 0.25, 0.50, and 1.00 g/100 ml, the peak I(Ca, L) was reduced by (19.22 +/- 1.10)%, (44.82 +/- 6.50)% and (50.69 +/- 5.64)%, respectively (n = 5, all P < 0.05). SSYX lifted the I - V curve of both I(Na) and I(Ca, L) without changing the threshold, peak and reversal potentials. At the concentration of 0.5%, the drug blocked the transient component of I(to) by 50.60% at membrane voltage of 60 mV and negatively shifted the inactive curve and delayed the recovery from channel inactivation. The tail current density of I(K) was decreased by (30.77 +/- 1.11)% (n = 5, P < 0.05) at membrane voltage of 50 mV after exposure to the medicine and the time-dependent activity of I(K) was also inhibited. Similar to the effect on I(K), the SSYX inhibited I(K1) by 33.10% at the test potential of -100 mV with little effect on reversal potential and the rectification property.

CONCLUSIONSThe experiments revealed that SSYX could block multiple ion channels such as I(Na) I(Ca, L), I(k), I(to) and I(K1), which may change the action potential duration and contribute to some of its antiarrhythmic effects.

Animals ; Anti-Arrhythmia Agents ; pharmacology ; Calcium Channels ; drug effects ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; Guinea Pigs ; Heart Ventricles ; Ion Channels ; drug effects ; Male ; Myocytes, Cardiac ; drug effects ; Potassium Channels ; drug effects ; Rats ; Sodium Channels ; drug effects

Mitochondrial complex inhibition has been described in the pathophysiology of many neurodegenerative diseases, and the functional changes of neuron induced by mitochondrial complex inhibition and the mechanism are concerned. Neuronal function depends on action potentials and neurotransmitter release. Voltage dependent sodium/potassium ion channels mediate generation of neuron action potentials. And voltage dependent calcium ion channels are directly involved in the process of neurotransmitter release. The functional changes of those ion channels under some pathological conditions can induce neuron dysfunction, even death. Therefore, understanding the influence of mitochondrial complex inhibition on neuronal ion channels and neurotransmitter release is helpful to illuminate the pathophysiology of neurodegenerative diseases. This review will highlight recent progress in this field.
Action Potentials ; Biological Transport ; Calcium Channels ; physiology ; Humans ; Ion Channels ; physiology ; Mitochondria ; physiology ; Neurodegenerative Diseases ; physiopathology ; Neurons ; physiology ; Neurotransmitter Agents ; physiology ; Potassium Channels ; physiology ; Sodium Channels ; physiology ; Synaptic Transmission

Management of cardiac arrhythmias involves antiarrhythmic drugs (AADs), catheter ablation, pacemakers, and implantable defibrillators. The effects of AADs are mediated by blocking various cardiac ion channels, mostly the cardiac sodium, calcium, or potassium channels. A simple classification of AADs based upon the target sites of drug action is useful for clinical application of AADs for common cardiac arrhythmias. Atrioventricular nodal blocking agents are useful for management of tachycardias with the atrioventricular node as a part of the reentrant circuit. Membrane active AADs are used for tachycardias occurring within the atrium or ventricle. Recent large randomized clinical trials have failed to show any beneficial effects of AADs for reducing cardiac mortality in patients with heart failure and at risk of sudden cardiac death or in patients with atrial fibrillation. In spite of these limitations, AAD medication remains an important initial or adjunctive therapy in the management of cardiac arrhythmias.
Anti-Arrhythmia Agents ; Arrhythmias, Cardiac ; Atrial Fibrillation ; Atrioventricular Node ; Calcium ; Catheter Ablation ; Death, Sudden, Cardiac ; Defibrillators, Implantable ; Heart Failure ; Humans ; Ion Channels ; Membranes ; Potassium Channels ; Sodium ; Tachycardia

No abstract available.
Acidosis, Respiratory* ; Ion Channels* ; N-Methylaspartate* ; Receptors, N-Methyl-D-Aspartate

PURPOSE: In order to elucidate the actual mechanism and the optimal concentration of Lamotrigine(LTG) that suppresses epileptiform discharges, we observed epileptiform discharges from hippocampal slices of immature rat in 4-aminopyridine(4-AP) added Mg2+ - free medium of artificial cerebrospinal fluid(aCSF) with various LTG concentrations. METHODS: We divided 19-23 day-old Sprague-Dawley rats into 4 groups; control group(n=12) and 3 LTG groups depending on the concentrations of LTG such as 400 (n=9), 800(n=7), and 1,000(n=8) microM. The rats were anesthetized and their brains were taken, soaked in aCSF(NaCl 125 mM, KCl 2.5 mM, NaH2PO4 2 mM, MgSO4 1.25 mM NaHCO3 25 mM, CaCl2 2 mM, Glucose 10 mM, pH 7.3-7.4). And then the brains were cut into 400 microm hippocampal slices by a vibratome. The slices of control group were soaked in 200 microM 4-AP added Mg2+ -free medium of aCSF for 1 hour, and then extracellular recordings were performed in hippocampal CA1 pyramidal region. The slices of LTG groups were soaked in the solution containing 400, 800, and 1,000 microM LTG, then extracellular recordings were performed. RESULTS: Interictal discharges were observed in all the control and the LTG groups. The latency to the first interictal discharges after 4-AP addition was 52.7+/-26.9 sec in control group, but was 225.0+/-28.2 sec in 800 microM and 322.1+/-116.4 sec in 1,000 microM group of LTG(P<0.05). The duration of interictal discharges was 64.6+/-35.6 sec in control group, but was the shortest in 800 microM group of LTG at 39.3+/-12.6 sec. Ictal discharges were observed in all of control and 400 microM group, but the frequency was decreased as the concentration of LTG increases, 57.1% in 800 microM, 12.5% in 1,000 microM group. The latency to ictal discharge after 4-AP addition was 142.1+/-52.6 sec in control group, but increased as the concentration of LTG increases, 304.4+/-84.5 sec in 400 microM group and 689.8+/-213.1 sec in 800 microM group(P<0.05). The duration of ictal discharges was 1,534.7/-339.3 sec in control group, but decreased as the concentration of LTG increases, it was 126.5+/-76.1 sec in 800 microM group(P <0.05) and 42 sec in 1,000 microM group. CONCLUSION: The antiepileptic effects of LTG were most significant when the concentration, inhibiting epileptiform discharges induced by 4-AP and Mg2+ -free medium in hippocampal slices of immature rats, was 800 microM or higher. Although the basic pharmacologic mechanism of LTG is the inhibition of sodium channel, it may also work on potassium channel at higher concentrations.
4-Aminopyridine* ; Animals ; Brain ; Glucose ; Hydrogen-Ion Concentration ; Potassium Channels ; Rats* ; Rats, Sprague-Dawley ; Sodium Channels

AIM AND METHODSWhole-cell recording technique was used to observe the changes of voltage-dependent ion channels and NMDA receptor currents of rat hippocampal neurons during primary culture.

RESULTSThere was no significant difference of voltage-dependent Na+ current (I(Na)) at 7 d, 14 d and 21 d in culture. It's the same for delayed rectifier K+ current (Ik). However, voltage-dependent Ca2+ current (I(Ca)) and its density were continuously and markedly increased. Further studies showed that the increase of I(Ca) was resulted from the increase of L-type voltage-dependent Ca2+ channels (L-VDCC). NMDA receptor current was also significantly increased with time of culture.

CONCLUSIONCa2+ influx through VDCC and NMIDA receptor is the fatal factor in the aging and death of hippocampal neurons.

Animals ; Animals, Newborn ; Calcium ; metabolism ; Calcium Channels, L-Type ; metabolism ; Cell Membrane ; metabolism ; Cells, Cultured ; Cellular Senescence ; Hippocampus ; cytology ; Ion Channels ; metabolism ; Neurons ; metabolism ; Patch-Clamp Techniques ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Time Factors