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Channel Blockers (channel + blocker)
Kinds of Channel Blockers Terms modified by Channel Blockers Selected AbstractsEFFECT OF COMBINATION THERAPY (ANG II ANTAGONIST, VALSARTAN AND A CALCIUM CHANNEL BLOCKER) IN A HYPERTENSIVE MODEL OF DIABETIC NEPHROPATHYNEPHROLOGY, Issue 3 2000Allen Tj Davis Bj [source] N-type Calcium Channel Blocker for Pain TreatmentPAIN MEDICINE, Issue 2 2010Jianren Mao MD No abstract is available for this article. [source] KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic PropertiesCARDIOVASCULAR THERAPEUTICS, Issue 1 2004Gareth W. John ABSTRACT KC 12291 was designed as a voltage-gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non-inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+ loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+ current. In isolated atria and Langendorff-perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+ loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activity in vivo in the absence of major hemodynamic effects. Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+ current, represent, therefore, promising potential antiischemic and cardioprotective drugs. [source] Pharmacologic and Therapeutic Considerations in Hypertension Therapy With Calcium Channel Blockers: Focus on VerapamilJOURNAL OF CLINICAL HYPERTENSION, Issue 2 2007Domenic A. Sica MD In the past 2 decades, calcium channel blockers have emerged as important and useful agents for treating hypertension. The safety of this drug class has been vigorously debated for some time, and it has only been in the past few years that such debate has been quieted by favorable outcomes data with these compounds. Calcium channel blockers are a heterogeneous group of compounds as alike as they are dissimilar. Calcium channel blockers can be separated into dihydropyridine and nondihydropyridine subclasses, with representatives of the latter being verapamil and diltiazem. A lengthy treatment experience exists for verapamil, a compound that has progressed from an immediate-release to a sustained-release and, more recently, a delayed/sustained-release formulation designated for administration at bedtime. This latter formulation synchronizes drug delivery with the early morning rise in blood pressure, which is a particularly attractive feature when viewed in the context of the distinctive pharmacokinetic and pharmacodynamic features of verapamil. [source] Pharmacotherapy Review: Calcium Channel BlockersJOURNAL OF CLINICAL HYPERTENSION, Issue 1 2006Domenic A. Sica MD As a drug class, calcium channel blockers encompass a heterogeneous group of compounds with distinctive structures and pharmacologic characteristics. These agents are widely used in the treatment of hypertension, chronic coronary ischemia, and/or supraventricular arrhythmias. Much of the early debate alluding to increased cardiovascular risk associated with calcium channel blocker use has been silenced by an array of outcomes trials that show these drugs to be both safe and effective in reducing hard cardiovascular end points. The most common side effects associated with calcium channel blockers are vasodilatory in nature and include a non-volume-dependent form of peripheral edema, flushing, and headache. Despite the sometimes discomforting side effects seen with calcium channel blocker therapy, their robust blood pressure-lowering effect makes them an important component of most multidrug regimens used for blood pressure control. [source] Topical Application of Calcium Channel Blockers to Reduce the Progression of Experimentally Induced Myringosclerosis and TympanosclerosisTHE LARYNGOSCOPE, Issue 4 2008Adin Selcuk MD Abstract Objectives: This study aimed to evaluate the ability of topically applied calcium channel blockers (diltiazem) to reduce the progression of experimentally induced myringosclerosis and tympanosclerosis. Study Design: Animal model. Experimental prospective study. Methods: The study included 25 adult albino guinea pigs that were bilaterally myringotomized and inoculated with a suspension of Streptococcus pneumonia type 3. The right ears were treated with topical application of diltiazem, and the untreated left ears served as the control group. Otomicroscopy and remyringotomy were conducted every week. One animal was sacrificed after 1 week and the remaining at the end of 6 weeks. Temporal bones were dissected, and tympanic bullae were analyzed with light microscopy. Results: The untreated control ears showed evidence of extensive myringosclerosis on otomicroscopy, and the ears treated with calcium channel blockers did as well although to a lesser degree. Under light microscopy, the lamina propria of both tympanic membranes and middle ear mucosae of the control group exhibited thicker (P < .1 and P < .05, respectively) and larger (P < .01 and P < .01, respectively) sclerotic tissue in comparison with the treatment group. Conclusion: The results suggest that calcium channel blockers had an influence in the prevention of tympanosclerosis. [source] Sodium Channel Blockers Enhance the Temporal QT Interval Variability in the Right Precordial Leads in Brugada SyndromeANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 1 2008Tetsuzou Kanemori M.D. Background: Temporal QT interval variability is associated with sudden cardiac death. The purpose of this study was to evaluate temporal QT interval variability in Brugada syndrome (BS). Methods: We measured QT and RR intervals in precordial leads (V1,V6) based on 12-beat resting ECG recordings from 16 BS patients (B group) with spontaneous ST elevation in right precordial leads (V1,V2) and from 10 patients with normal hearts (C group). We measured the response in B group before and after administration of pilsicainide (1 mg/kg). The standard deviation (QT-SD, RR-SD) of the time domain and total frequency power (QT-TP, RR-TP) were calculated for all precordial leads, and the latter was to analyze the frequency domain. Results: The right precordial leads in BS exhibited an additional and prominent ST elevation (coved-type) after pilsicainide administration. Both QT-SD and QT-TP values were significantly more increased in B, than in C (5.1 ± 1.2 vs 3.6 ± 0.2 and 23.4 ± 2.9 vs 12.3 ± 1.7 msec2, P < 0.01, respectively) and after pilsicainide administration in B. (5.1 ± 0.4 vs 3.9 ± 0.3, 25.8 ± 3.4 vs 16.3 ± 2.6 msec2, P < 0.01, respectively) However, QT-SD and QT-TP did not significantly change in any of other leads (V3,V6) and RR-SD and RR-TP were similar for both groups, as well as after intravenous pilsicainide administration in B. Conclusions: The temporal QT interval variability was identified in BS. Moreover, sodium channel blocker induced temporal fluctuation in QT interval and it may possibly provide a substrate for ventricular arrhythmia in BS patients. [source] ChemInform Abstract: Chlorahololides C,F: A New Class of Potent and Selective Potassium Channel Blockers from Chloranthus holostegius.CHEMINFORM, Issue 37 2008Sheng-Ping Yang Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] 4-Phenyl-4H-pyrans as IKCa Channel Blockers.CHEMINFORM, Issue 50 2003Klaus Urbahns Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Synthesis and Biological Evaluation of New 4-Arylpiperidines and 4-Aryl-4-piperidinols: Dual Na+ and Ca2+ Channel Blockers with Reduced Affinity for Dopamine D2 Receptors.CHEMINFORM, Issue 15 2002Hirokazu Annoura Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Structurally Minimized ,-Conotoxin Analogues as Sodium Channel Blockers: Implications for Designing Conopeptide-Based TherapeuticsCHEMMEDCHEM, Issue 3 2009Tiffany Abstract Transforming the neuroactive toxins of cone snails into small-size compounds poses a challenge due to the presence of multiple disulfide bridges. Herein we describe our successful efforts in minimizing the size of ,-conotoxin while retaining its biological activity. Disulfide bridges that stabilize the native conformation of conotoxins pose a challenge in the synthesis of smaller conotoxin analogues. Herein we describe the synthesis of a minimized analogue of the analgesic ,-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal NaV1.2 and skeletal muscle NaV1.4. Three disulfide-deficient analogues of KIIIA were initially synthesized in which the native disulfide bridge formed between either C1C9, C2C15, or C4C16 was removed. Deletion of the first bridge only slightly affected the peptide's bioactivity. To further minimize this analogue, the N-terminal residue was removed and two nonessential serine residues were replaced by a single 5-amino-3-oxapentanoic acid residue. The resulting "polytide" analogue retained the ability to block sodium channels and to produce analgesia. Until now, the peptidomimetic approach applied to conotoxins has progressed only modestly at best; thus, the disulfide-deficient analogues containing backbone spacers provide an alternative advance toward the development of conopeptide-based therapeutics. [source] Old Molecules for New Receptors: Trp(Nps) Dipeptide Derivatives as Vanilloid TRPV1 Channel BlockersCHEMMEDCHEM, Issue 4 2006Angeles Bonache Dr. Abstract The transient receptor potential vanilloid member 1 (TRPV1), an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptides, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel blockers. We also report the synthesis and biological investigation of a series of new conformationally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/NMDA selectivity. Compound 15,b, which incorporates an N-terminal 2S -azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/toxicity balance. [source] B2 kinin receptors mediate the Indian red scorpion venom-induced augmentation of visceral reflexes via the nitric oxide cyclic guanosine monophosphate pathwayACTA PHYSIOLOGICA, Issue 4 2009S. Kanoo Abstract Aim:, This study was performed to delineate the kinin (receptor)-dependent pathways in the Indian red scorpion (Mesobuthus tamulus; MBT) venom-induced pulmonary oedema as well as the augmentation of cardio-pulmonary reflexes evoked by phenyldiguanide (PDG). Methods:, In urethane-anaesthetized adult rats, the effect of venom on the PDG reflex responses (blood pressure, heart rate and respiration rate) and the pulmonary water content was ascertained using various antagonists(des- Arg, B1 receptor antagonist; Hoe 140, B2 receptor antagonist; N, -nitro- l -arginine methyl ester (l -NAME), nitric oxide (NO) synthase inhibitor; methylene blue, soluble guanylate cyclase inhibitor; and glibenclamide, K+ATP channel blocker). The effect of phosphodiesterase V inhibitor (sildenafil citrate) on the reflex response and the pulmonary water content was also examined and compared with venom-induced responses. Results:, Intravenous injection of PDG (10 ,g kg,1) evoked apnoea, bradycardia and hypotension lasting >60 s. Exposure to MBT venom (100 ,g kg,1) for 30 min augmented the PDG reflex responses by two times and increased the pulmonary water content, significantly. Hoe 140 blocked the venom-induced responses (augmentation of PDG reflex and increased pulmonary water content) whereas des-Arg did not. l -NAME, methylene blue or glibenclamide also blocked the venom-induced responses. Furthermore, sildenafil citrate (that increases cGMP levels) produced augmentation of PDG reflex response and increased the pulmonary water content as seen with venom. Conclusion:, The results indicate that venom-induced responses involve B2 kinin receptors via the NO-dependent guanylate cyclase-cGMP pathway involving K+ATP channels. [source] Gadolinium, a mechano-sensitive channel blocker, inhibits osmosis-initiated motility of sea- and freshwater fish sperm, but does not affect human or ascidian sperm motilityCYTOSKELETON, Issue 4 2003Zoltán Krasznai Abstract Exposure to hypo-osmotic or hyperosmotic environment triggers the initiation of fish sperm motility. In this article, we report that calcium and potassium channel blockers do not influence motility of puffer fish sperm but calmodulin antagonists reversibly decrease it, suggesting that calmodulin,Ca2+ interactions are prerequisite for the initiation of sperm motility in this species. Gadolinium (a stretch activated ion channel blocker) decreased the motility of puffer fish sperm from 92 ± 3% to 6 ± 3% and that of carp sperm from 91 ± 7% to 3.5 ± 4.3% in a dose-dependent manner (10,40 ,M). The effect of gadolinium was reversible, suggesting that stretch activated ion channels participate in the initiation of sperm motility of the two species. Gadolinium inhibits changes in the isoelectric point of certain proteins of puffer fish sperm, which occur when sperm motility is initiated in a hypertonic solution. Anisotropy measurements showed that hypo-osmotic treatment, which initiates carp sperm motility, increased membrane fluidity. When hypo-osmotic treatment was given in the presence of gadolinium, the sperm membrane remained as rigid as in quiescent cells, while motility was blocked. By contrast, gadolinium did not influence the motility parameters of Ciona or human sperm. Based on these lines of evidence, we suggest that conformational changes of mechanosensitive membrane proteins are involved in osmolality-dependent but not osmolality-independent sperm. Cell Motil. Cytoskeleton 55:232,243, 2003. © 2003 Wiley-Liss, Inc. [source] Gap junctional coupling between progenitor cells at the retinal margin of adult goldfishDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2001Fuminobu Tamalu Abstract We prepared living slice preparations of the peripheral retina of adult goldfish to examine electrical membrane properties of progenitor cells at the retinal margin. Cells were voltage-clamped near resting potential and then stepped to either hyperpolarizing or depolarizing test potentials using whole-cell voltage-clamp recordings. Electrophysiologically examined cells were morphologically identified by injecting both Lucifer Yellow (LY) and biocytin. All progenitor cells examined (n = 37) showed a large amount of passively flowing currents of either sign under suppression of the nonjunctional currents flowing through K+ and Ca2+ channels in the cell membrane. They did not exhibit any voltage-gated Na+ currents. Cells identified by LY fills were typically slender. As the difference between the test potential and the resting potential increased, 13 out of 37 cells exhibited symmetrically voltage- and time-dependent current decline on either sign at the resting potential. The symmetric current profile suggests that the current may be driven and modulated by the junctional potential difference between the clamping cell and its neighbors. The remaining 24 cells did not exhibit voltage dependency. A gap junction channel blocker, halothane, suppressed the currents. A decrease in extracellular pH reduced coupling currents and its increase enhanced them. Dopamine, cAMP, and retinoic acid did not influence coupling currents. Injection of biocytin into single progenitor cells revealed strong tracer coupling, which was restricted in the marginal region. Immature ganglion cells closely located to the retinal margin exhibited voltage-gated Na+ currents. They did not reveal apparent tracer coupling. These results demonstrate that the marginal progenitor cells couple with each other via gap junctions, and communicate biochemical molecules, which may subserve or interfere with cellular differentiation. © 2001 John Wiley & Sons, Inc. J Neurobiol 48: 204,214, 2001 [source] Treatment of diabetic hypertensionDIABETES OBESITY & METABOLISM, Issue 5 2009David S. H. Bell Insulin resistance and hyperglycaemia combine to make hypertension more prevalent in the type 2 diabetic patient. Blood pressure goals below those for the non-diabetic subject have been shown to be more effective in lowering mortality and cardiovascular events in the diabetic patient. To achieve these goals in most cases, three to five antihypertensives from different therapeutic groups need to be utilized. Suppression of the renin,angiotensin system (RAS) with angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers or a renin inhibitor should be the primary therapy. A second goal should be suppression of the sympathetic nervous system utilizing a beta-blocker that does not increase insulin resistance. The addition of a diuretic, calcium channel blocker or a vasodilator to suppressors of the RAS and sympathetic nervous system aid in achieving hypertensive goals in the diabetic patient. Achieving hypertensive goals with suppression of the RAS and sympathetic nervous system should result in a decrease in mortality and cardiovascular events in the diabetic hypertensive patient. In this review article, the benefits and disadvantages of the different antihypertensive therapies in the diabetic patient are discussed. [source] Effects of sulfonylureas on mitochondrial ATP-sensitive K+ channels in cardiac myocytes: implications for sulfonylurea controversyDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2006Toshiaki Sato Abstract Background Mitochondrial ATP-sensitive K+ (mitoKATP) channel plays a key role in cardioprotection. Hence, a sulfonylurea that does not block mitoKATP channels would be desirable to avoid damage to the heart. Accordingly, we examined the effects of sulfonylureas on the mitoKATP channel and mitochondrial Ca2+ overload. Methods Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoKATP channel activity. The mitochondrial Ca2+ concentration was measured by loading cells with rhod-2. Results The mitoKATP channel opener diazoxide (100 µM) reversibly increased flavoprotein oxidation to 31.8 ± 4.3% (n = 5) of the maximum value induced by 2,4-dinitrophenol. Glimepiride (10 µM) alone did not oxidize the flavoprotein, and the oxidative effect of diazoxide was unaffected by glimepiride (35.4 ± 3.2%, n = 5). Similarly, the diazoxide-induced flavoprotein oxidation was unaffected both by gliclazide (10 µM) and by tolbutamide (100 µM). Exposure to ouabain (1 mM) for 30 min produced mitochondrial Ca2+ overload, and the intensity of rhod-2 fluorescence increased to 197.4 ± 7.2% of baseline (n = 11). Treatment with diazoxide significantly reduced the ouabain-induced mitochondrial Ca2+ overload (149.6 ± 5.1%, n = 11, p < 0.05 versus ouabain alone), and the effect was antagonized by the mitoKATP channel blocker 5-hydroxydecanoate (189.8 ± 27.8%, n = 5) and glibenclamide (193.1 ± 7.7%, n = 8). On the contrary, cardioprotective effect of diazoxide was not abolished by glimepiride (141.8 ± 7.8%, n = 6), gliclazide (139.0 ± 9.4%, n = 5), and tolbutamide (141.1 ± 4.5%, n = 7). Conclusions Our results indicate that glimepiride, gliclazide, and tolbutamide have no effect on mitoKATP channel, and do not abolish the cardioprotective effects of diazoxide. Therefore, these sulfonylureas, unlike glibenclamide, do not interfere with the cellular pathways that confer cardioprotection. Copyright © 2006 John Wiley & Sons, Ltd. [source] CPU-86017 improves the compromised blood,brain barrier permeability mediated by impaired endothelial no system and oxidative stress caused by L -thyroxineDRUG DEVELOPMENT RESEARCH, Issue 3 2005Rong-Hui Du Abstract Impaired endothelial cell (EC) function leads to alterations in the permeability of the blood,brain barrier (BBB). There are two aspects of the transport through the BBB: from the blood to the brain (influx) and from the brain to the blood (efflux). An impaired EC model induced by L -thyroxine that compromises the influx and efflux properties of the BBB was used to assess responses to the intervention of CPU-86017 (an antioxidant and calcium channel blocker) and propranolol. CPU-86017 (t1/2=1.5 h) was also used as a target drug, leaving no traces in the brain and blood 24 h after administration. The permeability of the BBB was evaluated by using CPU-86017 after iv and icv injection and concentrations in the blood and brain being measured by high-performance liquid chromatography. The bidirectional permeability of CPU-86017 was impaired and associated with a reduced NO bioavailability assessed functionally by the vasoactivity in the model. Partial relief of NO bioavailability and oxidative stress induced by propranolol was consistent with a recovery of BBB efflux alone. Complete recovery in the efflux and influx of the BBB by CPU-86017 was a result of the complete restoration of NO bioavailability and reduction in oxidative stress. Normal BBB influx is dependent on an intact endothelial NO system, and efflux could be restored easily by partial improvement of NO bioavailability. CPU-86017 is thus more effective than propranolol in protecting the endothelium from damage produced by L -thyroxine through oxidative stress. Drug Dev. Res. 64:145,156, 2005. © 2005 Wiley-Liss, Inc. [source] Xanthine-analog, KMUP-2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erectionDRUG DEVELOPMENT RESEARCH, Issue 3 2002Rong-Jyh Lin Abstract The pharmacological properties of KMUP-2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP-2 caused relaxations that were attenuated by removed endothelium, high K+, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 ,M) and ODQ (1 ,M), a NOS inhibitor, L-NAME (100 ,M), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 ,M), a voltage-dependent K+ channel blocker 4-AP (100 ,M), and the Ca2+ -dependent K+ channel blockers apamin (1 ,M) and charybdotoxin (ChTX, 0.1 ,M). The relaxant responses of KMUP-2 (0.01, 0.05, 0.1 ,M) together with a PDE inhibitor, IBMX (0.5 ,M), had additive effects on rabbit aorta and CCSM. Additionally, KMUP-2 (100 ,M) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP-2 (0.1,100 ,M) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 ,M) and ODQ (10 ,M). Obviously, the relaxant effects of KMUP-2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP-2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K+ channels in rabbit aorta and CCSM. KMUP-2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP-1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. It is concluded that both the increases of cGMP and the opening activity of K+ channels play prominent roles in KMUP-2-induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162,172, 2002. © 2002 Wiley-Liss, Inc. [source] Behavioral effects of ivermectin in a freshwater oligochaete, Lumbriculus variegatusENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2001Jing Ding Abstract Ivermectin is a potent antiparasitic drug against nematode and arthropod parasites. In this study, we examined the lethal and sublethal effects of ivermectin in a freshwater oligochaete, Lumbriculus variegatus. The median lethal concentration (LC50) at 72 h after ivermectin exposure was 560 nM. Sublethal endpoints focused on several stimulus-evoked locomotor behaviors: escape reflexes controlled by giant interneuron pathways, swimming and reversal, and crawling. Swimming, reversal, and crawling are controlled by nongiant interneuron pathways. Ivermectin inhibited swimming, reversal, crawling frequency, and crawling speed in a time- and concentration-dependent manner with a mean inhibitory concentration (IC50) at 3 h of 1.1, 16, 91, and 51nM, respectively. Ivermectin at 0.3 nM also significantly decreased the frequency of helical swimming waves. Picrotoxin, a Cl, channel blocker, antagonized the ivermectin-induced decrease in swimming frequency, crawling frequency, and crawling speed. There were no adverse effects on escape reflex 3 h after exposure to 300 nM ivermectin. Electrophysiological recordings showed that ivermectin had no effects on the conduction velocity of giant fiber systems. The results indicated that locomotor behaviors controlled by nongiant locomotor pathways were more sensitive to ivermectin than pathways controlled by giant interneurons and that Cl, channels may be involved in mediating ivermectin's inhibitory effects. [source] Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence ReviewedEPILEPSIA, Issue 11 2000Charles L. P. Deckers Summary: Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy. [source] Abnormal Excitability of Hippocampal CA3 Neurons in Noda Epileptic Rat (NER): Alteration of Seizure with AgingEPILEPSIA, Issue 2000Ryosuke Hanaya Purpose: Noda epileptic rat (NER), a mutant found in thc colony of Crj:Wistar rats, spontaneously shows tonic-clonic convulsions approximately once every 30 hours from 8,16 weeks of age. A long-lasting dcpolarization shift accompanied by repetitivc firings are observed in hippocampal CA3 pyramidal neurons of NER with seizures. Using hippocampal slice preparations of NER, the present electrophysiologi- cal study was performed to elucidate whether this abnormal firing in CA3 neurons developed with age and if abnormality of Ca2+ channel was involved. Methods: Hippocampal slices (40Opm) werc prepared from NER and normal Wistar rats (age; 4,29 weeks). A single rectangular pulse stimulus composed of 0.1-ms duration was delivered to the mossy fibers every 5 seconds though a bipolar electrode placed in the granular cell layer of the dentate gyrus. Intracellular recording was made from the CA3 pyramidal cell using a microelectrode containing 3M KCI intracellular recordings. A Ca2+ spike was elicited by applying a depolarizing pulse (InA, 120ms) in the cell through the recording electrode under a blockadc of Na+ and K+ channels using 1 pM tetrodotoxin and I 0mM tctraethylammonium added to the artificial CSF, respectivcly. Nicardipine (I-IOOnM), a Ca2+ channel blocker, was applicd to the bath. Results: Thirty-seven slices from I9 NER and 6 slices from 4 normal Wishe rats were used. There were no obvious changes in the resting membrane potentials of CA3 neurons between NER and Wistar rats tested. When a single stimulus was delivered to the mossy fibers, a long-lasting depolarization shift accompanied by repetitive firings followed by after-hyperpolarization werc also obtained i n hippocampal CA3 neurons of young NER (4,5 weeks of age) before occurrence of any seizurcs, although the depolarization shift in younger NER was shorter than that in NER aged more than 6 weeks. These abnormal firings werc evokcd in 58% and 30% of all CA3 neurons tested in the younger and mature NER (6,1 5 weeks of age), respectively. Furthermore, abnormal firing was not elicited in NER aged after I6 weeks. Agc-matched Wistar rats showed only single action potentials without any depolarization shift with single mossy fiber stimulation. Bath application of nicardipine (IOnM) inhibited this long-lasting depolarization shift and the accompanying repetitive firing followed by afterhypcrpolarization without affecting the first spike induced by mossy fiber stimulations. Furthermore, nicai-dipine (IOnM) inhibited the Ca2+ spikes elicited by applying a depolarizing pulse in the neurons of NER with seizures, although a higher dose (100nM) did not affect those in Wistar rats. Conclusions: These findings indicate that abnormal excitability of the NER CA3 pyramidal neurons is probably due to abnormality in the Ca2+ channcls. The abnorinal excitability was observed in NER at an age when tonic-clonic convulsions were not detected, suggesting that thc hippocampus may probably scrve as an epileptogenic focus in younger NER and the seizure impulses originating i n this area are transinittcd to the new other seizurc foci in mature NER. [source] Amiodarone Attenuates Fluoride-induced Hyperkalemia in VitroACADEMIC EMERGENCY MEDICINE, Issue 2 2003Mark Su MD Abstract Poisoning by hydrofluoric acid or fluoride salts results in hypocalcemia, hypomagnesemia, and hyperkalemia with subsequent cardiac dysrhythmias. In previous studies, quinidine attenuated fluoride-induced hyperkalemia in vitro, and enhanced survival in animals. Like quinidine, amiodarone is a potassium channel blocker, although amiodarone is more familiar to clinicians due to its recent inclusion in advanced cardiac life support (ACLS) protocols. Objectives: This in-vitro study of human erythrocytes was designed to determine whether amiodarone could attenuate fluoride-induced hyperkalemia. Methods: Six healthy volunteers each donated 60 mL of blood on three occasions. Each specimen was divided into 12 tubes, incubated at 37°C, and oxygenated with room air. An aqueous sodium fluoride (F,) solution was added to tubes 1,9. Incremental amounts of quinidine were added to tubes 1,4 (Q1,Q4) to attain calculated concentrations of 0.73 ,g/mL, 1.45 ,g/mL, 2.9 ,g/mL, and 5.8 ,g/mL, respectively. Incremental amounts of amiodarone were added to tubes 5,8 (A1,A4) to attain calculated concentrations of 0.38 ,g/mL, 0.75 ,g/mL, 1.5 ,g/mL, and 3.0 ,g/mL, respectively. Tubes 9,12 were controls for each of F,, amiodarone, quinidine alone, and no additive, respectively. Extracellular potassium concentration ([K+]) was followed, and an objective endpoint was defined as the rise in potassium concentration at 6 hours. Results: Fluoride produced a significant change in [K+] by 6 hours in all samples. Quinidine produced a J-shaped curve in its ability to attenuate the rise in [K+], with only one concentration, Q3, demonstrating significance versus tube 9 (control). Amiodarone also demonstrated a J-shaped dose,response effect, with statistical significance at A1, A2, and A3 versus tube 9 (control). There was no significant difference among the effective concentrations (Q3, A1, A2, and A3) of both drugs. Conclusions: In this in-vitro model using human blood, amiodarone and quinidine both attenuated F, -induced hyperkalemia. Further study is indicated to determine whether amiodarone enhances survival in F, -poisoned animals. [source] Excitatory actions of substance P in the rat lateral posterior nucleusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2010Kush Paul Abstract The lateral posterior nucleus (LP) receives inputs from both neocortex and superior colliculus (SC), and is involved with integration and processing of higher-level visual information. Relay neurons in LP contain tachykinin receptors and are innervated by substance P (SP)-containing SC neurons and by layer V neurons of the visual cortex. In this study, we investigated the actions of SP on LP relay neurons using whole-cell recording techniques. SP produced a graded depolarizing response in LP neurons along the rostro-caudal extent of the lateral subdivision of LP nuclei (LPl), with a significantly larger response in rostral LPl neurons compared with caudal LPl neurons. In rostral LPl, SP (5,2000 nm) depolarized nearly all relay neurons tested (> 98%) in a concentration-dependent manner. Voltage-clamp experiments revealed that SP produced an inward current associated with a decreased conductance. The inward current was mediated primarily by neurokinin receptor (NK)1 tachykinin receptors, although significantly smaller inward currents were produced by specific NK2 and NK3 receptor agonists. The selective NK1 receptor antagonist RP67580 attenuated the SP-mediated response by 71.5% and was significantly larger than the attenuation of the SP response obtained by NK2 and NK3 receptor antagonists, GR159897 and SB222200, respectively. The SP-mediated response showed voltage characteristics consistent with a K+ conductance, and was attenuated by Cs+, a K+ channel blocker. Our data suggest that SP may modulate visual information that is being processed and integrated in the LPl with inputs from collicular sources. [source] Acute action of rotenone on nigral dopaminergic neurons , involvement of reactive oxygen species and disruption of Ca2+ homeostasisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2009Peter S. Freestone Abstract Rotenone is a toxin used to generate animal models of Parkinson's disease; however, the mechanisms of toxicity in substantia nigra pars compacta (SNc) neurons have not been well characterized. We have investigated rotenone (0.05,1 ,m) effects on SNc neurons in acute rat midbrain slices, using whole-cell patch-clamp recording combined with microfluorometry. Rotenone evoked a tolbutamide-sensitive outward current (94 ± 15 pA) associated with increases in intracellular [Ca2+] ([Ca2+]i) (73.8 ± 7.7 nm) and intracellular [Na+] (3.1 ± 0.6 mm) (all with 1 ,m). The outward current was not affected by a high ATP level (10 mm) in the patch pipette but was decreased by Trolox. The [Ca2+]i rise was abolished by removing extracellular Ca2+, and attenuated by Trolox and a transient receptor potential M2 (TRPM2) channel blocker, N -(p -amylcinnamoyl) anthranilic acid. Other effects included mitochondrial depolarization (rhodamine-123) and increased mitochondrial reactive oxygen species (ROS) production (MitoSox), which was also abolished by Trolox. A low concentration of rotenone (5 nm) that, by itself, did not evoke a [Ca2+]i rise resulted in a large (46.6 ± 25.3 nm) Ca2+ response when baseline [Ca2+]i was increased by a ,priming' protocol that activated voltage-gated Ca2+ channels. There was also a positive correlation between ,naturally' occurring variations in baseline [Ca2+]i and the rotenone-induced [Ca2+]i rise. This correlation was not seen in non-dopaminergic neurons of the substantia nigra pars reticulata (SNr). Our results show that mitochondrial ROS production is a key element in the effect of rotenone on ATP-gated K+ channels and TRPM2-like channels in SNc neurons, and demonstrate, in these neurons (but not in the SNr), a large potentiation of rotenone-induced [Ca2+]i rise by a small increase in baseline [Ca2+]i. [source] L-type calcium channels are involved in fast endocytosis at the mouse neuromuscular junctionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2008Paula P. Perissinotti Abstract We used fluorescence microscopy of FM dyes-labeled synaptic vesicles and electrophysiological recordings to examine the functional characteristics of vesicle recycling and study how different types of voltage-dependent Ca2+ channels (VDCCs) regulate the coupling of exocytosis and endocytosis at mouse neuromuscular junction. Our results demonstrate the presence of at least two different pools of recycling vesicles: a high-probability release pool (i.e. a fast destaining vesicle pool), which is preferentially loaded during the first 5 s (250 action potentials) at 50 Hz; and a low-probability release pool (i.e. a slow destaining vesicle pool), which is loaded during prolonged stimulation and keeps on refilling after end of stimulation. Our results suggest that a fast recycling pool mediates neurotransmitter release when vesicle use is minimal (i.e. during brief high-frequency stimulation), while vesicle mobilization from a reserve pool is the prevailing mechanism when the level of synaptic activity increases. We observed that specific N- and L -type VDCC blockers had no effect on evoked transmitter release upon low-frequency stimulation (5 Hz). However, at high-frequency stimulation (50 Hz), L -type Ca2+ channel blocker increased FM2-10 destaining and at the same time diminished quantal release. Furthermore, when L -type channels were blocked, FM2-10 loading during stimulation was diminished, while the amount of endocytosis after stimulation was increased. Our experiments suggest that L -type VDCCs promote endocytosis of synaptic vesicles, directing the newly formed vesicles to a high-probability release pool where they compete against unused vesicles. [source] Mechanisms of ATP action on motor nerve terminals at the frog neuromuscular junctionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2005S. Grishin Abstract We have shown previously that ATP inhibits transmitter release at the neuromuscular junction through the action on metabotropic P2Y receptors coupled to specific second messenger cascades. In the present study we recorded K+ or Ca2+ currents in motor nerve endings or blocked K+ or Ca2+ channels in order to explore the nature of downstream presynaptic effectors. Endplate currents were presynaptically depressed by ATP. Blockers of Ca2+ -activated K+ -channels, such as iberiotoxin, apamin or tetraethylammonium, did not change the depressant action of ATP. By contrast, K+ channel blocker 4-aminopyridine (4-AP) and raised extracellular Ca2+ attenuated the effect of ATP. However, these effects of 4-AP and high Ca2+ were reversed by Mg2+, suggesting Ca2+ -dependence of the ATP action. Ba2+ promoted the depressant action of ATP as did glibenclamide, a blocker of ATP-sensitive K+ channels, or mild depolarization produced by 7.5 mm K+. None of the K+ channel blockers affected the depressant action of adenosine. Focal recording revealed that neither ATP nor adenosine affected the fast K+ currents of the motor nerve endings. However, unlike adenosine, ATP or UTP, an agonist of P2Y receptors, reversibly reduced the presynaptic Ca2+ -current. This effect was abolished by suramin, an antagonist of P2 receptors. Depressant effect of ATP on the endplate and Ca2+ -currents was mimicked by arachidonate, which precluded the action of ATP. ATP reduced acetylcholine release triggered by ionomycin or sucrose, suggesting inhibition of release machinery. Thus, the presynaptic depressant action of ATP is mediated by inhibition of Ca2+ channels and by mechanism acting downstream of Ca2+ entry. [source] Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine toleranceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2004Kazuaki Yokoyama Abstract Morphine is the drug of choice to treat intractable pain, although prolonged administration often causes undesirable side-effects including analgesic tolerance. It is speculated that voltage-dependent Ca2+ channels (VDCCs) play a key role in morphine analgesia and tolerance. To examine the subtype specificity of VDCCs in these processes, we analysed mice lacking N-type (Cav2.2) or R-type (Cav2.3) VDCCs. Systemic morphine administration or exposure to warm water swim-stress, known to induce endogenous opioid release, resulted in greater analgesia in Cav2.3,/, mice than in controls. Moreover, Cav2.3,/, mice showed resistance to morphine tolerance. In contrast, Cav2.2,/, mice showed similar levels of analgesia and tolerance to control mice. Intracerebroventricular (i.c.v.) but not intrathecal (i.t.) administration of morphine reproduced the result of systemic morphine in Cav2.3,/, mice. Furthermore, i.c.v. administration of an R-type channel blocker potentiated morphine analgesia in wild-type mice. Thus, the inhibition of R-type Ca2+ current could lead to high-efficiency opioid therapy without tolerance. [source] AMPA receptor-mediated presynaptic inhibition at cerebellar GABAergic synapses: a characterization of molecular mechanismsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2004Shin'Ichiro Satake Abstract A major subtype of glutamate receptors, AMPA receptors (AMPARs), are generally thought to mediate excitation at mammalian central synapses via the ionotropic action of ligand-gated channel opening. It has recently emerged, however, that synaptic activation of AMPARs by glutamate released from the climbing fibre input elicits not only postsynaptic excitation but also presynaptic inhibition of GABAergic transmission onto Purkinje cells in the cerebellar cortex. Although presynaptic inhibition is critical for information processing at central synapses, the molecular mechanisms by which AMPARs take part in such actions are not known. This study therefore aimed at further examining the properties of AMPAR-mediated presynaptic inhibition at GABAergic synapses in the rat cerebellum. Our data provide evidence that the climbing fibre-induced inhibition of GABA release from interneurons depends on AMPAR-mediated activation of GTP-binding proteins coupled with down-regulation of presynaptic voltage-dependent Ca2+ channels. A Gi/o -protein inhibitor, N-ethylmaleimide, selectively abolished the AMPAR-mediated presynaptic inhibition at cerebellar GABAergic synapses but did not affect AMPAR-mediated excitatory actions on Purkinje cells. Furthermore, both Gi/o -coupled receptor agonists, baclofen and DCG-IV, and the P/Q-type calcium channel blocker ,-agatoxin IVA markedly occluded the AMPAR-mediated inhibition of GABAergic transmission. Conversely, AMPAR activation inhibited action potential-triggered Ca2+ influx into individual axonal boutons of cerebellar GABAergic interneurons. By suppressing the inhibitory inputs to Purkinje cells, the AMPAR-mediated presynaptic inhibition could thus provide a feed-forward mechanism for the information flow from the cerebellar cortex. [source] Pre- and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2004B. Heinke Abstract Activation of voltage-dependent Ca2+ channels (VDCCs) is critical for neurotransmitter release, neuronal excitability and postsynaptic Ca2+ signalling. Antagonists of VDCCs can be antinociceptive in different animal pain models. Neurons in lamina I of the spinal dorsal horn play a pivotal role in the processing of pain-related information, but the role of VDCCs to the activity-dependent Ca2+ increase in lamina I neurons and to the synaptic transmission between nociceptive afferents and second order neurons in lamina I is not known. This has now been investigated in a lumbar spinal cord slice preparation from young Sprague,Dawley rats. Microfluorometric Ca2+ measurements with fura-2 have been used to analyse the Ca2+ increase in lamina I neurons after depolarization of the cells, resulting in a distinct and transient increase of the cytosolic Ca2+ concentration. This Ca2+ peak was reduced by the T-type channel blocker, Ni2+, by the L-type channel blockers, nifedipine and verapamil, and by the N-type channel blocker, ,-conotoxin GVIA. The P/Q-type channel antagonist, ,-agatoxin TK, had no effect on postsynaptic [Ca2+]i. The NMDA receptor channel blocker D-AP5 reduced the Ca2+ peak, whereas the AMPA receptor channel blocker CNQX had no effect. Postsynaptic currents, monosynaptically evoked by electrical stimulation of the attached dorsal roots with C-fibre and A,-fibre intensity, respectively, were reduced by N-type channel blocker ,-conotoxin GVIA and to a much lesser extent, by P/Q-type channel antagonist ,-agatoxin TK, and the L-type channel blockers verapamil, respectively. No difference was found between unidentified neurons and neurons projecting to the periaqueductal grey matter. This is the first quantitative description of the relative contribution of voltage-dependent Ca2+ channels to the synaptic transmission in lamina I of the spinal dorsal horn, which is essential in the processing of pain-related information in the central nervous system. [source] | ||||||||||||||||||||||||||||||||||||||||