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Akira Tsuji - One of the best experts on this subject based on the ideXlab platform.
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Carrier-Mediated Transport of H_1-Antagonist at the Blood-Brain Barrier: A Common Transport System of H_1-Antagonists and Lipophilic Basic Drugs
Pharmaceutical Research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The blood-brain barrier (BBB) transport system for H_1 antagonists was studied using primary cultured bovine brain capillary endothelial cells (BCEC). The uptake of [^3H]Mepyramine was inhibited by various H_1-antagonists. Ketotifen competitively inhibited [^3H]Mepyramine uptake with an inhibition constant (K_i ) of 46.8 µM. Lipophilic basic drugs such as propranolol, lidocaine and imipramine significantly inhibited [^3H]Mepyramine uptake. In particular, propranolol inhibited [^3H]Mepyramine uptake competitively at an inhibition constant (K_i) of 51.1 µM. Moreover, in ATP-depleted BCEC, [^3H]Mepyramine uptake was stimulated by preloading with H_1- antagonists and lipophilic basic drugs. These results indicated that H_1-antagonists are transported across the BBB via a carrier-mediated transport system common to lipophilic basic drugs.
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Carrier-mediated transport of H1-antagonist at the blood-brain barrier: a common transport system of H1-antagonists and lipophilic basic drugs.
Pharmaceutical research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The blood-brain barrier (BBB) transport system for H1 antagonists was studied using primary cultured bovine brain capillary endothelial cells (BCEC). The uptake of [3H]Mepyramine was inhibited by various H1-antagonists. Ketotifen competitively inhibited [3H]Mepyramine uptake with an inhibition constant (Ki ) of 46.8 µM. Lipophilic basic drugs such as propranolol, lidocaine and imipramine significantly inhibited [3H]Mepyramine uptake. In particular, propranolol inhibited [3H]Mepyramine uptake competitively at an inhibition constant (Ki) of 51.1 µM. Moreover, in ATP-depleted BCEC, [3H]Mepyramine uptake was stimulated by preloading with H1- antagonists and lipophilic basic drugs. These results indicated that H1-antagonists are transported across the BBB via a carrier-mediated transport system common to lipophilic basic drugs.
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Carrier-mediated transport of H1-antagonist at the blood-brain barrier: Mepyramine uptake into bovine brain capillary endothelial cells in primary monolayer cultures.
Pharmaceutical research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The transport mechanism of the H1antagonist Mepyramine at the blood-brain barrier (BBB) was studied by using primary cultured monolayers of bovine brain capillary endothelial cells (BCEC). The initial uptake of [3H]Mepyramine into the BCEC showed strong temperature and concentration dependency, indicating that it involves both saturable and nonsaturable processes. Transport at the luminal membrane may be the rate-limiting process in the transcellular transport, since the values of the uptake coefficient of [3H]Mepyramine at the luminal membrane (609 µl/mg protein/min) and the transcellular permeability coefficient (488 µl/mg protein/min) are very similar. The initial uptake of [3H]Mepyramine was not affected by metabolic inhibitors, but was stimulated by preloading with the drug. Mepyramine appears to be transported into the BCEC by a carrier-mediated transport system which does not require metabolic energy, probably via a facilitated diffusion mechanism.
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Transport Mechanism of an H1-Antagonist at the Blood-Brain Barrier : Transport Mechanism of Mepyramine Using the Carotid Injection Technique
Biological & pharmaceutical bulletin, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Osamu Nagata, Hideo Kato, Yasuo Ito, Hideaki Fukuoka, Akira TsujiAbstract:The blood-brain barrier (BBB) permeability of Mepyramine was measured by the carotid injection technique to elucidate the transport mechanism of an H1-antagonist in the central nervous system. Mepyramine was found to enter the brain by saturable and carrier-mediated transport. The in vivo kinetic parameters were estimated as follows : the maximum uptake rate (Jmax) was 7.12±1.37μmol/min/g of brain, the Michaelis constant (Kd) was 4.40±2.00mM, and the nonsaturable first order rate (Kd) was 0.28±0.02ml/min/g of brain. The Mepyramine transport was not inhibited either by nutrients or by choline, hemicholinium-3, though it was inhibited by the classical H1-antagonists such as diphenhydramine, diphenylpyraline, and also by propranolol. The above inhibitory effects suggest that a transport system different from the amine transport system exists for the BBB transport of Mepyramine, and that this transporter is common not only for H1-antagonists but also for basic drugs.
Hailin Zhang - One of the best experts on this subject based on the ideXlab platform.
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antihistamine Mepyramine directly inhibits kcnq m channel and depolarizes rat superior cervical ganglion neurons
Neuropharmacology, 2008Co-Authors: Boyi Liu, Xuan Zhang, Chuan Wang, Guohong Zhang, Hailin ZhangAbstract:Abstract The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H 1 receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K + channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC 50 (12.5 and 48.1 μM, respectively) is within the range of drug concentrations detected in poisoned patients (30–300 μM). Both drugs shifted the I–V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1–4 and heteromeric KCNQ3/Q5 currents. Moreover, Mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, Mepyramine reduced the M type K + current in a concentration-dependent manner and led to marked membrane potential depolarization. It is likely that these effects may be involved in the adverse neuroexcitatory effects observed in patients experiencing an overdose of antihistamines.
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Antihistamine Mepyramine directly inhibits KCNQ/M channel and depolarizes rat superior cervical ganglion neurons.
Neuropharmacology, 2007Co-Authors: Boyi Liu, Xuan Zhang, Chuan Wang, Guohong Zhang, Hailin ZhangAbstract:Abstract The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H 1 receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K + channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC 50 (12.5 and 48.1 μM, respectively) is within the range of drug concentrations detected in poisoned patients (30–300 μM). Both drugs shifted the I–V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1–4 and heteromeric KCNQ3/Q5 currents. Moreover, Mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, Mepyramine reduced the M type K + current in a concentration-dependent manner and led to marked membrane potential depolarization. It is likely that these effects may be involved in the adverse neuroexcitatory effects observed in patients experiencing an overdose of antihistamines.
Hiroyuki Fukui - One of the best experts on this subject based on the ideXlab platform.
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Mepyramine, a histamine H1 receptor antagonist, inhibits the metabolic activity of rat and human P450 2D forms.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: Toyoko Hiroi, Norihisa Ohishi, Susumu Imaoka, Yoshiyasu Yabusaki, Hiroyuki Fukui, Yoshihiko FunaeAbstract:The interaction of antihistaminics, including Mepyramine, with rat hepatic cytochrome P450s (P450s) was investigated. We first investigated Mepyramine binding to eight forms of rat hepatic P450s. Mepyramine bound specifically to P450 2D1, which suggests that it inhibits P450 2D activity. Histamine H1 receptor antagonists (Mepyramine, diphenhydramine, chlorpheniramine and triprolidine) inhibited the lidocaine 3-hydroxylation activity catalyzed by P450 2D1 but did not inhibit the testosterone hydroxylation activities catalyzed by P450s other than P450 2D forms. The Ki values of these antagonists for the catalytic activity of P450 2D1 were low and were similar to those of quinine and quinidine, which are specific inhibitors of P450 2D forms. The Ki value of Mepyramine was especially low, at 34 nM. Furthermore, the effects of Mepyramine on human P450 2D6 were investigated. Among the ten forms of human P450 expressed in yeast, Mepyramine bound specifically to P450 2D6 in a binding assay. In human hepatic microsomes, Mepyramine inhibited the debrisoquine 4-hydroxylation activity catalyzed by P450 2D6. These results indicate that histamine H1 receptor antagonists such as Mepyramine are potent inhibitors of P450 2D forms because of their high affinity for these enzymes.
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Purification and characterization of [3H]Mepyramine (histamine H1 antagonist)-binding protein from rat liver: a highly homologous protein with cytochrome P450 2D.
Journal of biochemistry, 1995Co-Authors: Hiroyuki Fukui, Nai Ping Wang, Hiroyuki Mizuguchi, R Leurs, Ye Qi Liu, Hideyuki Hayashi, Kenji Kangawa, Tateaki Wakamiya, Tetsuo Shiba, Hisayuki MatsuoAbstract:A protein having a high-affinity binding site for [3H]Mepyramine (MBP) was purified to homogeneity from rat liver membranes. The purified MBP has a single type of binding site for [3H]Mepyramine with Kd value of 18.5 nM, and its molecular weight was determined to be 56,000 by SDS polyacrylamide gel electrophoresis. Amino acid sequences of twelve tryptic peptides derived from MBP are highly homologous with those of rat debrisoquine 4-hydroxylase (cytochrome P450 2D1) and other rat P450 2D subfamily members. In immunoblotting analysis, an antibody against rat P450 2D1 stained a band corresponding to MBP with Mr of 56,000; its migration position was clearly different from that of rat P450 2D1. Substrates and inhibitors of debrisoquine 4-hydroxylase potently displace [3H]-Mepyramine binding to MBP. Quinine and quinidine showed 400 and 80 times, respectively, higher affinity for MBP than for debrisoquine 4-hydroxylase. These results suggest that MBP is a novel P450 2D family member.
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Does the [3H]Mepyramine binding site represent the histamine H1 receptor? Re-examination of the histamine H1 receptor with quinine.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: Q Liu, Yoshiyuki Horio, Katsumi Fujimoto, Hiroyuki FukuiAbstract:Mepyramine is a potent H1 receptor antagonist, and [3H]Mepyramine generally is used to label histamine H1 receptors. However, we found that [3H]Mepyramine labeled not only the H1 receptor but also a [3H]Mepyramine binding protein (MBP) in the liver, which protein appears to be related to the subfamily of debrisoquine 4-hydroxylase (cytochrome P450IID) isozymes. The binding of [3H]Mepyramine to the cloned H1 receptor was not affected by 1 microM quinine, an inhibitor of debrisoquine 4-hydroxylase. On the other hand, the binding to MBP in the liver membranes was completely inhibited by 1 microM quinine. These data indicate that the labeling by [3H]Mepyramine of H1 receptors and MBP can be completely separated with 1 microM quinine. The majority of [3H] Mepyramine binding sites in the cerebral cortex, thalamus and hypothalamus, hippocampus, heart, aorta, lung and spleen were H1 receptors. On the other hand, almost all [3H]Mepyramine binding sites in the liver and kidney were MBP. Both H1 receptors and MBP were expressed in the stomach, ileum, cerebellum and adrenal gland. Kd values of [3H]Mepyramine for membranes from the cerebellum and stomach in the presence of quinine, which tissues contain both H1 receptors and MBP, approached that value of the cloned H1 receptor. The improved [3H]Mepyramine binding assay using quinine is a precise method to characterize H1 receptors by the separate determination of H1 receptors and MBP.
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Re-examination of [3H]Mepyramine binding assay for histamine H1 receptor using quinine.
Biochemical and biophysical research communications, 1992Co-Authors: Ye Qi Liu, Yoshiyuki Horio, Katsumi Fujimoto, Hiroyuki Mizuguchi, Ikuo Imamura, Yoshiyuki Abe, Hiroyuki FukuiAbstract:Abstract [ 3 H]Mepyramine, a potent antagonist of the histamine H 1 receptor, has been widely used as a radioligand binding assay for the H 1 receptor. Previously, we purified a Mepyramine binding protein (MBP) from rat liver, but found that its partial amino acid sequences were very similar to those of debrisoquine 4-hydroxylase isozymes (P450 db1 and db2), which are members of the superfamily of cytochrome P450. Using cloned histamine H 1 receptor cDNA, we found that [ 3 H]Mepyramine could bind only the H 1 receptor did not bind MBP in the presence of 10 −5 M quinine, an inhibitor of debrisquine 4-hydroxylase isozymes. We developed a method to determine the contents of the H 1 receptor and MBP separately using [ 3 H]Mepyramine and quinine and found that MBP is abundant in certain areas of bovine brain.
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Synaptic and extra-synaptic distribution of histamine H1-receptors in rat and guinea pig brains.
Biochemical and biophysical research communications, 1991Co-Authors: Hiroyuki Mizuguchi, Hiroyuki Fukui, Masami Yabumoto, Hiroshi WadaAbstract:Localization of histamine H1-receptors in subcellular fractions from rat and guinea pig brains was examined in a [3H]Mepyramine binding study. Major [3H]Mepyramine binding sites with increased specific activities ([3H]Mepyramine binding vs. protein amount) were recovered from P2 fractions from both rat and guinea pig brains by differential centrifugation. Further subfractionation of both rat and guinea pig P2 fractions by a discontinuous sucrose density gradient centrifugation showed the highest recovery of [3H]Mepyramine binding with further increased specific activities found in synaptic plasma membrane (SPM) fractions. Minor [3H]Mepyramine binding sites with increased specific activities were detected in both rat and guinea pig P3 fractions. [3H]Mepyramine binding sites in SPM and P3 fractions showed identical Kd values in each species. These results indicate that histamine H1-receptors are located not only in synaptic but also in extrasynaptic membranes of both rat and guinea pig brains.
Masahiro Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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Carrier-Mediated Transport of H_1-Antagonist at the Blood-Brain Barrier: A Common Transport System of H_1-Antagonists and Lipophilic Basic Drugs
Pharmaceutical Research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The blood-brain barrier (BBB) transport system for H_1 antagonists was studied using primary cultured bovine brain capillary endothelial cells (BCEC). The uptake of [^3H]Mepyramine was inhibited by various H_1-antagonists. Ketotifen competitively inhibited [^3H]Mepyramine uptake with an inhibition constant (K_i ) of 46.8 µM. Lipophilic basic drugs such as propranolol, lidocaine and imipramine significantly inhibited [^3H]Mepyramine uptake. In particular, propranolol inhibited [^3H]Mepyramine uptake competitively at an inhibition constant (K_i) of 51.1 µM. Moreover, in ATP-depleted BCEC, [^3H]Mepyramine uptake was stimulated by preloading with H_1- antagonists and lipophilic basic drugs. These results indicated that H_1-antagonists are transported across the BBB via a carrier-mediated transport system common to lipophilic basic drugs.
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Carrier-mediated transport of H1-antagonist at the blood-brain barrier: a common transport system of H1-antagonists and lipophilic basic drugs.
Pharmaceutical research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The blood-brain barrier (BBB) transport system for H1 antagonists was studied using primary cultured bovine brain capillary endothelial cells (BCEC). The uptake of [3H]Mepyramine was inhibited by various H1-antagonists. Ketotifen competitively inhibited [3H]Mepyramine uptake with an inhibition constant (Ki ) of 46.8 µM. Lipophilic basic drugs such as propranolol, lidocaine and imipramine significantly inhibited [3H]Mepyramine uptake. In particular, propranolol inhibited [3H]Mepyramine uptake competitively at an inhibition constant (Ki) of 51.1 µM. Moreover, in ATP-depleted BCEC, [3H]Mepyramine uptake was stimulated by preloading with H1- antagonists and lipophilic basic drugs. These results indicated that H1-antagonists are transported across the BBB via a carrier-mediated transport system common to lipophilic basic drugs.
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Carrier-mediated transport of H1-antagonist at the blood-brain barrier: Mepyramine uptake into bovine brain capillary endothelial cells in primary monolayer cultures.
Pharmaceutical research, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Kuniaki Yoshioka, Osamu Nagata, Hideo Kato, Yasuo Ito, Akira TsujiAbstract:The transport mechanism of the H1antagonist Mepyramine at the blood-brain barrier (BBB) was studied by using primary cultured monolayers of bovine brain capillary endothelial cells (BCEC). The initial uptake of [3H]Mepyramine into the BCEC showed strong temperature and concentration dependency, indicating that it involves both saturable and nonsaturable processes. Transport at the luminal membrane may be the rate-limiting process in the transcellular transport, since the values of the uptake coefficient of [3H]Mepyramine at the luminal membrane (609 µl/mg protein/min) and the transcellular permeability coefficient (488 µl/mg protein/min) are very similar. The initial uptake of [3H]Mepyramine was not affected by metabolic inhibitors, but was stimulated by preloading with the drug. Mepyramine appears to be transported into the BCEC by a carrier-mediated transport system which does not require metabolic energy, probably via a facilitated diffusion mechanism.
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Transport Mechanism of an H1-Antagonist at the Blood-Brain Barrier : Transport Mechanism of Mepyramine Using the Carotid Injection Technique
Biological & pharmaceutical bulletin, 1994Co-Authors: Masahiro Yamazaki, Tetsuya Terasaki, Osamu Nagata, Hideo Kato, Yasuo Ito, Hideaki Fukuoka, Akira TsujiAbstract:The blood-brain barrier (BBB) permeability of Mepyramine was measured by the carotid injection technique to elucidate the transport mechanism of an H1-antagonist in the central nervous system. Mepyramine was found to enter the brain by saturable and carrier-mediated transport. The in vivo kinetic parameters were estimated as follows : the maximum uptake rate (Jmax) was 7.12±1.37μmol/min/g of brain, the Michaelis constant (Kd) was 4.40±2.00mM, and the nonsaturable first order rate (Kd) was 0.28±0.02ml/min/g of brain. The Mepyramine transport was not inhibited either by nutrients or by choline, hemicholinium-3, though it was inhibited by the classical H1-antagonists such as diphenhydramine, diphenylpyraline, and also by propranolol. The above inhibitory effects suggest that a transport system different from the amine transport system exists for the BBB transport of Mepyramine, and that this transporter is common not only for H1-antagonists but also for basic drugs.
Boyi Liu - One of the best experts on this subject based on the ideXlab platform.
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antihistamine Mepyramine directly inhibits kcnq m channel and depolarizes rat superior cervical ganglion neurons
Neuropharmacology, 2008Co-Authors: Boyi Liu, Xuan Zhang, Chuan Wang, Guohong Zhang, Hailin ZhangAbstract:Abstract The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H 1 receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K + channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC 50 (12.5 and 48.1 μM, respectively) is within the range of drug concentrations detected in poisoned patients (30–300 μM). Both drugs shifted the I–V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1–4 and heteromeric KCNQ3/Q5 currents. Moreover, Mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, Mepyramine reduced the M type K + current in a concentration-dependent manner and led to marked membrane potential depolarization. It is likely that these effects may be involved in the adverse neuroexcitatory effects observed in patients experiencing an overdose of antihistamines.
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Antihistamine Mepyramine directly inhibits KCNQ/M channel and depolarizes rat superior cervical ganglion neurons.
Neuropharmacology, 2007Co-Authors: Boyi Liu, Xuan Zhang, Chuan Wang, Guohong Zhang, Hailin ZhangAbstract:Abstract The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H 1 receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K + channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC 50 (12.5 and 48.1 μM, respectively) is within the range of drug concentrations detected in poisoned patients (30–300 μM). Both drugs shifted the I–V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1–4 and heteromeric KCNQ3/Q5 currents. Moreover, Mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, Mepyramine reduced the M type K + current in a concentration-dependent manner and led to marked membrane potential depolarization. It is likely that these effects may be involved in the adverse neuroexcitatory effects observed in patients experiencing an overdose of antihistamines.
