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Jhijoung Wang - One of the best experts on this subject based on the ideXlab platform.
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isobolographic analysis of interaction between Nisoxetine and mepivacaine induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2014Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats
Pharmacological Reports, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na^+ channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na^+ currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na^+ currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na^+ currents (IC_50 of 3.7 and 74.2 µM at holding potentials of–70 and–100 mV, respectively). Nisoxetine was more potent (IC_50 of 1.6 and 28.6 μM at holding potentials of–70 and–100mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p < 0.05) over motor blockade in a dose-related fashion. Intrathecal 5% dextrose (vehicle) produced no spinal anesthesia. On the 50% effective dose (ED_50) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p < 0.05). Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na^+ currents.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats.
Pharmacological reports : PR, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Abstract Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na + channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na + currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na + currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na + currents (IC50 of 3.7 and 74.2 μM at holding potentials of −70 and −100 mV, respectively). Nisoxetine was more potent (IC 50 of 1.6 and 28.6 μM at holding potentials of −70 and −100 mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p 50 ) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na + currents.
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Isobolographic analysis of interaction between Nisoxetine‐ and mepivacaine‐induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2012Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
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Nisoxetine produces local but not systemic analgesia against cutaneous nociceptive stimuli in the rat.
European Journal of Pharmacology, 2011Co-Authors: Yu Wen Chen, Ching Hsia Hung, Jhijoung Wang, Chin-chen Chu, Yu Chung Chen, Dong Zi ShaoAbstract:Abstract The aim of this study was to evaluate the local anesthetic effect of Nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with Nisoxetine, dose–response curves were constructed. The cutaneous anesthetic effect of Nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that Nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was Nisoxetine > MK-801 > lidocaine (P d -aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of Nisoxetine or lidocaine.
Yuk Man Leung - One of the best experts on this subject based on the ideXlab platform.
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isobolographic analysis of interaction between Nisoxetine and mepivacaine induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2014Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats
Pharmacological Reports, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na^+ channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na^+ currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na^+ currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na^+ currents (IC_50 of 3.7 and 74.2 µM at holding potentials of–70 and–100 mV, respectively). Nisoxetine was more potent (IC_50 of 1.6 and 28.6 μM at holding potentials of–70 and–100mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p < 0.05) over motor blockade in a dose-related fashion. Intrathecal 5% dextrose (vehicle) produced no spinal anesthesia. On the 50% effective dose (ED_50) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p < 0.05). Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na^+ currents.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats.
Pharmacological reports : PR, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Abstract Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na + channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na + currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na + currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na + currents (IC50 of 3.7 and 74.2 μM at holding potentials of −70 and −100 mV, respectively). Nisoxetine was more potent (IC 50 of 1.6 and 28.6 μM at holding potentials of −70 and −100 mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p 50 ) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na + currents.
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Isobolographic analysis of interaction between Nisoxetine‐ and mepivacaine‐induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2012Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
Yu Wen Chen - One of the best experts on this subject based on the ideXlab platform.
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isobolographic analysis of interaction between Nisoxetine and mepivacaine induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2014Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats
Pharmacological Reports, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na^+ channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na^+ currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na^+ currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na^+ currents (IC_50 of 3.7 and 74.2 µM at holding potentials of–70 and–100 mV, respectively). Nisoxetine was more potent (IC_50 of 1.6 and 28.6 μM at holding potentials of–70 and–100mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p < 0.05) over motor blockade in a dose-related fashion. Intrathecal 5% dextrose (vehicle) produced no spinal anesthesia. On the 50% effective dose (ED_50) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p < 0.05). Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na^+ currents.
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Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats.
Pharmacological reports : PR, 2013Co-Authors: Yuk Man Leung, Yu Wen Chen, Chin-chen Chu, Chang-shin Kuo, Jhijoung WangAbstract:Abstract Background Although Nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na + channels by Nisoxetine has not been reported. The aim of this study was to evaluate the effect of Nisoxetine on Na + currents and its efficacy on spinal anesthesia. Methods In in vitro studies, the voltage-clamp method was employed to examine whether Nisoxetine blocked Na + currents in mouse neuroblastoma N2A cells. Results Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na + currents (IC50 of 3.7 and 74.2 μM at holding potentials of −70 and −100 mV, respectively). Nisoxetine was more potent (IC 50 of 1.6 and 28.6 μM at holding potentials of −70 and −100 mV, respectively). In in vivo studies, after rats were intrathecally injected with Nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p 50 ) basis, Nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p Conclusions Our results showed that Nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of Nisoxetine could be probably due to the suppression of Na + currents.
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Isobolographic analysis of interaction between Nisoxetine‐ and mepivacaine‐induced spinal blockades in rats
Fundamental & Clinical Pharmacology, 2012Co-Authors: Yuk Man Leung, Ching Hsia Hung, Yu Wen Chen, Jhijoung WangAbstract:: Although Nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with Nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of Nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared Nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that Nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of Nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both Nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of Nisoxetine with mepivacaine displayed an additive effect. Our data reported Nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal Nisoxetine elicited more potent spinal anesthesia than mepivacaine.
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Nisoxetine produces local but not systemic analgesia against cutaneous nociceptive stimuli in the rat.
European Journal of Pharmacology, 2011Co-Authors: Yu Wen Chen, Ching Hsia Hung, Jhijoung Wang, Chin-chen Chu, Yu Chung Chen, Dong Zi ShaoAbstract:Abstract The aim of this study was to evaluate the local anesthetic effect of Nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with Nisoxetine, dose–response curves were constructed. The cutaneous anesthetic effect of Nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that Nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was Nisoxetine > MK-801 > lidocaine (P d -aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of Nisoxetine or lidocaine.
Naoki Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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Noradrenergic Mechanisms Controlling Urethral Smooth and Striated Muscle Function in Urethral Continence Reflex in Rats.
Lower urinary tract symptoms, 2014Co-Authors: Akira Furuta, Yasuyuki Suzuki, Shouji Kimura, Kouji Asano, Shin Egawa, Naoki YoshimuraAbstract:Objectives To investigate the role of noradrenergic pathways in the urethral continence reflex during abdominal compression in rats. Methods Under urethane anesthesia, urethral baseline pressure (UBP) and urethral pressure response (UPR) during momentary abdominal compression using a 100 g weight was measured using a transurethral microtransducer-tipped catheter placed at the middle urethra in Sprague–Dawley female rats. Following intravenous (i.v.) application of hexamethonium or α-bungarotoxin to block urethral smooth or striated muscle function, respectively, the effects of terazosin, an α1-adrenoceptor (AR) antagonist (0.3 mg/kg, i.v.), medetomidine, an α2-AR agonist (0.3 mg/kg, i.v.) or Nisoxetine, a norepinephrine reuptake inhibitor (1 mg/kg, i.v.) followed by terazosin on UBP and UPR were examined. Results After hexamethonium pretreatment, terazosin did not alter UBP or UPR, whereas medetomidine significantly decreased UPR by 28% without UBP changes. Nisoxetine significantly increased UPR by 64%, which was eliminated by terazosin, but UBP was not altered by Nisoxetine. After α-bungarotoxin pretreatment, UBP and UPR were significantly decreased by terazosin or medetomidine. Nisoxetine induced significant increases in UBP and UPR by 16 and 15%, respectively, which were antagonized by terazosin. Conclusion These results suggest that: the baseline activity and reflex contraction of urethral smooth muscle are decreased by α1-AR inhibition or α2-AR stimulation; the reflex contraction of urethral striated muscle is decreased by α2-AR stimulation, but not by α1-AR inhibition; and Nisoxetine increases baseline and reflex activity of smooth muscle in addition to striated muscle reflex activity by α1-AR stimulation. These findings will be useful to understand nerve-mediated urethral closure mechanisms.
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Roles of the spinal glutamatergic pathway activated through α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and its interactions with spinal noradrenergic and serotonergic pathways in the rat urethral continence mechanisms
Neurourology and urodynamics, 2014Co-Authors: Naoki Kawamorita, Yoichi Arai, Yasuhiro Kaiho, Minoru Miyazato, Naoki YoshimuraAbstract:Aims To investigate the role of the glutamatergic pathway and its relationship to noradrenergic and serotonergic pathways in modulation of the urethral continence reflex during sneezing in rats. Methods In female Sprague-Dawley rats under urethane anesthesia, the effects of an α-amino-3-hydroxy-5-meth-ylisoxazole-4-propionic acid (AMPA) glutamate receptor antagonist, a norepinephrine reuptake inhibitor and a serotonin [5-hydeoxytripitamine (5-HT)]2B/2C agonist on the amplitude of urethral responses during sneezing (AURS), urethral baseline pressure (UBP), and sneeze-induced leak point pressure (S-LPP) were investigated. Results Intrathecal application (i.t.) of NBQX disodium salt (an AMPA receptor antagonist) decreased AURS dose-dependently by approximately 60% without affecting UBP and caused stress urinary incontinence (SUI) during sneezing in 60% of normal rats. Nisoxetine (i.t.), a norepinephrine reuptake inhibitor, and mCPP (i.t.), a 5-HT2B/2C, agonist increased AURS, and NBQX (i.t.) abolished these excitatory effects of Nisoxetine (i.t.) and mCPP (i.t.), whereas Nisoxetine (i.t.) and mCPP (i.t.) did not enhance AURS in the presence of NBQX (i.t.). Conclusion These results indicate that the glutamatergic pathway acting through AMPA receptors plays a crucial role on the active urethral closure reflex during sneezing at the spinal level, and noradrenergic and serotonergic pathways modulate the reflex via the spinal glutamatergic system in rats. Neurourol. Urodynam. 34:475–481, 2015. © 2014 Wiley Periodicals, Inc.
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Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats.
American journal of physiology. Renal physiology, 2006Co-Authors: Yasuhiro Kaiho, Izumi Kamo, Michael B. Chancellor, Yoichi Arai, William C. De Groat, Naoki YoshimuraAbstract:To clarify the role of noradrenergic pathways in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of the norepinephrine reuptake inhibitor Nisoxetine and α-a...
Maarten E. A. Reith - One of the best experts on this subject based on the ideXlab platform.
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Novel Structure–Function Information on Biogenic Amine Transporters Revealed by Site-Directed Mutagenesis and Alkylation
Neurochemical Research, 2013Co-Authors: Maarten E. A. ReithAbstract:The study reported by Wenge and Bönisch in this issue provides critical structural information regarding extracellular loop 2 (EL2) of the human norepinephrine transporter (NET). A systematic search among all 10 cysteine and 13 histidine residues in NET led to His222 in EL2 as the target for N -ethylmaleimide: its alkylation interferes with [^3H]Nisoxetine binding, indicating the part of EL2 containing His 222 reaches back into the protein interior where it prevents access by Nisoxetine to its binding site. Thus, EL2 in human NET does much more than conformationally assisting substrate translocation. The present study underscores the importance of site-directed mutagenesis approaches to elucidate structural features that cannot be deduced from crystals of homolog proteins. In the case of NET, the closest crystal structure is that of the homolog LeuT, but EL2 is difficult to align with 22 less loop residues in LeuT than in NET. The present results could only be achieved by the systematic mutagenesis study of all cysteines and all histidines in NET.
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novel structure function information on biogenic amine transporters revealed by site directed mutagenesis and alkylation
Neurochemical Research, 2013Co-Authors: Maarten E. A. ReithAbstract:The study reported by Wenge and Bonisch in this issue provides critical structural information regarding extracellular loop 2 (EL2) of the human norepinephrine transporter (NET). A systematic search among all 10 cysteine and 13 histidine residues in NET led to His222 in EL2 as the target for N-ethylmaleimide: its alkylation interferes with [3H]Nisoxetine binding, indicating the part of EL2 containing His 222 reaches back into the protein interior where it prevents access by Nisoxetine to its binding site. Thus, EL2 in human NET does much more than conformationally assisting substrate translocation. The present study underscores the importance of site-directed mutagenesis approaches to elucidate structural features that cannot be deduced from crystals of homolog proteins. In the case of NET, the closest crystal structure is that of the homolog LeuT, but EL2 is difficult to align with 22 less loop residues in LeuT than in NET. The present results could only be achieved by the systematic mutagenesis study of all cysteines and all histidines in NET.
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Characterization of [3H]CFT binding to the norepinephrine transporter suggests that binding of CFT and Nisoxetine is not mutually exclusive
Journal of neuroscience methods, 2011Co-Authors: Juan Zhen, Solav Ali, Aloke K. Dutta, Maarten E. A. ReithAbstract:The norepinephrine transporter (NET) is an important target for a wide variety of antidepressants and psychostimulants. Despite its prominence as a drug target, there is only one radioligand in use for NET competitive binding assays, [ 3 H]Nisoxetine. However, traditional [ 3 H]Nisoxetine binding protocols often give an underestimation for the affinity of certain classes of NET ligands, particularly cocaine and other tropanes. Here, we explore the feasibility of using the phenyltropane [ 3 H]CFT for labeling human NET (hNET) in heterologous cell-based binding studies. Assays were optimized for time and protein content and specific, one-site binding was observed. Potencies of tested NET ligands for inhibition of [ 3 H]CFT binding to whole cells (at physiological [Na + ] and 25°C) were similar to potencies observed in the [ 3 H]NE uptake assay. Inhibition constants (Ki) for binding assays were highly correlated with uptake inhibition constants for all compounds tested (R 2 = 0.99, p < 0.0001). Cell-free membrane preparations did not display the same pharmacological profile. Under conditions routinely used for measuring [ 3 H]Nisoxetine binding to membrane preparations (4°C for 3 h, [Na + ] at 295 mM), the potency of Nisoxetine and desipramine in inhibiting [ 3 H]CFT binding became greater than that measured in a functional assay of [ 3 H]NE uptake at physiological [Na + ]. However, the opposite was true for CFT and cocaine. Interestingly, while investigating [ 3 H]CFT as a potential NET radioligand, we uncovered evidence suggesting that CFT and Nisoxetine are not mutually exclusive in binding to the NET. Dixon plots of the interaction between Nisoxetine and CFT in inhibition of [ 3 H]dopamine uptake by the NET indicate that the two compounds can simultaneously bind to the transporter.
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Pharmacological profile of radioligand binding to the norepinephrine transporter: instances of poor indication of functional activity.
Journal of neuroscience methods, 2005Co-Authors: Maarten E. A. Reith, Lijuan C. Wang, Aloke K. DuttaAbstract:Abstract Binding assays for the norepinephrine (NE) transporter (NET) with [ 3 H]Nisoxetine have generally yielded weak potencies for compounds related to cocaine and 1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909), as compared with their functional activity in inhibiting NE uptake. In the present work with HEK-293 cells expressing the human NET (hNET), potential underlying causes for this discrepancy have been addressed: ambient temperature of the binding assay, buffer in the assay, preparation used for source of the NET, and radioligand. The results indicate that the standard [ 3 H]Nisoxetine binding assay at 0 °C with cell membrane preparations in high Na + buffer underestimates the functional potency of compounds related to cocaine and GBR 12909; in drug development studies it is advisable to either carry out [ 3 H]Nisoxetine binding assays with intact cells under uptake conditions, or perform classical [ 3 H]NE uptake studies with intact cells (or with synaptosomes from brain tissue).