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Naoki Yoshimura - One of the best experts on this subject based on the ideXlab platform.

  • overview of pharmacological mechanisms controlling Micturition in the central nervous system
    Folia Pharmacologica Japonica, 2020
    Co-Authors: Naoki Yoshimura, Takeya Kitta, Katsumi Kadekawa, Minoru Miyazato, Takahiro Shimizu
    Abstract:

    The functions of the lower urinary tract, to storage and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra and external urethral sphincter. This activity is in turn controlled by neural circuits not only in the periphery, but also in the central nervous system (CNS). During urine storage, the outlet is closed and the bladder smooth muscle is quiescent by the neural control mechanism mainly organized in the spinal cord. When bladder volume reaches the Micturition threshold, activation of a Micturition center in the dorsolateral pons (the pontine Micturition center) induces Micturition through activation of sacral parasympathetic (pelvic) nerves. The brain rostral to the pons (diencephalon and cerebral cortex) is also involved in excitatory and inhibitory regulation of the Micturition Reflex. Various transmitters including dopamine, serotonin, norepenephrine, GABA, excitatory and inhibitory amino acids, opioids and acetylcholine are implicated in the modulation of the Micturition Reflex in the CNS. Therefore, injury or neurodegenerative diseases of the CNS as well as drugs can produce bladder and urethral dysfunctions such as urinary frequency, urgency and incontinence or inefficient bladder emptying.

  • brain serotoninergic nervous system is involved in bombesin induced frequent urination through brain 5 ht7 receptors in rats
    British Journal of Pharmacology, 2017
    Co-Authors: Takahiro Shimizu, Katsumi Kadekawa, Shogo Shimizu, Naoki Wada, Shun Takai, Nobutaka Shimizu, Youichirou Higashi, Tsuyoshi Majima, Motoaki Saito, Naoki Yoshimura
    Abstract:

    Background and Purpose Psychological stress exacerbates symptoms of urinary bladder dysfunction; however, underlying brain mechanisms are unclear. We reported that centrally administered bombesin, a stress-related neuropeptide, facilitates the rat Micturition Reflex. Brain bombesin-like peptides modulate the serotoninergic nervous system activity under stress conditions; therefore, we examined whether brain serotonin is involved in bombesin-induced frequent urination in urethane-anesthetized (0.9-1.0 g•kg-1, ip) male Sprague-Dawley rats. Experimental Approach Evaluation of intercontraction intervals (ICI) and maximal voiding pressure (MVP) during cystometrograms was started 1 hour before intracerebroventricular (icv) administration of bombesin or icv pretreatment with 5-HT receptor antagonists. Key Results Bombesin (0.03 nmol• per animal, icv) significantly reduced ICI without affecting MVP. The bombesin-induced response was significantly suppressed by acute depletion of brain serotonin which was induced by pretreatment with p-chlorophenylalanine, a serotonin synthesis inhibitor (200 mg•kg-1• per day for 2 days, ip). Bombesin at a lower dose (0.01 nmol• per animal, icv) showed no significant effect on ICI, while the bombesin significantly reduced ICI in the presence of WAY-100635 (5-HT1A receptor antagonist, 0.1 or 0.3 μg• per animal, icv), which can block a negative feedback control of serotonin release. Bombesin (0.03 nmol• per animal, icv)-induced ICI reduction was significantly attenuated by SB269970 (5-HT7 receptor antagonist, 0.1 or 0.3 μg• per animal, icv), but not by ritanserin (5-HT2 receptor antagonist, 0.3 or 1 μg• per animal, icv). Conclusions and Implications The brain serotoninergic nervous system is involved in bombesin-like peptides-induced facilitation of the rat Micturition Reflex at least in part through brain 5-HT7 receptors.

  • spinal glycine transporter 1 inhibition influences the Micturition Reflex in urethane anesthetized rats
    International Urology and Nephrology, 2016
    Co-Authors: Michael B Chancellor, Shogo Shimizu, Motoaki Saito, Masashi Honda, Katsuya Hikita, Bunya Kawamoto, Kuniyasu Muraoka, Takehiro Sejima, Naoki Yoshimura
    Abstract:

    Glycine is an inhibitory neurotransmitter in the central nervous system. So far, two types of glycine transporters (GlyTs), GlyT-1 and GlyT-2, have been cloned. The aim of this study is to investigate the effects of a selective GlyT-1 inhibitor that can increase endogenous glycine concentration on the Micturition Reflex in urethane-anesthetized rats. Continuous cystometrograms (0.04 ml/min) were performed in female Sprague–Dawley rats (232–265 g) under urethane anesthesia. After stable Micturition cycles were established, ALX5407, a selective GlyT-1 inhibitor, was administered intrathecally or intracerebroventricularly to evaluate changes in bladder activity. Cystometric parameters were recorded and compared before and after drug administration. Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) increased intercontraction intervals at doses of 3 μg or higher in a dose-dependent fashion. Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) also increased pressure threshold at doses of 3 μg or higher in a dose-dependent fashion. However, when ALX5407 (1, 3, 10 and 30 μg) was administered intracerebroventricularly, there were no significant changes in intercontraction intervals, pressure threshold, maximum voiding pressure or baseline pressure or post-void residual urine volume at any doses tested. The results of our study indicate that GlyT-1 plays an important role in the modulation of Micturition. Furthermore, these findings indicate that in urethane-anesthetized rats suppression of GlyT-1 can inhibit the Micturition Reflex at the spinal cord level. Thus, GlyT-1 could be a potential target for the treatment of bladder dysfunction such as overactive bladder.

  • suppression of bladder overactivity by adenosine a2a receptor antagonist in a rat model of parkinson disease
    The Journal of Urology, 2010
    Co-Authors: Takeya Kitta, Katsuya Nonomura, Michael B Chancellor, William C De Groat, Sadako Kuno, Naoki Yoshimura
    Abstract:

    Purpose: Overactive bladder is highly prevalent among patients with Parkinson disease. Adenosine is an important neurotransmitter in the central nervous system but it is not fully clarified how adenosine receptors regulate the Micturition Reflex. Thus, we examined the effect of an adenosine A2A receptor antagonist on the Micturition Reflex in a rat model of Parkinson disease.Materials and Methods: In a rat model of Parkinson disease induced by 6-hydroxydopamine (Tocris Bioscience, Ellisville, Missouri) injection we examined the effects of the adenosine A2A receptor antagonist ZM241385, the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole on bladder activity.Results: Intravenous administration of ZM241385 increased the intercontraction interval in a dose dependent manner in rats with Parkinson disease and sham operated rats but the inhibitory effect was greater in the Parkinson disease group. Intrathecal and intracerebroventricular administration of ZM241385 increased t...

  • effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the Micturition Reflex in rats
    BJUI, 2009
    Co-Authors: Hitoshi Masuda, William C De Groat, M B Chancellor, Kazunori Kihara, Yasuyuki Sakai, Fumitaka Koga, Hiroshi Azuma, Naoki Yoshimura
    Abstract:

    OBJECTIVE To investigate whether activation of brain and spinal cholinergic pathways affects the Micturition Reflex in rats. MATERIALS AND METHODS The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the Micturition Reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin. RESULTS Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M1 mAChR antagonist) = atropine > 4-DAMP (an M3 mAChR antagonist) >> methoctramine (an M2 mAChR antagonist) and tropicamide (an M4 mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively. CONCLUSIONS These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the Micturition Reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M1/M3 receptor subtypes in the brain, while in the spinal cord, the M1/M2 receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.

William C De Groat - One of the best experts on this subject based on the ideXlab platform.

  • mp11 04 sympathetic afferents in the hypogastric nerve facilitate nociceptive bladder activity in cats
    The Journal of Urology, 2019
    Co-Authors: Yan Zheng, James R Roppolo, William C De Groat, Jicheng Wang, Todd Yecies, Tara Nikonow, Haotian Cai, Bing Shen, Nathalie Pace, Changfeng Tai
    Abstract:

    INTRODUCTION AND OBJECTIVES:The normal Micturition Reflex in cats is mediated by Aδ-afferents in the pelvic nerve, while pelvic C-fiber afferents do not respond to bladder distension in normal phys...

  • effect of methysergide on pudendal inhibition of Micturition Reflex in cats
    Experimental Neurology, 2013
    Co-Authors: Yosuke Matsuta, James R Roppolo, Jicheng Wang, Bing Shen, Zeyad Schwen, Abhijith Mally, William C De Groat
    Abstract:

    Abstract The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P

  • suppression of bladder overactivity by adenosine a2a receptor antagonist in a rat model of parkinson disease
    The Journal of Urology, 2010
    Co-Authors: Takeya Kitta, Katsuya Nonomura, Michael B Chancellor, William C De Groat, Sadako Kuno, Naoki Yoshimura
    Abstract:

    Purpose: Overactive bladder is highly prevalent among patients with Parkinson disease. Adenosine is an important neurotransmitter in the central nervous system but it is not fully clarified how adenosine receptors regulate the Micturition Reflex. Thus, we examined the effect of an adenosine A2A receptor antagonist on the Micturition Reflex in a rat model of Parkinson disease.Materials and Methods: In a rat model of Parkinson disease induced by 6-hydroxydopamine (Tocris Bioscience, Ellisville, Missouri) injection we examined the effects of the adenosine A2A receptor antagonist ZM241385, the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole on bladder activity.Results: Intravenous administration of ZM241385 increased the intercontraction interval in a dose dependent manner in rats with Parkinson disease and sham operated rats but the inhibitory effect was greater in the Parkinson disease group. Intrathecal and intracerebroventricular administration of ZM241385 increased t...

  • effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the Micturition Reflex in rats
    BJUI, 2009
    Co-Authors: Hitoshi Masuda, William C De Groat, M B Chancellor, Kazunori Kihara, Yasuyuki Sakai, Fumitaka Koga, Hiroshi Azuma, Naoki Yoshimura
    Abstract:

    OBJECTIVE To investigate whether activation of brain and spinal cholinergic pathways affects the Micturition Reflex in rats. MATERIALS AND METHODS The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the Micturition Reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin. RESULTS Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M1 mAChR antagonist) = atropine > 4-DAMP (an M3 mAChR antagonist) >> methoctramine (an M2 mAChR antagonist) and tropicamide (an M4 mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively. CONCLUSIONS These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the Micturition Reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M1/M3 receptor subtypes in the brain, while in the spinal cord, the M1/M2 receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.

  • elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c fos expression induced by bladder irritation
    American Journal of Physiology-renal Physiology, 2005
    Co-Authors: Satoshi Seki, Yasuhiko Igawa, Osamu Nishizawa, Michael B Chancellor, William C De Groat, Kristin A Erickson, Masako Seki, Teruyuki Ogawa, Naoki Yoshimura
    Abstract:

    Substance P (SP) binding to neurokinin 1 receptors (NK1R) in the spinal cord reportedly plays an important role in the Micturition Reflex as well as in nociceptive responses. We therefore investiga...

Mitsuharu Yoshiyama - One of the best experts on this subject based on the ideXlab platform.

  • NETUPITANT, A POTENT AND HIGHLY SELECTIVE NK1 RECEPTOR ANTAGONIST, ALLEVIATES ACETIC ACID-INDUCED BLADDER OVERACTIVITY IN ANESTHETIZED GUINEA-PIGS
    Frontiers Media S.A., 2016
    Co-Authors: Stefano Palea, Philippe Lluel, Veronique Guilloteau, Moez Rekik, Emanuela Lovati, Marc Guerard, Maria-alba Guardia, Claudio Pietra, Mitsuharu Yoshiyama
    Abstract:

    Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the Micturition Reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, Reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of acetic acid (AA). After a 30 min stabilization period, netupitant (0.1-3 mg/kg, i.v.) or L-733,060 (3-10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of Micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of Reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the Micturition Reflex circuit and therefore may be useful clinically in treating bladder overactivity symptoms

  • supraspinal and spinal α amino 3 hydroxy 5 methylisoxazole 4 propionic acid and n methyl d aspartate glutamatergic control of the Micturition Reflex in the urethane anesthetized rat
    Neuroscience, 2005
    Co-Authors: Mitsuharu Yoshiyama, W C De Groat
    Abstract:

    Effects of i.c.v. and i.t. administration of (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY215490), a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist and MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist on the Micturition Reflex were evaluated in urethane-anesthetized rats, to determine if glutamatergic mechanisms in brain as well as spinal cord are important for the control of Micturition. I.c.v. or i.t. injection of LY215490 in low doses (0.01-0.03 microg) did not change rhythmic bladder or external urethral sphincter (EUS) electromyogram (EMG) activity during continuous cystometrograms (CMGs; 0.21 ml/min), whereas higher doses (0.1-1 microg) markedly suppressed these responses. During single CMGs (0.04 ml/min), 0.1-1 microg i.c.v. or 0.1-10 microg i.t. doses increased volume threshold and pressure threshold for inducing Micturition, and decreased bladder contraction amplitude and voiding efficiency. MK-801 in low doses (0.6 microg i.c.v. or 0.6-1.8 microg for i.t.) did not change bladder contraction amplitude or EUS EMG activity during continuous CMGs, whereas higher doses 6-60 microg markedly suppressed these responses. During single CMGs, MK-801 (6-60 microg i.c.v. or 60 microg i.t.) increased volume threshold and pressure threshold, and decreased voiding efficiency and bladder contraction amplitude. Pretreatment i.c.v. with MK-801 in a dose 1.8 microg which alone had little effect on bladder contraction amplitude and EUS EMG activity, markedly enhanced depressant effects of LY215490 (0.03 microg i.c.v.) on these responses. Administration of same doses of drugs by i.t. route did not elicit a similar synergistic interaction. These data indicate that in urethane-anesthetized rats glutamatergic mechanisms in brain and spinal cord are essential for controlling Micturition and that interactions between AMPA and NMDA glutamatergic transmission are important at supraspinal but not spinal sites.

  • developmental and injury induced plasticity in the Micturition Reflex pathway
    Behavioural Brain Research, 1998
    Co-Authors: Isao Araki, Naoki Yoshimura, Kimio Sugaya, Mitsuharu Yoshiyama, Margaret A Vizzard, Changfeng Tai
    Abstract:

    The storage and periodic elimination of urine are dependent upon neural circuits in the brain and spinal cord that co-ordinate the activity of the urinary bladder, the urethra and the striated urethral sphincter. This study utilized anatomical, electrophysiological and pharmacological techniques to examine: (1) the organization of the parasympathetic excitatory Reflex mechanisms that control the urinary bladder of the rat and the cat; and (2) the changes in these Reflexes during postnatal development and after spinal cord injury. In normal adult cats and rats, the parasympathetic excitatory input to the bladder is dependent upon a spinobulbospinal Reflex pathway that is activated by myelinated (Aδ) bladder afferents and that passes through an integrative center (the pontine Micturition center, PMC) in the rostral brain stem. Transneuronal tracing studies using pseudorabies virus as well as physiological methods have revealed that the PMC is located in close proximity to the locus coeruleus. Single unit recordings indicate that neurons in the PMC respond to afferent input from the bladder and are excited prior to or during Reflex bladder contractions. Glutamic acid is the major excitatory transmitter in the Micturition Reflex pathway. Glutamatergic transmission which is mediated by AMPA/kainate and NMDA receptors can be modulated by a variety of other transmitters. In neonatal animals, a spinal Micturition Reflex is activated by somatic afferent fibers from the perigenital region. This Reflex is suppressed during postnatal development, but can be unmasked in adult animals following spinal cord injury. Spinal injury also causes the emergence of a spinal bladder-to-bladder Reflex which in the cat is activated by capsaicin-sensitive C-fiber bladder afferents. Patch clamp studies in spinal cord slice preparations indicate that developmental and spinal cord injury induced plasticity in sacral parasympathetic Reflex pathways is due in part to alterations in glutamatergic excitatory transmission between interneurons and preganglionic neurons. Changes in the electrical properties of bladder afferent pathways may also contribute to the reorganization of bladder Reflexes in paraplegic animals.

  • effects of gyki 52466 and cnqx ampa kainate receptor antagonists on the Micturition Reflex in the rat
    Brain Research, 1995
    Co-Authors: Mitsuharu Yoshiyama, James R Roppolo, William C De Groat
    Abstract:

    Abstract GYKI 52466, a non-competitive AMPA/kainate glutamate receptor antagonist, administered in graded doses (0.5–8 mg/kg, i.v.) at 10 min intervals, decreased the amplitude and duration of Reflex bladder contractions (maximal inhibition = 63%), the intercontraction interval (maximal inhibition = 83%) and external urethral spincter activity (maximal inhibition = 91%) in urethane-anesthetized (1.2 g/kg, s.c.) intact rats during continuous transurethral cystometrograms. On the other hand, in unanesthetized decebrate rats, the drug did not alter Reflex bladder activity but did produce a significant depression of sphincter activity (maximal inhibition = 59%). The depressant effects of single doses of GYKI 52466 (4 mg/kg, i.v.) on external urethral sphincter EMG activity occurred with similar time courses in both urethane-anesthetized (1.2 g/kg, s.c.) intact and unanesthetized decerebrate rats during continuous transurethral cystometrograms. In urethane-treated (0.6 g/kg, i.p.) decerebrate rats, GYKI 52466 (0.5-4 mg/kg, i.v.) depressed bladder contraction amplitude and sphincter EMG activity, similar to the effects in urethane-anesthetized (1.2 g/kg, s.c.) intact rats. CNQX (0.01-1 mg/kg, i.v.), a competitive AMPA/kainate receptor antagonists, administered to urethane-anesthetized (1.2 g/kg. s.c.) intact or unanesthetized decerebrate rats did not alter the bladder or the external urethral sphincter activity during continuous transurethral cystometrograms, possibly due to the inability of the drug to readily cross the blood-brain barrier. The present results indicate that glutamatergic excitatory transmission mediated by AMPA/kainate receptors is essential for the activation of external urethral sphincter activity during Micturition in anesthetized and unanesthetized preparation. However, the depressant effect of GYKI 52466 on Reflex bladder activity is only unmasked by urethane anesthesia, raising the possibility that urethane interacts with AMPA/kainate glutamate receptors in the spinobulbospinal Micturition Reflex pathway.

  • effects of gyki 52466 and cnqx ampa kainate receptor antagonists on the Micturition Reflex in the rat
    Brain Research, 1995
    Co-Authors: Mitsuharu Yoshiyama, James R Roppolo, William C De Groat
    Abstract:

    GYKI 52466, a non-competitive AMPA/kainate glutamate receptor antagonist, administered in graded doses (0.5-8 mg/kg, i.v.) at 10 min intervals, decreased the amplitude and duration of Reflex bladder contractions (maximal inhibition = 63%), the intercontraction interval (maximal inhibition = 83%) and external urethral sphincter activity (maximal inhibition = 91%) in urethane-anesthetized (1.2 g/kg, s.c.) intact rats during continuous transurethral cystometrograms. On the other hand, in unanesthetized decerebrate rats, the drug did not alter Reflex bladder activity but did produce a significant depression of sphincter activity (maximal inhibition = 59%). The depressant effects of single doses of GYKI 52466 (4 mg/kg, i.v.) on external urethral sphincter EMG activity occurred with similar time courses in both urethane-anesthetized (1.2 g/kg, s.c.) intact and unanesthetized decerebrate rats during continuous transurethral cystometrograms. In urethane-treated (0.6 g/kg, i.p.) decerebrate rats, GYKI 52466 (0.5-4 mg/kg, i.v.) depressed bladder contraction amplitude and sphincter EMG activity, similar to the effects in urethane-anesthetized (1.2 g/kg, s.c.) intact rats. CNQX (0.01-1 mg/kg, i.v.), a competitive AMPA/kainate receptor antagonist, administered to urethane-anesthetized (1.2 g/kg, s.c.) intact or unanesthetized decerebrate rats did not alter the bladder or the external urethral sphincter activity during continuous transurethral cystometrograms, possibly due to the inability of the drug to readily cross the blood-brain barrier. The present results indicate that glutamatergic excitatory transmission mediated by AMPA/kainate receptors is essential for the activation of external urethral sphincter activity during Micturition in anesthetized and unanesthetized preparation. However, the depressant effect of GYKI 52466 on Reflex bladder activity is only unmasked by urethane anesthesia, raising the possibility that urethane interacts with AMPA/kainate glutamate receptors in the spinobulbospinal Micturition Reflex pathway.

Osamu Yoshida - One of the best experts on this subject based on the ideXlab platform.

  • therapeutic effects of dopamine d1 d2 receptor agonists on detrusor hyperReflexia in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine lesioned parkinsonian cynomolgus monkeys
    Journal of Pharmacology and Experimental Therapeutics, 1998
    Co-Authors: Naoki Yoshimura, E Mizuta, Osamu Yoshida, Sadako Kuno
    Abstract:

    The effects of dopamine receptor agonists on urinary bladder function were evaluated in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys to investigate the therapeutic efficacy in the treatment of urinary symptoms in Parkinson’s disease. Under ketamine anesthesia, cystometrograms exhibited significant reduction in the volume threshold for the Micturition Reflex in MPTP-lesioned parkinsonian monkeys when compared with those of normal monkeys. The selective dopamine D 2 receptor agonist bromocriptine significantly reduced the bladder volume threshold for the Micturition Reflex by 25 to 30% in both normal and MPTP-lesioned animals. The nonselective D 1 /D 2 receptor agonist pergolide significantly reduced the bladder volume threshold by 22% in normal monkeys, but increased the volume threshold by 50% in MPTP-lesioned parkinsonian monkeys. Another D 1 /D 2 agonist (5 R ,8 R ,10 R )-6-methyl-8-(1,2,4-triazol-1-ylmethyl) ergoline maleate (BAM-1110) also increased the bladder volume threshold (by 80%) in parkinsonian monkeys without significant effects on the Micturition Reflex in normal monkeys. The reduction in the volume threshold by bromocriptine in both normal and MPTP-treated groups and by pergolide in normal monkeys was suppressed by pretreatment with the selective D 2 antagonist sulpiride, whereas the increment in the volume threshold by pergolide and BAM-1110 in parkinsonian monkeys was antagonized by pretreatment with the selective D 1 antagonist SCH 23390, but not by sulpiride. These findings suggest that concurrent activation of D 1 /D 2 receptors, rather than selective stimulation of D 2 receptors, might be beneficial for treating urinary symptoms caused by detrusor hyperReflexia in Parkinson’s disease.

  • the dopamine d1 receptor agonist skf 38393 suppresses detrusor hyperReflexia in the monkey with parkinsonism induced by 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp
    Neuropharmacology, 1993
    Co-Authors: Naoki Yoshimura, E Mizuta, S Kuno, Masashi Sasa, Osamu Yoshida
    Abstract:

    A pharmacological study using monkeys, in which parkinsonism was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was undertaken to elucidate the mechanism underlying urinary bladder dysfunctions in Parkinson's disease. Under ketamine anesthesia, cystometrograms showed that, in MPTP-treated monkeys, a contraction of the urinary bladder was induced with smaller bladder volume than that in normal monkeys. In MPTP-treated monkeys, subcutaneously injected SKF 38393, a dopamine D1 receptor agonist, significantly increased the bladder volume and pressure thresholds for inducing the Micturition Reflex without affecting those in normal monkeys. In contrast, subcutaneous injections of quinpirole, a dopamine D2 receptor agonist, and apomorphine, a dopamine D1 and D2 receptor agonist, slightly, but significantly reduced the volume threshold of the bladder for the Micturition Reflex in both normal and MPTP-treated groups. These results indicate that, in parkinsonism, the degeneration of dopaminergic neurons in the substantia nigra leads to the detrusor hyperReflexia, probably due to a failure of activation of dopamine D1 receptors.

  • inhibitory effects of hachimijiogan on Micturition Reflex via the locus coeruleus
    Folia Pharmacologica Japonica, 1992
    Co-Authors: Naoki Yoshimura, Masashi Sasa, Osamu Yoshida, Shuji Takaori
    Abstract:

    Pharmacological studies were undertaken to elucidate the role of Hachimijiogan in the Micturition Reflex via the locus coeruleus, using alpha-chloralose-anesthetized cats. Rhythmic contractions of the urinary bladder induced by continuous infusion of saline into the bladder were dose-dependently inhibited by intravenous injection of Hachimijiogan (10, 30 and 90 mg/kg), as well as flavoxate hydrochloride (1 and 3 mg/kg). In contrast, contraction of the urinary bladder elicited by electrical stimulation of the locus coeruleus was significantly suppressed by intravenous injection of flavoxate, but not affected by that of Hachimijiogan. These results suggest that Hachimijiogan acts on the afferent pathway from the urinary bladder to the locus coeruleus, thereby inhibiting the Micturition Reflex, while it has no effects on the efferent pathway from the locus coeruleus to the urinary bladder.

Andrew G Ramage - One of the best experts on this subject based on the ideXlab platform.

  • 5 ht2a receptor activation of the external urethral sphincter and 5 ht2c receptor inhibition of Micturition a study based on pharmacokinetics in the anaesthetized female rat
    European Journal of Pharmacology, 2012
    Co-Authors: Yvonne Mbaki, Jennife C Gardine, Gordo Mcmurray, Andrew G Ramage
    Abstract:

    Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of Micturition. Bolus doses of 5-HT(2A/2C) receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit Micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of Micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the Micturition Reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats. The effects of intravenous (i.v.) infusions of the 5-HT(2) receptor agonist (2S)-1-(6-chloro-5-fluoroindol-1-yl)propan-2-amine fumarate (Ro 60-0175) in the absence or presence of the selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride (SB 242084) or 5-HT(2A) receptor antagonist (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (MDL-100,907) were studied on these variables. Continuous infusion of increasing concentrations of Ro 60-0175 only evoked EUS-EMG activity at the highest concentration, which was blocked by co-infusion of MDL-100,907 but not SB 242084. Urethral pressure was unaffected by any drug infusion. Ro 60-0175 at the lowest concentration inhibited the Micturition Reflex but as the concentration increased this was reversed to facilitation. SB 242084 blocked the inhibition while MDL-100,907 blocked the excitation. Activation of 5-HT(2A) not 5-HT(2C) receptors evoked EUS-EMG activity. In conclusion, 5-HT(2A) receptor activation facilitated the Micturition Reflex and evoked EUS-EMG while 5-HT(2C) receptor activation only inhibited the Micturition Reflex.

  • investigation of the role of 5 ht2 receptor subtypes in the control of the bladder and the urethra in the anaesthetized female rat
    British Journal of Pharmacology, 2009
    Co-Authors: Yvonne Mbaki, Andrew G Ramage
    Abstract:

    Background and purpose: Micturition is controlled by central 5-HT-containing pathways. 5-HT2 receptors have been implicated in this system especially in control of the urethra, which is a drug target for treating urinary incontinence. This study investigates the role of each of the three subtypes of this receptor with emphasis on sphincter regulation. Experimental approach: Recordings of urethral and bladder pressure, external urethral sphincter (EUS) EMG, as well as the Micturition Reflex induced by bladder distension along with blood pressure and heart rate were made in anaesthetized rats. The effects of agonists and antagonists for 5-HT2 receptor subtypes were studied on these variables. Key results: The 5-HT2C agonists Ro 60-0175, WAY 161503 and mCPP, i.v., activated the EUS, increased urethral pressure and inhibited the Micturition Reflex. The effects of Ro 60-0175 on the EUS were blocked by the 5-HT2C antagonist SB 242084 and the 5-HT2A antagonists, ketanserin and MDL 100907. SB 242084 also blocked the inhibitory action on the Reflex, while the 5-HT2B antagonist RS 127445 only blocked the increase in urethral pressure. The 5-HT2A receptor agonist DOI given i.v. or i.t. but not i.c.v. activated the EUS. Conclusions and implications: 5-HT2A/2C receptors located in the sacral spinal cord activate the EUS, while central 5-HT2C receptors inhibit the Micturition Reflex and 5-HT2B receptors, probably at the level of the urethra, increase urethral smooth muscle tone. Furthermore, 5-HT2B and 5-HT2C receptors do not seem to play an important role in the physiological regulation of Micturition. British Journal of Pharmacology (2008) 155, 343–356; doi:10.1038/bjp.2008.273; published online 7 July 2008

  • Investigation of the effects of P2 purinoceptor ligands on the Micturition Reflex in female urethane-anaesthetized rats
    British Journal of Pharmacology, 2004
    Co-Authors: Brian F. King, Geoffrey Burnstock, Ian D Knowles, Andrew G Ramage
    Abstract:

    The effects of purinoceptor ligands for P2X1 and/or P2X3 receptors (α,β-meATP, IP5I, TNP-ATP, MRS 2179, PPADS, Phenol red and RO116-6446/008; i.v., n=4–5) and for P2Y1 receptors (PPADS, MRS 2179 and MRS 2269; i.v., n=3–5) were investigated on the distension-evoked ‘Micturition Reflex’ in the urethane-anaesthetized female rat. α,β-meATP (180 nmol kg−1 min−1), IP5I (10, 30 and 100 nmol kg−1), TNP-ATP (1 μmol kg−1), MRS 2179 (1 μmol kg−1) and PPADS (17 μmol kg−1) each caused maintained bladder contractions to occur during the infusion of saline into the bladder. PPADS (17 μmol kg−1 min−1) had a similar effect when infused intravesicularly. Regular bladder contractions were not observed until the infusion of saline was halted. For IP5I, TNP-ATP, MRS 2179 and PPADS, the magnitude of postinfusion isovolumetric contractions was significantly reduced and, for IP5I, this action was also associated with a significant reduction in urethral relaxation. Additionally, TNP-ATP caused a significant increase in the pressure and volume thresholds required to initiate a Reflex. Phenol red (a P2X1/P2X3 antagonist; 0.1 and 1 μmol kg−1) caused a significant increase in the pressure and volume thresholds required to initiate a Reflex and, at the higher dose, also caused a reduction in postinfusion isovolumetric contractions. RO116-6446/008 (a P2X1-selective antagonist; 1 and 10 μmol kg−1) only caused a reduction in postinfusion isovolumetric contractions. It is concluded that P2X1 and P2X3 receptors play a fundamental role in the Micturition Reflex in urethane-anesthetized female rats. P2X3 receptor blockade raised the pressure and volume thresholds for the Reflex, whereas P2X1 receptor blockade diminished motor activity associated with voiding. P2Y1 receptors may be involved in inhibition of rat detrusor tone. British Journal of Pharmacology (2004) 142, 519–530. doi:10.1038/sj.bjp.0705790