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Martin C. Michel - One of the best experts on this subject based on the ideXlab platform.

  • signal transduction underlying the control of urinary Bladder smooth muscle tone by muscarinic receptors and β adrenoceptors
    Naunyn-schmiedebergs Archives of Pharmacology, 2008
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Michael R. Ruggieri, Martin C. Michel
    Abstract:

    The normal physiological Contraction of the urinary Bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of Contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to Bladder dysfunction known as the overactive Bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive Bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the Bladder. Nevertheless, PLC apparently contributes only in a very minor way to Bladder Contraction. Rather, muscarinic-receptor-mediated Bladder Contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated Bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated Bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive Bladder.

  • Does Phospholipase C Mediate Muscarinic Receptor-Induced Rat Urinary Bladder Contraction?
    The Journal of pharmacology and experimental therapeutics, 2007
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Martin C. Michel, Michael R. Ruggieri
    Abstract:

    Muscarinic acetylcholine receptors, particularly M 3 receptors, are physiologically the most important mechanism to induced urinary Bladder smooth muscle Contraction. Their prototypical signaling response is a stimulation of phospholipase C (PLC), and this also has been shown in the urinary Bladder. Nevertheless, it has remained controversial whether PLC signaling mediates Bladder Contraction induced by muscarinic receptor agonists. Studies in favor and against a role for PLC differed in their experimental protocol (single versus repeated concentration-response curves within a single preparation) and in the PLC inhibitors that have been used. We have now tested whether previous differential conclusions regarding a role for PLC are related to inhibitors and/or experimental protocols. In a single curve protocol, U-73,122 [1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1 H -pyrrole-2,5-dione] did not attenuate carbachol responses. In a repeated curve protocol, ET-18-OCH 3 (1- O -octadecyl-2- O -methyl- sn -glycero-3-phosphorylcholine) lacked significant inhibition relative to vehicle time controls. In contrast, D609 ( O -tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt) depressed maximal carbachol effects but also nonspecifically inhibited Contraction induced by KCl. Neomycin did not affect the carbachol-induced rat urinary Bladder Contraction. We conclude that previously reported differences relate to the use of inhibitors rather than experimental protocols and that the overall data do not support a role for PLC in M 3 muscarinic receptor-mediated rat Bladder Contraction.

  • signal transduction underlying carbachol induced Contraction of human urinary Bladder
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Tim Schneider, Charlotte Fetscher, Susanne Krege, Martin C. Michel
    Abstract:

    The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbachol-induced Contraction of human urinary Bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), Contraction occurs via M(3) receptors. The phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 microM) did not significantly affect carbachol-stimulated Bladder Contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of carbachol-induced Bladder Contraction. The Ca(2+) entry blocker nifedipine (10-100 nM) strongly inhibited carbachol-induced Bladder Contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 microM), an inhibitor of store-operated Ca(2+) channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 microM) did not significantly affected carbachol-induced Bladder Contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 microM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the carbachol responses. We conclude that carbachol-induced Contraction of human urinary Bladder via M(3) receptors largely depends on Ca(2+) entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca(2+) channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.

  • Extracts from Rhois aromatica and Solidaginis virgaurea inhibit rat and human Bladder Contraction
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
    Co-Authors: Verena E. Borchert, Peter Czyborra, Charlotte Fetscher, Mark Goepel, Martin C. Michel
    Abstract:

    Since extracts from the plants Rhois aromatica and Solidaginis virgaurea are being used in the phytotherapy of Bladder dysfunction including the overactive Bladder syndrome, and since muscarinic receptors are the main pharmacological target in the treatment of Bladder dysfunction, we have investigated whether these extracts can inhibit carbachol-induced, muscarinic receptor-mediated Contraction of rat and human Bladder. In vitro Contraction experiments were performed with rat and human Bladder strips. Radioligand binding and inositol phosphate accumulation studies were done with cells transfected with human M_2 or M_3 muscarinic receptors. Both extracts concentration-dependently (final concentrations 0.01–0.1%) inhibited carbachol-induced Contraction of rat and human Bladder with insurmountable antagonism. Radioligand binding experiments and inositol phosphate accumulation studies with cloned receptors demonstrated direct but non-competitive effects on muscarinic receptors. Reductions of KCl-induced Bladder Contraction demonstrated that inhibition by the higher extract concentrations also involved receptor-independent effects. We conclude that extracts from Rhois aromatica and Solidaginis virgaurea inhibit muscarinic receptor-mediated Contraction of rat and human Bladder. While this could contribute to the beneficial effects of these extracts in patients with Bladder dysfunction, such therapeutic effects remain to be demonstrated in controlled clinical studies.

  • signal transduction underlying carbachol induced Contraction of rat urinary Bladder i phospholipases and ca2 sources
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Tim Schneider, Peter Hein, Martin C. Michel
    Abstract:

    We have reexamined the muscarinic receptor subtype mediating carbachol-induced Contraction of rat urinary Bladder and investigated the role of phospholipase (PL)C, D, and A2 and of intra- and extracellular Ca2+ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M2 receptor-selective ( R )-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), Contraction occurs via M3 receptors. Carbachol stimulated inositol phosphate formation in rat Bladder slices, and this was abolished by the phospholipase C inhibitor 1-(6-[([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1 H -pyrrole-2,5-dione (U 73,122; 10 μM). Nevertheless, U 73,122 (1–10 μM) did not significantly affect carbachol-stimulated Bladder Contraction. Carbachol had only little effect on PLD activity in Bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of carbachol-induced Bladder Contraction. The cytosolic PLA2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited carbachol-induced Contraction at a concentration of 300 μM, but the cyclooxygenase inhibitor indomethacin (1–10 μM) remained without effect. The Ca2+ entry blocker nifedipine (10–100 nM) almost completely inhibited carbachol-induced Bladder Contraction. In contrast, 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H -imidazole HCl (SKF 96,365; 10 μM), an inhibitor of store-operated Ca2+ channels, caused little inhibition. We conclude that carbachol-induced Contraction of rat Bladder largely depends on Ca2+ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA2, and store-operated Ca2+ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.

Michael R. Ruggieri - One of the best experts on this subject based on the ideXlab platform.

  • signal transduction underlying the control of urinary Bladder smooth muscle tone by muscarinic receptors and β adrenoceptors
    Naunyn-schmiedebergs Archives of Pharmacology, 2008
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Michael R. Ruggieri, Martin C. Michel
    Abstract:

    The normal physiological Contraction of the urinary Bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of Contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to Bladder dysfunction known as the overactive Bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive Bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the Bladder. Nevertheless, PLC apparently contributes only in a very minor way to Bladder Contraction. Rather, muscarinic-receptor-mediated Bladder Contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated Bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated Bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive Bladder.

  • Does Phospholipase C Mediate Muscarinic Receptor-Induced Rat Urinary Bladder Contraction?
    The Journal of pharmacology and experimental therapeutics, 2007
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Martin C. Michel, Michael R. Ruggieri
    Abstract:

    Muscarinic acetylcholine receptors, particularly M 3 receptors, are physiologically the most important mechanism to induced urinary Bladder smooth muscle Contraction. Their prototypical signaling response is a stimulation of phospholipase C (PLC), and this also has been shown in the urinary Bladder. Nevertheless, it has remained controversial whether PLC signaling mediates Bladder Contraction induced by muscarinic receptor agonists. Studies in favor and against a role for PLC differed in their experimental protocol (single versus repeated concentration-response curves within a single preparation) and in the PLC inhibitors that have been used. We have now tested whether previous differential conclusions regarding a role for PLC are related to inhibitors and/or experimental protocols. In a single curve protocol, U-73,122 [1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1 H -pyrrole-2,5-dione] did not attenuate carbachol responses. In a repeated curve protocol, ET-18-OCH 3 (1- O -octadecyl-2- O -methyl- sn -glycero-3-phosphorylcholine) lacked significant inhibition relative to vehicle time controls. In contrast, D609 ( O -tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt) depressed maximal carbachol effects but also nonspecifically inhibited Contraction induced by KCl. Neomycin did not affect the carbachol-induced rat urinary Bladder Contraction. We conclude that previously reported differences relate to the use of inhibitors rather than experimental protocols and that the overall data do not support a role for PLC in M 3 muscarinic receptor-mediated rat Bladder Contraction.

  • hypertrophy changes the muscarinic receptor subtype mediating Bladder Contraction from m3 toward m2
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
    Co-Authors: Alan S. Braverman, Michael R. Ruggieri
    Abstract:

    Major pelvic ganglion electrocautery (MPGE) and spinal cord injury in the rat induce Bladder hypertrophy and a change in muscarinic receptor subtypes mediating Bladder Contraction from predominantly M3 to a combination of M2 and M3. To determine whether this is a result of Bladder hypertrophy or denervation, we studied the following groups: sham-operated controls, urinary diversion (DIV), MPGE together with urinary diversion (DIV-DEN), bilateral MPGE (DEN), Bladder outlet obstruction (BOO), and MPG decentralization (MPGDEC). The degree of Bladder denervation was determined by the maximal carbachol response normalized to the response to electric field stimulation. Receptor subtype density was determined by immunoprecipitation. The affinity of subtype-selective muscarinic antagonists for inhibition of carbachol-induced Contractions was used to determine the subtype-mediating Contraction. DEN, MPG-DEC, and BOO Bladders were hypertrophic whereas DIV Bladders were atrophic compared with sham operated. Bladder Contraction in sham-operated, DIV, and DIV-DEN was mediated by the M3 receptor subtype, whereas the M2 subtype participated in Contraction in the DEN, MPG-DEC, and BOO groups. The hypertrophied Bladders had an increase in total and M2 receptor density while all experimental groups showed a reduction in M3 receptor density. Thus Bladder hypertrophy, independent from Bladder denervation, causes a shift in the muscarinic receptor subtype mediating Bladder Contraction from M3 toward M2.

  • interaction between muscarinic receptor subtype signal transduction pathways mediating Bladder Contraction
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2002
    Co-Authors: Alan S. Braverman, Ronald J Tallarida, Michael R. Ruggieri
    Abstract:

    M3 muscarinic receptors mediate cholinergic-induced Contraction in most smooth muscles. However, in the denervated rat Bladder, M2 receptors participate in Contraction because M3-selective antagoni...

Kimio Sugaya - One of the best experts on this subject based on the ideXlab platform.

  • Effect of distigmine combined with propiverine on Bladder activity in rats with spinal cord injury
    International journal of urology : official journal of the Japanese Urological Association, 2012
    Co-Authors: Kimio Sugaya, Katsuhiro Ashitomi, Saori Nishijima, Katsumi Kadekawa, Hideyuki Yamamoto
    Abstract:

    It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti-muscarinic agents for this condition. Therefore, the effect of co-administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti-muscarinic agent) on Bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The Bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01–1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum Bladder Contraction pressure was significantly increased, and the duration of Bladder Contraction and the interval between Bladder Contractions were significantly prolonged. The baseline Bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between Bladder Contractions was significantly further prolonged without any change of the maximum Contraction pressure, baseline pressure or duration of Bladder Contraction. The residual volume after voiding Bladder Contraction was less than 0.1 mL in all animals. In conclusion, co-administration of distigmine with propiverine might improve both Bladder underactivity during the voiding phase and Bladder overactivity during the storage phase.

  • Restoration of Bladder Contraction by bone marrow transplantation in rats with underactive Bladder.
    Biomedical research (Tokyo Japan), 2007
    Co-Authors: Saori Nishijima, Minoru Miyazato, Kimio Sugaya, Katsumi Kadekawa, Yoshinori Oshiro, Atsushi Uchida, Sanehiro Hokama, Yoshihide Ogawa
    Abstract:

    We attempted to increase Bladder Contraction by bone marrow cell transplantation in rats with underactive Bladder due to Bladder outlet obstruction (BOO). Twelve female rats were anesthetized with halothane to create BOO. After 1 month, the urethral obstruction was removed and they were divided into a transplant group and a sham-operated group (n = 6 each). Bone marrow cells (1 × 107 / 0.2 mL) isolated from green fluorescent protein transgenic rats were injected into the Bladder wall of the transplant group. Rats from the sham-operated group received injection of culture medium alone. One month after transplantation, isovolumetric cystometry parameters and histological features of Bladder were observed as well as intact control rats (n = 6). The amplitude of Bladder Contractions was larger and the interval between Contractions was shorter in the transplant group than the sham-operated group, and there were no differences in these parameters between the transplant group and the control group. Some green fluorescent muscle layers were found in the Bladder wall of the transplant group, and these layers were also labeled by anti alpha-smooth muscle actin antibody. These results suggest that transplanted bone marrow cells may improve Bladder contractility by differentiating into smooth muscle-like cells.

  • activation of the rostral pontine reticular formation increases the spinal glycine level and inhibits Bladder Contraction in rats
    The Journal of Urology, 2005
    Co-Authors: Saori Nishijima, Minoru Miyazato, Kimio Sugaya, Shuichi Shimabukuro, Makoto Morozumi, Yoshihide Ogawa
    Abstract:

    ABSTRACT Purpose: We examined the mechanism involved in the inhibition of Bladder activity in rats by stimulating the rostral pontine reticular formation (RPRF) using carbachol, flavoxate and propiverine, and by analysis of amino acid levels in the lumbosacral cord. Materials and Methods: A total of 82 female rats were anesthetized with urethane. Under isovolumetric conditions physiological saline, carbachol, flavoxate or propiverine was injected into the RPRF or intravenously. Changes in Bladder activity and amino acid levels in the lumbosacral cord were examined. Results: Injection of carbachol or flavoxate (0.3 μM each) into the RPRF abolished Bladder Contraction but there was no change after injection of physiological saline or propiverine. Intravenous injection of flavoxate or propiverine (0.1 to 10 mg/kg each) inhibited Bladder Contraction. Amino acid analysis revealed that injection of carbachol into the RPRF increased glutamate and glycine levels in the lumbosacral cord, while injection of flavoxate into the RPRF or intravenously caused an increase in glycine the lumbosacral cord. Injection of propiverine into the RPRF or intravenously did not influence lumbosacral cord amino acid levels. Conclusions: These results suggest that the RPRF has an important role in the inhibition of Bladder Contraction and carbachol or flavoxate can activate descending RPRF neurons and inhibit Bladder Contraction via spinal glycinergic neurons.

  • Rectal distention inhibits Bladder activity via glycinergic and GABAergic mechanisms in rats.
    The Journal of urology, 2004
    Co-Authors: Minoru Miyazato, Katsuhiro Ashitomi, Kimio Sugaya, Saori Nishijima, Choko Ohyama, Yoshihide Ogawa
    Abstract:

    ABSTRACTPurpose: We examined the influence of rectal distention on the spinobulbospinal micturition reflex and the mechanism underlying the inhibition of Bladder Contraction.Materials and Methods: A total of 22 female Sprague-Dawley rats were used in this study. Using urethane anesthesia isovolumetric cystometry was performed before and after distention of the rectum by inflation of a rectal balloon (0 to 3 cm3), followed by the intrathecal injection of strychnine (a glycine receptor antagonist, 0.001 to 10 μg) and/or bicuculline (a γ-aminobutyric acidA receptor antagonist, 0.001 to 1 μg) at the lumbosacral level of the spinal cord.Results: Rectal distention (1.5 to 3.0 cm3) prolonged the interval, decreased the amplitude and shortened the duration of Bladder Contraction and finally almost abolished Bladder activity. After intrathecal injection of strychnine or bicuculline in animals with inhibition of the Bladder by rectal distention the interval and duration of Bladder Contraction returned to baseline b...

  • Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adrenergic receptor antagonists, on Bladder activity in rats.
    Neuroscience Letters, 2002
    Co-Authors: Kimio Sugaya, Katsuhiro Ashitomi, Tadashi Hatano, Minoru Miyazato, Saori Nishijima, Yoshihide Ogawa
    Abstract:

    Abstract The effects of intrathecal injection of tamsulosin (an alpha-1A adrenergic receptor antagonist) and naftopidil (an alpha-1D adrenergic receptor antagonist) on isovolumetric Bladder Contraction were investigated in rats under urethane anesthesia. Intrathecal injection of tamsulosin (10–30 μg) or naftopidil (0.1–30 μg) transiently abolished isovolumetric rhythmic Bladder Contraction. Following the recovery of Bladder Contraction, the interval between Contractions was the same as the control value before the injection. The amplitude of Bladder Contraction was decreased by intrathecal injection of naftopidil (3–30 μg), but not by tamsulosin. Therefore, in addition to the antagonistic action of these agents on the alpha-1 adrenergic receptors of prostatic smooth muscle, both agents (especially naftopidil) may also act on the lumbosacral cord, and thus may improve collecting disorders in patients with benign prostatic hyperplasia.

Alan S. Braverman - One of the best experts on this subject based on the ideXlab platform.

  • signal transduction underlying the control of urinary Bladder smooth muscle tone by muscarinic receptors and β adrenoceptors
    Naunyn-schmiedebergs Archives of Pharmacology, 2008
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Michael R. Ruggieri, Martin C. Michel
    Abstract:

    The normal physiological Contraction of the urinary Bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of Contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to Bladder dysfunction known as the overactive Bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive Bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the Bladder. Nevertheless, PLC apparently contributes only in a very minor way to Bladder Contraction. Rather, muscarinic-receptor-mediated Bladder Contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated Bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated Bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive Bladder.

  • Does Phospholipase C Mediate Muscarinic Receptor-Induced Rat Urinary Bladder Contraction?
    The Journal of pharmacology and experimental therapeutics, 2007
    Co-Authors: Elfaridah P. Frazier, Alan S. Braverman, Stephan L. M. Peters, Martin C. Michel, Michael R. Ruggieri
    Abstract:

    Muscarinic acetylcholine receptors, particularly M 3 receptors, are physiologically the most important mechanism to induced urinary Bladder smooth muscle Contraction. Their prototypical signaling response is a stimulation of phospholipase C (PLC), and this also has been shown in the urinary Bladder. Nevertheless, it has remained controversial whether PLC signaling mediates Bladder Contraction induced by muscarinic receptor agonists. Studies in favor and against a role for PLC differed in their experimental protocol (single versus repeated concentration-response curves within a single preparation) and in the PLC inhibitors that have been used. We have now tested whether previous differential conclusions regarding a role for PLC are related to inhibitors and/or experimental protocols. In a single curve protocol, U-73,122 [1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1 H -pyrrole-2,5-dione] did not attenuate carbachol responses. In a repeated curve protocol, ET-18-OCH 3 (1- O -octadecyl-2- O -methyl- sn -glycero-3-phosphorylcholine) lacked significant inhibition relative to vehicle time controls. In contrast, D609 ( O -tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt) depressed maximal carbachol effects but also nonspecifically inhibited Contraction induced by KCl. Neomycin did not affect the carbachol-induced rat urinary Bladder Contraction. We conclude that previously reported differences relate to the use of inhibitors rather than experimental protocols and that the overall data do not support a role for PLC in M 3 muscarinic receptor-mediated rat Bladder Contraction.

  • hypertrophy changes the muscarinic receptor subtype mediating Bladder Contraction from m3 toward m2
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
    Co-Authors: Alan S. Braverman, Michael R. Ruggieri
    Abstract:

    Major pelvic ganglion electrocautery (MPGE) and spinal cord injury in the rat induce Bladder hypertrophy and a change in muscarinic receptor subtypes mediating Bladder Contraction from predominantly M3 to a combination of M2 and M3. To determine whether this is a result of Bladder hypertrophy or denervation, we studied the following groups: sham-operated controls, urinary diversion (DIV), MPGE together with urinary diversion (DIV-DEN), bilateral MPGE (DEN), Bladder outlet obstruction (BOO), and MPG decentralization (MPGDEC). The degree of Bladder denervation was determined by the maximal carbachol response normalized to the response to electric field stimulation. Receptor subtype density was determined by immunoprecipitation. The affinity of subtype-selective muscarinic antagonists for inhibition of carbachol-induced Contractions was used to determine the subtype-mediating Contraction. DEN, MPG-DEC, and BOO Bladders were hypertrophic whereas DIV Bladders were atrophic compared with sham operated. Bladder Contraction in sham-operated, DIV, and DIV-DEN was mediated by the M3 receptor subtype, whereas the M2 subtype participated in Contraction in the DEN, MPG-DEC, and BOO groups. The hypertrophied Bladders had an increase in total and M2 receptor density while all experimental groups showed a reduction in M3 receptor density. Thus Bladder hypertrophy, independent from Bladder denervation, causes a shift in the muscarinic receptor subtype mediating Bladder Contraction from M3 toward M2.

  • interaction between muscarinic receptor subtype signal transduction pathways mediating Bladder Contraction
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2002
    Co-Authors: Alan S. Braverman, Ronald J Tallarida, Michael R. Ruggieri
    Abstract:

    M3 muscarinic receptors mediate cholinergic-induced Contraction in most smooth muscles. However, in the denervated rat Bladder, M2 receptors participate in Contraction because M3-selective antagoni...

Kenneth C Bovee - One of the best experts on this subject based on the ideXlab platform.

  • effects of bethanechol on canine urinary Bladder smooth muscle function
    Research in Veterinary Science, 2001
    Co-Authors: Chollada Buranakarl, Anusak Kijtawornrat, Kris Angkanaporn, Siripen Komolvanich, Kenneth C Bovee
    Abstract:

    We studied whether the effects of bethanechol are mediated via a muscarinic receptor, the role of extracellular calcium on Bladder Contraction, and down-regulation of Bladder Contraction by bethanechol after activation with potassium chloride (KCl) and acetylcholine (Ach). Smooth muscle strips of normal urinary Bladder were studied with standard methods to measure isometric force. Bethanechol caused a dose-dependent increase in Bladder Contraction. The potency of bethanechol is higher than Ach, as shown by higher peak active isometric stress (P(max)) and lower half-maximal Contraction (ED(50)) (P< 0.01). The contractile responses to bethanechol were diminished in the presence of atropine, nifedipine and in calcium-free medium as shown by P(max) decreased by 58%, 87% and 65% and ED(50) increased by 314-, 24- and 16-fold, respectively. When Bladder strips were stimulated with KCl and Ach, pre-treatment with bethanechol reduced the responses to KCl by 116-242% (P<0.05), while the contractile responses to Ach were unaltered. Thus, bethanechol induces Bladder Contraction via muscarinic receptor activation while both intracellular and extracellular calcium play a crucial role on Bladder smooth muscle Contraction. The mechanisms of down-regulation by bethanechol may be related to interference with calcium influx into the smooth muscle cells, rather than the desensitisation of muscarinic receptors or post-receptor steps of signal transduction following bethanechol binding to the receptor.

  • Effects of bethanechol on canine urinary Bladder smooth muscle function.
    Research in veterinary science, 2001
    Co-Authors: Chollada Buranakarl, Anusak Kijtawornrat, Kris Angkanaporn, Siripen Komolvanich, Kenneth C Bovee
    Abstract:

    We studied whether the effects of bethanechol are mediated via a muscarinic receptor, the role of extracellular calcium on Bladder Contraction, and down-regulation of Bladder Contraction by bethanechol after activation with potassium chloride (KCl) and acetylcholine (Ach). Smooth muscle strips of normal urinary Bladder were studied with standard methods to measure isometric force. Bethanechol caused a dose-dependent increase in Bladder Contraction. The potency of bethanechol is higher than Ach, as shown by higher peak active isometric stress (P(max)) and lower half-maximal Contraction (ED(50)) (P< 0.01). The contractile responses to bethanechol were diminished in the presence of atropine, nifedipine and in calcium-free medium as shown by P(max) decreased by 58%, 87% and 65% and ED(50) increased by 314-, 24- and 16-fold, respectively. When Bladder strips were stimulated with KCl and Ach, pre-treatment with bethanechol reduced the responses to KCl by 116-242% (P