QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.058248v1 308/1/47    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schneider, T. Articles by Michel, M. C. Search for Related Content PubMed PubMed Citation Articles by Schneider, T. Articles by Michel, M. C.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca²⁺ Sources

Departments of Medicine (T.S., P.H., M.C.M.) and Urology (T.S.), University of Essen, Essen, Germany; and Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Amsterdam, The Netherlands (M.C.M.)

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-[([17]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-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-[-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-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.

Address correspondence to: Professor Martin C. Michel, Academisch Medisch Centrum, Afd. Farmacologie en Farmacotherapie, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: m.c.michel{at}amc.uva.nl

This article has been cited by other articles:

				M. Basha, E. F. LaBelle, G. M. Northington, T. Wang, A. J. Wein, and S. Chacko Functional significance of muscarinic receptor expression within the proximal and distal rat vagina Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1486 - R1493. [Abstract] [Full Text] [PDF]

				H.-L. Zhu, K. L. Brain, M. Aishima, A. Shibata, J. S. Young, K. Sueishi, and N. Teramoto Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 118 - 127. [Abstract] [Full Text] [PDF]

				E. P. Frazier, A. S. Braverman, S. L. M. Peters, M. C. Michel, and M. R. Ruggieri Sr. Does Phospholipase C Mediate Muscarinic Receptor-Induced Rat Urinary Bladder Contraction? J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 998 - 1002. [Abstract] [Full Text] [PDF]

				J. Benitez-Rajal, M.-J. Lorite, A. D. Burt, C. P. Day, and M. G. Thompson Phospholipase D and extracellular signal-regulated kinase in hepatic stellate cells: effects of platelet-derived growth factor and extracellular nucleotides. Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291(5): G977 - G986. [Abstract] [Full Text] [PDF]

				A. S. Braverman, A. S. Tibb, and M. R. Ruggieri Sr M2 and M3 Muscarinic Receptor Activation of Urinary Bladder Contractile Signal Transduction. I. Normal Rat Bladder J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 869 - 874. [Abstract] [Full Text] [PDF]

				E. P. Frazier, M.-J. Mathy, S. L. M. Peters, and M. C. Michel Does Cyclic AMP Mediate Rat Urinary Bladder Relaxation by Isoproterenol? J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 260 - 267. [Abstract] [Full Text] [PDF]

				K.-E. Andersson and A. J. Wein Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence Pharmacol. Rev., December 1, 2004; 56(4): 581 - 631. [Abstract] [Full Text] [PDF]

				T. Schneider, C. Fetscher, S. Krege, and M. C. Michel Signal Transduction Underlying Carbachol-Induced Contraction of Human Urinary Bladder J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1148 - 1153. [Abstract] [Full Text] [PDF]

				M. Fleichman, T. Schneider, C. Fetscher, and M. C. Michel Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. II. Protein Kinases J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 54 - 58. [Abstract] [Full Text] [PDF]