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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Bradykinin Contracts Rat Urinary Bladder Largely Independently of Phospholipase C

Carsten Sand and Martin C. Michel
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 25-31; DOI: https://doi.org/10.1124/jpet.113.208025
Carsten Sand
Department of Pharmacology, University of Duisburg-Essen, Essen, Germany (C.S.); and Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.)
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Martin C. Michel
Department of Pharmacology, University of Duisburg-Essen, Essen, Germany (C.S.); and Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.)
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Abstract

Several receptor systems in the bladder causing detrusor smooth muscle contraction stimulate phospholipase C (PLC). PLC inhibition abolishes bladder contraction via P2Y6 but not that via M3 muscarinic receptors, indicating a receptor-dependent role of PLC. Therefore, we explored the role of PLC in rat bladder contraction by bradykinin. The PLC inhibitor U 73,122 [1-(6-[([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-pyrrole-2,5-dione] did not affect the bradykinin response to a significantly greater degree than its inactive analog U 73,343 [10 μM each; 1-(6-[-([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-2,5-pyrrolidinedione], whereas the phospholipase D inhibitor butan-1-ol relative to its inactive control butan-2-ol caused a weak but significant inhibition (0.3% each). The cytosolic phospholipase A2 inhibitor arachidonyltrifluoromethyl ketone (300 μM) and the cyclooxygenase inhibitor indomethacin (10 μM) caused strong inhibition of the bradykinin response. The L-type Ca2+ channel blocker nifedipine (10–100 nM) concentration-dependently caused strong inhibition, whereas only a small but significant inhibition was seen with SK&F 96,365 [10 μM; 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl], an inhibitor of receptor-operated Ca2+ channels. Several protein kinase C inhibitors yielded an equivocal picture (inhibition by 10 μM bisindolylmaleimide I and 1 μM calphostin but not by 10 μM chelerythrine). The rho kinase inhibitor Y 27,632 [1–10 μM; trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide] caused a strong and concentration-dependent inhibition of the bradykinin response. Our data support that not only M3 but also bradykinin receptors cause bladder contraction by a largely PLC-independent mechanism. Both responses strongly involve L-type Ca2+ channels and rho kinase, whereas only the bradykinin response additionally involves the phospholipase A2/cyclooxygenase pathway.

Footnotes

    • Received July 15, 2013.
    • Accepted October 21, 2013.
  • This work was supported in part by the Deutsche Forschungsgemeinschaft [Grant MI 294/7-2]; and Coordination Theme 1 (Health) of the European Community’s FP7 [Grant HEALTH-F2-2008-223234].

  • A part of this work has been presented previously: Michel MC (2005) Signal transduction underlying rat urinary bladder contraction by bradykinin. Experimental Biology 2005; 2–5 April 2005; San Diego, CA. American Federation for Medical Research, Beverly, MA.

  • After completion of the experiments, M.C.M. became an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The authors report no conflicts of interest.

  • dx.doi.org/10.1124/jpet.113.208025.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

PLC-Independent Rat Bladder Contraction by Bradykinin

Carsten Sand and Martin C. Michel
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 25-31; DOI: https://doi.org/10.1124/jpet.113.208025

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

PLC-Independent Rat Bladder Contraction by Bradykinin

Carsten Sand and Martin C. Michel
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 25-31; DOI: https://doi.org/10.1124/jpet.113.208025
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