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The Journal of Neuroscience, January 24, 2007, 27(4):845-851; doi:10.1523/JNEUROSCI.3115-06.2007

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Behavioral/Systems/Cognitive
Identification of Atropine- and P2X₁ Receptor Antagonist-Resistant, Neurogenic Contractions of the Urinary Bladder

Charles Kennedy, Paul N. Tasker, Gemma Gallacher, and Timothy D. Westfall

Division of Physiology and Pharmacology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 ONR, United Kingdom

Correspondence should be addressed to Dr. C. Kennedy, Division of Physiology and Pharmacology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 ONR, UK. Email: c.kennedy{at}strath.ac.uk

Acetylcholine and ATP are excitatory cotransmitters in parasympathetic nerves. We used P2X₁ receptor antagonists to further characterize the purinergic component of neurotransmission in isolated detrusor muscle of guinea pig urinary bladder. In the presence of atropine (1 µM) and prazosin (100 nM), pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (0.1–100 µM) and suramin (1–300 µM) inhibited contractions evoked by 4 Hz nerve stimulation in a concentration-dependent manner (IC₅₀ of 6.9 and 13.4 µM, respectively). Maximum inhibition was 50–60%, which was unaffected by coadministration of the ectonucleotidase inhibitor ARL67156 (6-N,N-diethyl-D-ß,-dibromomethyleneATP) (100 µM). The remaining responses were abolished by tetrodotoxin (1 µM). PPADS and suramin also reduced contractions to exogenous ATP (300 µM) by 40–50%, but abolished those to the P2X₁ agonist ,ß-methyleneATP (,ß-meATP) (1 µM). The P2X₁ antagonists reactive blue 2, NF279 (8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid), MRS2159 (pyridoxal-⁵-phosphate-6-phenylazo-4'-carboxylic acid) (100 µM), and NF449 [4,4',4,4-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid] (3 µM) abolished contractions to ,ß-meATP (1 µM; n = 4–5), but only reduced contractions evoked by 4 Hz nerve stimulation by 40–60% (n = 4–6) and ATP by 30–60% (n = 4–7). However, prolonged exposure to ,ß-meATP (50 µM) abolished contractions evoked by all three stimuli (n = 5–12). PPADS (100 µM) and suramin (300 µM) reduced the peak neurogenic contraction of the mouse urinary bladder to 30–40% of control. At the same concentrations, the P2X₁ antagonists abolished the nonadrenergic, purinergic component of neurogenic contractions in the guinea pig vas deferens (n = 4–5). Thus, P2X₁ receptor antagonists inhibit, but do not abolish, the noncholinergic component of neurogenic contractions of guinea pig and mouse urinary bladder, indicating a second mode of action of neuronally released ATP. This has important implications for treatment of dysfunctional urinary bladder, for which this atropine- and P2X₁ antagonist-resistant site represents a novel therapeutic target.

Key words: parasympathetic; urinary bladder; noncholinergic; ATP; P2X₁ receptor; P2X₄ receptor

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Received July 21, 2006; revised Dec. 8, 2006; accepted Dec. 15, 2006.

Correspondence should be addressed to Dr. C. Kennedy, Division of Physiology and Pharmacology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 ONR, UK. Email: c.kennedy{at}strath.ac.uk

This article has been cited by other articles:

				F. J. Ehlert, S. Ahn, K. J. Pak, G. J. Park, M. S. Sangnil, J. A. Tran, and M. Matsui Neuronally Released Acetylcholine Acts on the M2 Muscarinic Receptor to Oppose the Relaxant Effect of Isoproterenol on Cholinergic Contractions in Mouse Urinary Bladder J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 631 - 637. [Abstract] [Full Text] [PDF]

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