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The Journal of Neuroscience, February 20, 2008, 28(8):1977-1987; doi:10.1523/JNEUROSCI.4694-07.2008

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Behavioral/Systems/Cognitive
Activation of Muscarinic Receptors in Rat Bladder Sensory Pathways Alters Reflex Bladder Activity

F. Aura Kullmann,¹ Debra E. Artim,¹ Lori A. Birder,^1,2 and William C. de Groat¹

Departments of ¹Pharmacology and ²Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Correspondence should be addressed to Dr. F. Aura Kullmann, Department of Pharmacology, University of Pittsburgh School of Medicine, E 1340 Biomedical Science Tower, Pittsburgh, PA 15261. Email: flnst2{at}pitt.edu

Antimuscarinic drugs affect bladder sensory symptoms such as urgency and frequency, presumably by acting on muscarinic acetylcholine receptors (mAChRs) located in bladder sensory pathways including primary afferent nerves and urothelium. However, the expression and the function of these receptors are not well understood. This study investigated the role of mAChRs in bladder sensory pathways in vivo in urethane anesthetized rats. Intravesical administration of the mAChR agonist oxotremorine methiodide (OxoM) elicited concentration-dependent excitatory and inhibitory effects on the frequency of voiding. These effects were blocked by intravesical administration of the mAChR antagonist atropine methyl nitrate (5 µM) and were absent in rats pretreated with capsaicin to desensitize C-fiber afferent nerves. Low concentrations of OxoM (5 µM) decreased voiding frequency by 30%, an effect blunted by inhibiting nitric oxide (NO) synthesis with L-NAME (N-nitro-L-arginine methyl ester hydrochloride; 5 mg/kg; i.v.). High concentrations of OxoM (40 µM) increased voiding frequency by 45%, an effect blunted by blocking purinergic receptors with PPADS (0.1–1 mM; intravesically). mAChR agonists stimulated release of ATP from cultured urothelial cells. Intravenous administration of OxoM (0.01–5 µg/kg) did not mimic the intravesical effects on voiding frequency. These results suggest that activation of mAChRs located near the luminal surface of the bladder affects voiding functions via mechanisms involving ATP and NO release presumably from the urothelium, that in turn could act on bladder C-fiber afferent nerves to alter their firing properties. These findings suggest that the urothelial-afferent nerve interactions can influence reflex voiding function.

Key words: urethane; antimuscarinics; urothelium; capsaicin; oxotremorine methiodide; afferent nerves

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Received Oct. 16, 2007; revised Dec. 18, 2007; accepted Jan. 10, 2008.

Correspondence should be addressed to Dr. F. Aura Kullmann, Department of Pharmacology, University of Pittsburgh School of Medicine, E 1340 Biomedical Science Tower, Pittsburgh, PA 15261. Email: flnst2{at}pitt.edu

This article has been cited by other articles:

				F. A. Kullmann, D. Artim, J. Beckel, S. Barrick, W. C. de Groat, and L. A. Birder Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat Am J Physiol Renal Physiol, April 1, 2008; 294(4): F971 - F981. [Abstract] [Full Text] [PDF]

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