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THIRST AND VOLUME, ELECTROLYTE HOMEOSTASIS

The M₂ muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction

Departments of Urology and Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140-5104

Submitted 15 July 2003 ; accepted in final form 26 January 2004

Bladder muscle specimens from seven patients with neurogenic bladder dysfunction were analyzed to determine whether the muscarinic receptor subtype mediating contraction shifts from M₃ to the M₂ subtype as found in the denervated, hypertrophied rat bladder. Seven bladder specimens were analyzed from six female and one male patients. Six of the patients had traumatic cervical spinal cord injuries (C₄-C₇), and the other patient had an L₁ congenital myelomeningocele. This was compared with results from bladder specimens obtained from eight organ transplant donors. The affinities of three subtype-selective muscarinic receptor antagonists for inhibition of carbachol-induced contractions were determined. The affinity of the M₃ selective antagonists darifenacin or p-fluoro-hexahydrosiladifenadol (p-F-HHSiD) was determined in six of the seven spinal injury patient specimens. The affinity was consistent with M₂-mediated contractions in four of these six specimens, intermediate between M₂ and M₃ in one specimen, and within the M₃ range in one specimen. The other specimen, tested only with the M₂ selective antagonist methoctramine, showed an M₃ affinity. In the organ donors, the affinity of p-F-HHSiD was within the M₂ range for six of seven specimens, whereas the affinity of darifenacin was within the M₃ range for five of six and intermediate between M₂ and M₃ for the other specimen tested. The affinity of methoctramine in both organ donor specimens tested was within the M₃ range. Whereas normal detrusor contractions are mediated by the M₃ receptor subtype, in patients with neurogenic bladder dysfunction as well as certain organ transplant donors, contractions can be mediated by the M₂ muscarinic receptor subtype.

spinal cord injury

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