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

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Abstract
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.