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

Bladder muscle specimens from seven patients with neurogenic bladder dysfunction were analyzed to determine whether the muscarinic receptor subtype mediating contraction shifts from M-3 to the M-2 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 (C-4-C-7), and the other patient had an L-1 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 M-3 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 M-2-mediated contractions in four of these six specimens, intermediate between M-2 and M-3 in one specimen, and within the M-3 range in one specimen. The other specimen, tested only with the M-2 selective antagonist methoctramine, showed an M-3 affinity. In the organ donors, the affinity of p-F-HHSiD was within the M-2 range for six of seven specimens, whereas the affinity of darifenacin was within the M-3 range for five of six and intermediate between M-2 and M-3 for the other specimen tested. The affinity of methoctramine in both organ donor specimens tested was within the M-3 range. Whereas normal detrusor contractions are mediated by the M-3 receptor subtype, in patients with neurogenic bladder dysfunction as well as certain organ transplant donors, contractions can be mediated by the M-2 muscarinic receptor subtype.