Regulation of bladder muscarinic receptor subtypes by experimental pathologies

Publisher Website
Google Scholar
Abstract
Summary: 1 The M3muscarinic receptor subtype is widely accepted as the receptor on smooth muscle cells that mediates cholinergic contraction of the normal urinary bladder and other smooth muscle tissues, however, we have found that the M2receptor participates in contraction under certain abnormal conditions. The aim of this study was to determine the effects of various experimental pathologies on the muscarinic receptor subtype mediating urinary bladder contraction.2 Experimental pathologies resulting in bladder hypertrophy (denervation and outlet obstruction) result in an up‐regulation of bladder M2receptors and a change in the receptor subtype mediating contraction from M3towards M2. Preventing the denervation‐induced bladder hypertrophy by urinary diversion prevents this shift in contractile phenotype indicating that hypertrophy is responsible as opposed to denervationper se.3 The hypertrophy‐induced increase in M2receptor density and contractile response is accompanied by an increase in the tissue concentrations of mRNA coding for the M2receptor subtype, however, M3receptor protein density does not correlate with changes in M3receptor tissue mRNA concentrations across different experimental pathologies.4 This shift in contractile phenotype from M3towards M2subtype is also observed in aged male Sprague–Dawley rats but not females or either sex of the Fisher344 strain of rats.5 Four repeated, sequential agonist concentration response curves also cause this shift in contractile phenotype in normal rat bladder stripsin vitro, as evidenced by a decrease in the affinity of the M3selective antagonistp‐fluoro‐hexahydro‐sila‐diphenidol (p‐F‐HHSiD).6 A similar decrease in the contractile affinity of M3selective antagonists (darifenacin andp‐F‐HHSiD) is also observed in bladder specimens from patients with neurogenic bladder as well as certain organ transplant donors.7 It is concluded that although the M3receptor subtype predominately mediates contraction under normal circumstances, the M2receptor subtype can take over a contractile role when the M3subtype becomes inactivated by, for example, repeated agonist exposures or bladder hypertrophy. This finding has substantial implications for the clinical treatment of abnormal bladder contractions.

This publication has 50 references indexed in Scilit: