1 The
M3 muscarinic 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 M2 receptor 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 M2 receptors and a change in the receptor subtype mediating contraction from M3 towards M2. Preventing the
denervation-induced bladder
hypertrophy by
urinary diversion prevents this shift in contractile phenotype indicating that
hypertrophy is responsible as opposed to
denervation per se. 3 The
hypertrophy-induced increase in M2 receptor density and contractile response is accompanied by an increase in the tissue concentrations of
mRNA coding for the M2 receptor subtype, however, M3 receptor
protein density does not correlate with changes in M3 receptor tissue
mRNA concentrations across different experimental pathologies. 4 This shift in contractile phenotype from M3 towards M2 subtype 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 strips in vitro, as evidenced by a decrease in the affinity of the M3 selective antagonist
p-fluoro-hexahydro-sila-diphenidol (
p-F-HHSiD). 6 A similar decrease in the contractile affinity of M3 selective antagonists (
darifenacin and
p-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 M3 receptor subtype predominantly mediates contraction under normal circumstances, the M2 receptor subtype can take over a contractile role when the M3 subtype becomes inactivated by, for example, repeated agonist exposures or bladder
hypertrophy. This finding has substantial implications for the clinical treatment of abnormal bladder contractions.