Evidence for the presence of regional differences in the subtype specificity of muscarinic receptors in rabbit lower urinary tract

To elucidate the subtype specificity of muscarinic cholinergic receptors in mediating contractile responses in the lower urinary tract, we investigated contractile and biochemical properties of muscarinic receptors in bladder dome, bladder base and urethra of the rabbit. Isometric contractile response curves to increasing concentrations of carbachol were constructed in the absence and presence of various concentrations of subtype selective muscarinic antagonists. Bladder dome, bladder base, and urethra demonstrate different characteristics in terms of efficacy and potency with respect to carbachol-induced contractile responses. E(max) values are significantly larger and ED,, values are significantly smaller in bladder dome and bladder base than in urethra. Calculation of the pA(2) values, the negative logarithm of the antagonist affinity constant (K-B), for a series of muscarinic antagonists, i.e., atropine (nonselective), pirenzepine (M(1) selective), methoctramine (M(1) selective), and 4-DAMP (M1N3 selective) indicate that the carbachol-induced contractile response in bladder dome and bladder base is mediated through the M(3) receptor subtype whereas the carbachol-induced contractile response in urethra is probably mediated through the M(1) and/or M(3) and possibly M(2) subtypes. Muscarinic cholinergic antagonists inhibit [H-3]quinulidinyl benzilate binding to bladder dome, bladder base and urethra with the following rank order of affinities: atropine > 4-DAMP > methoctramine > pirenzepine. The binding data indicate the predominance of the M(2) receptor subtype in all three regions.