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. Emax values are significantly larger and ED50 values are significantly smaller in bladder dome and bladder base than in urethra. Calculation of the pA2 values, the negative logarithm of the antagonist affinity constant (KB), for a series of muscarinic antagonists, i.e., atropine (nonselective), pirenzepine (M1 selective), methoctramine (M2 selective), and 4-DAMP (M1/M3 selective) indicate that the carbachol-induced contractile response in bladder dome and bladder base is mediated through the M3 receptor subtype whereas the carbachol-induced contractile response in urethra is probably mediated through the M1 and/or M3 and possibly M2 subtypes. Muscarinic cholinergic antagonists inhibit [3H]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 M2 receptor subtype in all three regions.

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. Emax values are significantly larger and ED50 values are significantly smaller in bladder dome and bladder base than in urethra. Calculation of the pA2 values, the negative logarithm of the antagonist affinity constant (KB), for a series of muscarinic antagonists, i.e., atropine (nonselective), pirenzepine (M1 selective), methoctramine (M2 selective), and 4-DAMP (M1/M3 selective) indicate that the carbachol-induced contractile response in bladder dome and bladder base is mediated through the M3 receptor subtype whereas the carbachol-induced contractile response in urethra is probably mediated through the M1 and/or M3 and possibly M2 subtypes. Muscarinic cholinergic antagonists inhibit [3H]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 M2 receptor subtype in all three regions.

Effects of prostaglandins (PGs) E₁; E₂ and F_2Α on the vesical and urethral smooth muscles of dogs were isometrically investigated in vitro. In vesical smooth muscles, 10^––8–10^––6 g PGE₁/ml produced biphasic responses in the dome preparations; relaxation at 10^––8 g/ml and contractions at 10^––7–10^––6 g/ml. In the trigone preparations, 10^––8–10^––6 g PGE₁/ml caused dose-dependent contractions. 10^––8–10^––6 g PGE₂/ml and 10^––7–10^––6 g PGF_2Α/ml induced dose-dependent contractions of the dome and the trigone preparations. In urethral smooth muscles, 10^––8–10^––6 g PGE₁/ml and 10^––8–10^––6 g PGE₂/ml produced dose-dependent relaxations, while 10^––8–10^––6 g PGF_2Α/ml caused dose-dependent contractions. Results indicate that PGE, particularly PGE₂, is able to stimulate micturition through vesical contraction and urethral relaxation.

The effects of primary prostaglandins (PGs) on the dome and trigone of the human urinary bladder were investigated in vitro. In the dome preparations, PGE1 (10(-9) to 10(-6) gm./ml.) showed a weak contractile effect, while PGE2 (10(-9) to 10(-6) gm./ml.) produced dose-dependent contractions. PGF2 alpha (10(-9) to 10(-6) gm./ml.) induced contractions greater than those induced by PGE1 and PGE2. In the trigone preparations, PGE1 (10(-9) to 10(-6) gm./ml.) had no effect, and PGE2 (10(-9) to 10(-6) gm./ml.) produced only a weak contractile response. PGF2 alpha (10(-9) to 10(-6) gm./ml.) showed a greater contractile potency than PGE2. Contractile responses of both preparations to PGE1, PGE2 and PGF2 alpha were not affected by pretreatments of atropine, hexamethonium and phentolamine. These results suggest that the order of potency of primary PGs to induce contractile responses is PGF2 alpha greater than PGE2 greater than PGE1 in both the dome and the trigone preparations, and that the contractile effects of PGE1, PGE2 and PGF2 alpha may not be mediated by activation of muscarinic, nicotinic or adrenergic alpha-receptors.