Pharmacological characterization of muscarinic receptors in dog isolated ciliary and urinary bladder smooth muscle

The pharmacological characteristics of muscarinic receptors mediating contr action of dog isolated ciliary muscle were determined and compared to those mediating contraction of dog urinary bladder smooth muscle. 2 (+)-Cis-dioxolane induced concentration-dependent contractions of ciliary (pEC(50)=7.18+/-0.07. E-max=453+/-64 mg, N=19) and urinary bladder isolate d smooth muscle (pEC(50)=6.55+/-0.07, E-max= 11+/-1g, n=19). These response s were antagonized by several muscarinic receptor antagonists (pK(b) values for the ciliary muscle and the bladder smooth muscle, respectively): atrop ine (8.25+/-0.14 and 9.21+/-0.09). pirenzepine (6.31+/-0.13 and 6.70+/-0.25 ). tolterodine (7.97+/-0.14 and 8.68+/-0.123, oxybutynin (7.40+/-0.08 and 7 .88+/-0.12), zamifenacin (6.46 +/- 0.19 and 7.69 +/- 0.11), S-secoverine (6 .66 +/- 0.14 and 8.13 +/- 0.07), AQ-RA 741 (6.16 +/- 0.15 and 7.08+/-0.23), p-F-HHSiD (7.10+/-0.27 and 7.35+/-0.07) and responses were not antagonized by PD 102807 (up to 100 nM). 3 In urinary bladder smooth muscle, the profile of antagonist pk(B) values correlated significantly with pK(i) values at human recombinant m(3) muscar inic receptors, suggesting that Mj muscarinic receptors mediated the respon se. In the ciliary muscle, a significant (P<0.01) correlation was obtained with human recombinant m(3) and m(5) receptors. 4 Darifenacin displayed insurmountable antagonism at receptors in the bladd er. At receptors in the ciliary muscle, it exhibited two phases of antagoni sm comprising an initial low affinity (pK(B)<6) component and a high affini ty phase (pK(B)> 8). 5 The role of pigmentation in the atypical behaviour of darifenacin was exa mined. In blue coloured eves, darifenacin produced apparent surmountable, c ompetitive antagonism of the responses to (+)-cis-dioxolane (pK(B)=8.76+/-0 .07). The antagonist profile obtained in this tissue suggested the involvem ent of a site which has the pharmacological attributes of the MS receptor. 6 We suggest that the dog urinary bladder contracts in response to M-3 musc arinic receptor activation. Contraction of the brown-eyed dog ciliary muscl e is more complex and may include involvement of at least two receptors, po ssibly the M-5 and M-3, receptor, whereas blue-eyed dog ciliary muscle may involve a single population of Mg muscarinic receptors.