Muscarinic Acetylcholine Receptors in the Rabbit Ciliary Body Smooth Muscle: Spare Receptors and Threshold Phenomenon

Abstract

Interactions of several muscarinic drugs with their receptors were studied in the ciliary body smooth muscles of the rabbit. The ciliary body smooth muscles responded to carbachol, a muscarinic full agonist with concentration-dependent contractions, and the pD2 value of carbachol was 5.16±0.05. Atropine, a competitive antagonist of muscarinic receptors, produced a parallel shift to the right in the concentration-response curves for carbachol. Pilocarpine which is a well-known partial agonist on muscarinic receptors in most smooth muscles did not cause any contraction in this tissue. The drug, however, behaved as a competitive antagonist on the muscarinic receptors in the ciliary body smooth muscles. The pA2 values of atropine and pilocarpine versus carbachol obtained from the Schild plot are 8.97±0.25 and 5.17±0.09, respectively. On the other hand, arecoline and oxotremorine acted as a partial agonist in this tissue. The intrinsic activity, and pD2 and pA2 values were 0.41 ±0.02, 4.93±0.05 and 5.32±0.05 for arecoline respectively, and were 0.26±0.02, 5.64±0.08 and 6.12±0.16 for oxotremorine, respectively. The pA2 values of these drugs were significantly larger than the corresponding pD2 values of the drugs. The values of the negative log molar dissociation constant of carbachol, arecoline and oxotremorine estimated by the method of partial irreversible blockade of spare receptors with 3x10“6 M phenoxybenzamine were 4.53±0.08, 5.20±0.09 and 6.02±0.06, respectively. These values were practically equal to those obtained from other peripheral tissues, suggesting that the muscarinic receptors in rabbit ciliary body smooth muscles were qualitatively the same as those of other smooth muscles. However, the density of muscarinic receptors in this tissue is lower than that in other peripheral tissues, and the threshold phenomenon lay between the occupation of muscarinic receptors and the tissue responses. Therefore, the pA2 values of partial agonists were different from their pD2 values, and pilocarpine, a partial agonist with lower intrinsic efficacy, behaved as a competitive antagonist in this tissue. These results suggest the importance of the receptor density and the threshold in the tissue as well as the affinity and the intrinsic efficacy of the drug as a determinant of agonist potency.