A muscarinic receptor different from the M1, M2, M3 and M4 subtypes mediates the contraction of the rabbit iris sphincter

Abstract

In order to analyse the subtype of muscarinic receptors involved in the methacholine-induced contraction of the rabbit iris sphincter we have determined equilibrium dissociation constants (KB) of various antagonists in the sphincter muscle. The values were compared with those observed at M1 (rabbit vas deferens), M2 (heteroreceptors in rat iris) and M3 receptors (guinea-pig ileum), or at the muscarinic receptors in the guinea-pig uterus. The methacholine-induced contraction of the uterus from immature guinea-pigs was competitively antagonized by pirenzepine (6.64, -log KB), 4-DAMP (8.39), hexahydrodifenidol (HHD; 7.00 for the (R)- and 5.40 for the (S)-enantiomer), p-fluoro-hexahydrosiladifenidol (p-F-HHSiD; 6.25) and valethamate bromide (8.04). The affinity of the antagonists is consistent with the presence of an M2 receptor. The -log KB values of the antagonists in the rabbit iris sphincter (6.43, p-F-HHSiD; 6.22, AQ-RA 741; 7.23 and 5.34, (R)- and (S)-trihexyphenidyl) were lower than, or within the lowest range of, estimates in the other experimental models, irrespective of the subtype selectivity of the antagonist. This excludes the presence of an M1, M2, M3 or M4 receptor in this smooth muscle. The affinity of UH-AH 37 in the iris was intermediate between that for M1 or M3, and M2 receptors. The low affinity of AQ-RA 741 and the low enantiomeric ratio of trihexyphenidyl (THP) in the iris (77.6) would be compatible with a presumed M5 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Miosis Produced by McN-A-343 in Anesthetized Cats

“…This conclusion is based on observations that the pupillary constriction was blocked by atropine but not by gallamine, pirenzepine, or by cilliary ganglionectomy. Recently, others have found the M3 muscarinic receptor to be predominant in the iris sphincter of a variety of species including humans (22)(23)(24) although there is some evidence that it may resemble the putative M5 muscarinic receptor that has not yet been identified with a peripheral functional correlate (25). It is of interest that an earlier study showed that high doses of McN-A-343 produced a prolonged contraction of the isolated bovine iris by an atropine sensitive mechanism (26).…”

Muscarinic receptors and ligands in cancer

“…Likewise, all five muscarinic receptor subtypes are expressed in the eye, but M 3 R predominate (49). M 3 R and, to a lesser extent, M 5 R regulate cilliary muscle contraction, whereas M 2 R regulate pupillary constriction (13,20,32,87). M 1 R , M 2 R, M 3 R, and M 5 R are expressed in the heart (126); M 2 R activation results in bradycardia and reduced inotropy, whereas M 1 R activation results in tachycardia (1,33,37,67,118).…”

In vitro characterization of tripitramine, a polymethylene tetraamine displaying high selectivity and affinity for muscarinic M2 receptors

“…et al., 1989;Lazareno et al, 1990;Caulfield & Brown, 1991), chicken heart, rabbit lung (Lazareno et al, 1990) and guineapig uterus (Don6e et al, 1990). However, Eglen et al (1989) and Bognar et al (1992) have argued that guinea-pig uterus contains muscarinic M2 rather than M4 receptors. Recently, Bognar et al (1992) have suggested the existence in rabbit iris sphincter of a muscarinic receptor subtype differing from muscarinic MI-M4 receptors.…”

“…However, Eglen et al (1989) and Bognar et al (1992) have argued that guinea-pig uterus contains muscarinic M2 rather than M4 receptors. Recently, Bognar et al (1992) have suggested the existence in rabbit iris sphincter of a muscarinic receptor subtype differing from muscarinic MI-M4 receptors.…”