The Effect of Muscarinic Agonists and Selective Receptor Subtype Antagonists on the Contractile Response of the Isolated Rhesus Monkey Ciliary Muscle

There are ultrastructural and histochemical differences between the longitudinal (putatively more relevant to outflow facility) and circular (putatively more relevant to accommodation) portions of the primate ciliary muscle. Oxotremorine, a muscarinic agonist putatively somewhat selective for the M2 receptor subtype, binds preferentially to the longitudinal rather than the circular portion. Aceclidine, a putatively non-subtype selective muscarinic agonist, can dissociate accommodative and outflow facility responses in monkeys and humans. We used the muscarinic receptor subtype antagonists 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), 11-([2-(diethylamino)methyl]-1-piperidinyl)acetyl]- 5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one (AF-DX 116), and pirenzepine to inhibit contractile responses to the muscarinic agonists carbachol, aceclidine and oxotremorine in the longitudinal and circular vectors of the rhesus monkey ciliary muscle in vitro. Oxotremorine generated dose-response curves that were similar in both the circular and longitudinal vectors and intermediate to those previously reported for carbachol and aceclidine. 4-DAMP (M3 selective) was the most potent inhibitor of contractile responses to all three agonists, with IC50 values ranging from 33 to 68 nM for the circular and from 27 to 63 nM for the longitudinal vector, depending on the agonist used to elicit contraction. Pirenzepine (M1 selective) was > or = 25-fold less potent and AF-DX 116 (M2 selective) was > or = 108-fold less potent at inhibiting contractile responses to all three agonists in either vector, indicating that M3 is the predominant receptor subtype mediating ciliary muscle contraction in both vectors.(ABSTRACT TRUNCATED AT 250 WORDS)