Pharmacologic study of muscarinic receptor subtypes and arteriolar dilations: A comparison of conducted and local responses

Arteriolar relaxation caused by the application of muscarinic agonists is m ediated by multiple factors. One factor causes dilation only at the point o f drug microapplication (local response), and a second factor causes respon ses remote (500 mu m away) from the site of application (conducted response ). This study was performed to determine if different muscarinic subtypes m ediate the two responses. Arterioles of anesthetized hamster cheek pouch we re studied with videomicroscopy. Muscarinic antagonists methscopolamine, sc opolamine, pirenzepine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methio dide), and AFDX-116 [(11-2[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]- 5, 11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one)] were cumulatively applied, and the K-B for each antagonist was determined for the local and conducted responses caused by methacholine microapplication (10(-4) M, 5 s) . The pK(B) (local, conducted) were not significantly different for the two responses when using scopolamine (10.5, 10.4). When the antagonist AFDX-11 6 (5.6, 6.3), selective for muscarinic receptor (m2) subtype was applied, t he K-B was greater for the conducted response. The pK(B) was greater, howev er, for the local response when the mi subtype-selective pirenzepine (7.7, 6.9) or m3 subtype-selective 4-DAMP (10.1, 9.8) was applied. Thus the antag onist pK(B) ratio for on the local and conducted responses depends on the s ubtype selectivity of the antagonist. These data strongly suggest that diff erent receptors are involved in the two responses.