REGULATION OF GUINEA-PIG ILEAL ELECTROLYTE TRANSPORT BY M3-MUSCARINIC ACETYLCHOLINE-RECEPTORS INVITRO

To determine the muscarinic receptor subtype mediating guinea pig ileal mucosal electrolyte secretion, we compared the potencies (K(b)) of selective M1 (pirenzepine) (PZ), M2 (AF-DX 116, methoctramine), and M3 [4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), hexahydrosiladifenidol (HHSiD)] antagonists as inhibitors of carbachol-induced reductions in guinea pig atrial heart rate and ileal longitudinal muscle contractions, responses mediated by M2 and M3 receptors, respectively. Pretreatment with all five muscarinic antagonists shifted the carbachol concentration-response curve to the right, in a manner suggesting competitive antagonism. The following affinity profiles (K(b), nM) were obtained for: 1) ileal mucosa: 4-DAMP (2.7) > HHSiD (23.0) > PZ (110) greater-than-or-equal-to methoctramine (395) > AF-DX 116 (784); 2) atrial heart rate: 4-DAMP (9.5) congruent-to methoctramine (11) > AF-DX 116 (63) > HHSiD (222) > PZ (256); and 3) ileal longitudinal muscle: 4-DAMP (3.1) > HHSiD (21) > PZ (143) > methoctramine (388) greater-than-or-equal-to AF-DX 116 (482). The selectivity profiles of these antagonists suggest that muscarinic receptors in the ileal mucosa more closely resemble those in the ileal muscle (M3) than those in atrial muscle (M2). Moreover, M1-muscarinic receptors appear to be relatively unimportant in mediating the effects of carbachol on short circuit current (I(sc)). Carbachol-induced increased in I(sc) were also unaffected by pretreatment with 0.5-mu-M tetrodotoxin, suggesting that electrolyte transport in the guinea pig ileal mucosa may be mediated, in part, by postsynaptic M3-muscarinic receptors on the enterocytes.