FUNCTIONAL-ROLE OF M(2) MUSCARINIC RECEPTORS IN THE GUINEA-PIG ILEUM

Muscarinic agonists elicit contraction in the standard guinea pig ileum bioassay through activation of M(3) muscarinic, receptors that are also linked to phosphoinositide hydrolysis. Surprisingly, the most abundant muscarinic receptor in the ileum is the M(2) which causes a specific inhibition of cyclic AMP accumulation elicited by the beta-adrenergic receptor. After most of the M(3) receptors are inactivated, the ileum still retains high sensitivity to muscarinic agonists provided that the contractile responses are measured in the presence of histamine and forskolin, which together, have no effect on contraction. Under these conditions, the potencies of antagonists for blocking the contractile response are consistent with those expected for an M(2) response. Moreover, the muscarinic contractile response measured in the presence of histamine and forskolin after inactivation of M(3) receptors is pertussis toxin sensitive. In contrast, muscarinic contractions in the standard bioassay are pertussis toxin insensitive. These results demonstrate that the M(2) muscarinic receptor can cause an indirect contraction of the guinea pig ileum by preventing the relaxing effect of agents that increase cAMP.