Positive and negative inotropic effects of muscarinic receptor stimulationin mouse left atria

In isolated mouse left atria, acetylcholine (ACh) produced a biphasic inotr opic response; a transient decrease in developed tension was followed by an increase. Both negative and positive responses were concentration dependen t and were inhibited by atropine. The negative and positive inotropic respo nses were also observed with a nonselective muscarinic stimulant, oxotremor ine-M, but not with an M-1-receptor selective stimulant, McN-A343. Pirenzep ine, an M-1-receptor antagonist, inhibited both negative and positive inotr opic responses at high concentrations. Gallamine, an M-2-receptor antagonis t, inhibited the negative response.. Hexahydro-siladifenidol hydrochloride, p-fluoro analog (p-F-HHSiD), an MB-receptor antagonist, inhibited the posi tive response with no effect on: the negative phase. In pertussis toxin (PT X) treated preparations, negative inotropic response to ACh was not observe d. These results suggest that the negative and positive inotropic responses to acetylcholine in mouse atria are mediated by M-2 and M-3 receptors, res pectively. The negative phase, but not the positive phase, was mediated by a PTX-sensitive G protein.