Muscarinic M1 receptor activation reduces maximum upstroke velocity of action potential in mouse right atria.

We investigated whether acetylcholine affects cardiac action potentials through the muscarinic M1 in addition to M2 receptors in spontaneously beating mouse isolated right atria. A conventional glass microelectrode technique was used for the purpose. Acetylcholine (3-10 microM) reduced the maximum upstroke velocity of the action potentials (Vmax), followed by an increase. It shortened action potential duration at 90% repolarization, hyperpolarized the resting membrane and decreased the rate of beating. Atropine (3-100 nM) concentration dependently antagonized these effects of acetylcholine. Pirenzepine (10 and 30 nM), a selective muscarinic M1 receptor antagonist, antagonized acetylcholine (5 microM)-induced reduction of Vmax without affecting other effects of acetylcholine. In addition, pirenzepine (30 nM) induced an immediate and linear acceleration of the VmaX reduced by acetylcholine. In contrast, AF-DX 116 (11(¿2-[(diethylamino)-methyl]-1-piperidyl¿acetyl)-5,11-dihydro-6 H-pyridol[2,3-b][1,4]benzodiazepine-6-one base, 30-300 nM), a selective muscarinic M2 receptor antagonist, failed to antagonize acetylcholine-induced reduction of Vmax, but abolished its increase. It antagonized the shortening of action potential duration, membrane hyperpolarization and decreased the beating rate. McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride, 100 and 300 microM), a muscarinic M1 receptor agonist, reduced Vmax and prolonged action potential duration, while oxotremorine (100-300 nM), a muscarinic M2 receptor agonist, evoked reverse effects. These results suggest that acetylcholine exerts a mixed effect on Vmax, consisting of a reduction and a facilitation, possibly mediated by concurrent activation of muscarinic M1 and M2 receptors, respectively, in isolated right atria of mice.