Pilocarpine modulates the cellular electrical properties of mammalian hearts by activating a cardiac M-3 receptor and a K+ current

1 Pilocarpine, a muscarinic acetylcholine receptor (mAChR) agonist, is wide ly used for treatment of xerostomia and glaucoma. It can also cause many ot her cellular responses by activating different subtypes of mAChRs in differ ent tissues. However, the potential role of pilocarpine in modulating cardi ac function remained unstudied. 2 We found that pilocarpine produced concentration-dependent (0.1-10 mu M) decrease in sinus rhythm and action potential duration, and hyperpolarizati on of membrane potential in guinea-pig hearts. The effects were nearly comp letely reversed by 1 mu M atropine or 2 nM 4DAMP methiodide (an M-3-selecti ve antagonist). 3 Patch-clamp recordings in dispersed myocytes from guinea-pig and canine a tria revealed that pilocarpine induces a novel K+ current with delayed rect ifying properties. The current was suppressed by low concentrations of M-3- selective antagonists 4DAMP methiodide (2-10 nM), 4DAMP mustard (4-20 nM, a n ackylating agent) and p-F-HHSiD (20-200 nM). Antagonists towards other su btypes (M-1, M-2 or M-3) all failed to alter the current. 4 The affinity of pilocarpine (K-D) at mAChRs derived from displacement bin ding of [H-3]-NMS in the homogenates from dog atria was 2.2 mu M (65% of th e total binding) and that of 4DAMP methiodide was 2.8 nM (70% of total bind ing), consistent with the concentration of pilocarpine needed for the curre nt induction and for the modulation of the cardiac electrical activity and the concentration of 4DAMP to block pilocarpine effects. 5 Our data indicate, for the first time, that pilocarpine modulates the cel lular electrical properties of the hearts, likely by activating a K+ curren t mediated by M-3 receptors.