TY - JOUR T1 - Acetylcholine Inhibits Platelet Activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 182 LP - 187 DO - 10.1124/jpet.118.253583 VL - 369 IS - 2 AU - John A. Bennett AU - Sara K. Ture AU - Rachel A. Schmidt AU - Michael A. Mastrangelo AU - Scott J. Cameron AU - Lara E. Terry AU - David I. Yule AU - Craig N. Morrell AU - Charles J. Lowenstein Y1 - 2019/05/01 UR - http://jpet.aspetjournals.org/content/369/2/182.abstract N2 - Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO), have been identified. Acetylcholinesterase inhibitors, such as donepezil, can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogs of acetylcholine on human platelet activation ex vivo. Acetylcholine and analogs of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and glycoprotein IIb IIIa conformational changes. Conversely, we found that antagonists of the acetylcholine receptor, such as pancuronium, enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase, such as donepezil, also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for antithrombotic therapies. ER -