Acetylcholine Inhibits Platelet Activation

Abstract

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.

Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms

“…Over a decade ago, our group demonstrated platelets possess other functional signal transduction pathways common to neurons, including the NMDA receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (44). Recently, muscarinic acetylcholine receptors were found to regulate platelet reactivity and thrombosis (45). These previous studies and the current observations suggest that circulating platelets resemble neuronal synapses.…”

Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system

“…It is important to note that platelets express functional α7-AChRs [79] while hematopoietic α7 nAChR deficiency increases inflammation and platelet activity [80]. Recently, acetylcholine was found to be an endogenous inhibitor of platelet activation [81]. Therefore, dysfunction of the nicotinic cholinergic system could be implicated in the thrombotic and vascular complications of COVID-19.…”

Nicotine and the nicotinic cholinergic system in COVID‐19

“…Interestingly, platelets express functional α7 nAChRs, deficiency of which may increase platelet activity and increase the chance of clot formation [87]. Since acetylcholine may act as an endogenous inhibitor of platelet activation [88], it would be of significant interest to examine whether nicotine or selective nAChR agonists may also affect COVID‐19‐induced coagulopathy. In this regard, it is of interest to note that whereas extracts of electronic cigarettes can enhance platelet adhesion potential toward fibrinogen, pure nicotine may actually inhibit platelet function [89].…”