Adenosine 5′-triphiosphate (ATP) is released from cells under physiologic and pathophysiologic conditions. Extracellular ATP acts as an autocrine and paracrine agent affecting various cell types by activating cell surface P2 receptors (P2R), which include trans-cell membrane cationic channels, P2XR, and G protein coupled receptors, P2YR. We have previously shown that ATP stimulates vagal afferent nerve terminals in the lungs by activating P2X2/3R. This action could lead to bronchoconstriction, cough and the local release of pro-inflammatory neuropeptides. In addition, ATP markedly enhances the IgE-dependent histamine release from human lung mast cells. Thus, we have proposed for the first time that extracellular ATP plays a mechanistic role in pulmonary pathophysiology in general and chronic obstructive pulmonary disease (COPD), and acute bronchoconstriction in asthma in particular. The present review examines whether ATP could also play a role in bradycardia and syncope in a subset of patients with pulmonary embolism.