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Within the vasculature platelets and endothelial cells play crucial roles in hemostasis and thrombosis. Platelets, like endothelial cells, possess intermediate conductance Ca2+‐activated K+(IKCa) channels and generate nitric oxide (NO). Although NO limits platelet aggregation, the role of IKCachannels in platelet function and NO generation has not yet been explored. We investigated whether IKCachannel activation inhibits platelet aggregation, and per endothelial cells, enhances platelet NO production. Platelets were isolated from human volunteers. Aggregometry, confocal microscopy, and a novel flow chamber model, the Quartz Crystal Microbalance (QCM) were used to assess platelet function. Flow cytometry was used to measure platelet NO production, calcium signaling, membrane potential, integrin αIIb/β3activation, granule release, and procoagulant platelet formation. Platelet IKCachannel activation with SKA‐31 inhibited aggregation in a concentration‐dependent manner, an effect reversed by the selective IKCachannel blocker TRAM‐34. The QCM model along with confocal microscopy demonstrated that SKA‐31 inhibited platelet aggregation under flow conditions. Surprisingly, IKCaactivation by SKA‐31 inhibited platelet NO generation, but this could be explained by a concomitant reduction in platelet calcium signaling. IKCaactivation by SKA‐31 also inhibited dense and alpha‐granule secretion and integrin αIIb/β3activation, but maintained platelet phosphatidylserine surface exposure as a measure of procoagulant response. Platelet IKCachannel activation inhibits aggregation by reducing calcium‐signaling and granule secretion, but not by enhancing platelet NO generation. IKCachannels may be novel targets for the development of antiplatelet drugs that limit atherothrombosis, but not coagulation.

Within the vasculature platelets and endothelial cells play crucial roles in hemostasis and thrombosis. Platelets, like endothelial cells, possess intermediate conductance Ca2+‐activated K+(IKCa) channels and generate nitric oxide (NO). Although NO limits platelet aggregation, the role of IKCachannels in platelet function and NO generation has not yet been explored.