Background: Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphatesensitive potassium (K ATP ) channel opener diazoxide (DZX) via an unknown mechanism. K ATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with K ATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. PERSPECTIVE Diazoxide (DZX) with hyperkalemic cardioplegia is cardioprotective via an unknown molecular mechanism of action; however, DZX combined with cardioprotective mitochondrial S-nitrosating agent is detrimental. These results clarify the mechanisms and conditions necessary for DZX cardioprotection. Elucidation of DZX's mechanism of action will allow for its safe use in clinical trials in humans.See Commentaries on pages 355 and 357.

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