Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive

Abstract

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.

Commentary: A (Mito)SNO storm to protect the heart

“…In this issue of the Journal of Thoracic and Cardiovascular Surgery Open , Ahmad and colleagues 1 have dissected the use of 2 potential cardioprotective additives: mitochondria-selective S-nitrosating agent (MitoSNO) and diazoxide. Perioperative ischemia–reperfusion injury in cardiac surgery is a critical issue.…”

Commentary: One plus one does not always equal two: Mitochondrial cardioprotection

“…Several mitochondrial pathways have been targeted to find the Holy Grail for cardioprotection. In their recent paper, Ahmad and colleagues 1 investigated the cardioprotective properties of diazoxide (DZX) and mitochondria-targeted s-nitrosating agent separately and in combination. Based on their in vitro and ex vivo studies, the authors concluded that these 2 substances provide cardioprotection when administered separately, but this effect is reduced when combined.…”