BACKGROUND: ATP-sensitive potassium (K(ATP)) channel openers provide cardioprotection in multiple models. Ion flux at an unidentified mitochondrial K(ATP) channel has been proposed as the mechanism. The renal outer medullary kidney potassium channel subunit, potassium inward rectifying (Kir)1.1, has been implicated as a mitochondrial channel pore-forming subunit. We hypothesized that subunit Kir1.1 is involved in cardioprotection (maintenance of volume homeostasis and contractility) of the K(ATP) channel opener diazoxide (DZX) during stress (exposure to hyperkalemic cardioplegia [CPG]) at the myocyte and mitochondrial levels. METHODS AND RESULTS: Kir subunit inhibitor Tertiapin Q (TPN-Q) was utilized to evaluate response to stress. Mouse ventricular mitochondrial volume was measured in the following groups: isolation buffer; 200 μmol/L of ATP; 100 μmol/L of DZX+200 μmol/L of ATP; or 100 μmol/L of DZX+200 μmol/L of ATP+TPN-Q (500 or 100 nmol/L). Myocytes were exposed to Tyrode's solution (5 minutes), test solution (Tyrode's, cardioplegia [CPG], CPG+DZX, CPG+DZX+TPN-Q, Tyrode's+TPN-Q, or CPG+TPN-Q), N=12 for all (10 minutes); followed by Tyrode's (5 minutes). Volumes were compared. TPN-Q, with or without DZX, did not alter mitochondrial or myocyte volume. Stress (CPG) resulted in myocyte swelling and reduced contractility that was prevented by DZX. TPN-Q prevented the cardioprotection afforded by DZX (volume homeostasis and maintenance of contractility). CONCLUSIONS: TPN-Q inhibited myocyte cardioprotection provided by DZX during stress; however, it did not alter mitochondrial volume. Because TPN-Q inhibits Kir1.1, Kir3.1, and Kir3.4, these data support that any of these Kir subunits could be involved in the cardioprotection afforded by diazoxide. However, these data suggest that mitochondrial swelling by diazoxide does not involve Kir1.1, 3.1, or 3.4.
Henn, M. C., Janjua, M. B., Kanter, E. M., Makepeace, C. M., Schuessler, R. B., Nichols, C. G., & Lawton, J. S. (2015). Adenosine Triphosphate-Sensitive Potassium Channel Kir Subunits Implicated in Cardioprotection by Diazoxide. Journal of the American Heart Association, 4(8), e002016. https://doi.org/10.1161/JAHA.115.002016