Abstract 12053: Adenosine Triphosphate Sensitive Potassium Kir Subunits Implicated in Cardioprotection by Diazoxide
Introduction: Adenosine triphosphate -sensitive potassium (KATP) channel openers provide cardioprotection in multiple models. Ion flux at an unidentified mitochondrial KATP channel has been proposed as the mechanism. The potassium channel subunit Kir 1.1 has been implicated as the mitochondrial channel pore forming subunit.
Hypothesis: We hypothesized that subunit Kir 1.1 is involved in the cardioprotection (maintenance of volume homeostasis and contractility) of KATP channel opener diazoxide during stress (exposure to hyperkalemic cardioplegia) at the myocyte and mitochondrial levels.
Methods: Kir subunit inhibitor Tertiapin Q was utilized to evaluate response to stress. Mouse ventricular mitochondrial volume was measured in the following groups: 100 μM diazoxide + 200μM ATP + Tertiapin Q (0.5pM, 10pM, 90pM, or 1,000pM). Mouse myocytes were exposed to Tyrode’s solution (5 min), test solution (Tyrode’s, hyperkalemic cardioplegia (CPG) stress, CPG + diazoxide, CPG + diazoxide + Tertiapin Q, Tyrode’s + Tertiapin Q, or CPG + Tertiapin Q), N=12 for all (10 min); followed by Tyrode’s (5min). Volume (mitochondrial and myocyte) and myocyte contractility were compared.
Results: Tertiapin Q alone, or with diazoxide, did not alter mitochondrial or myocyte volume. Stress (CPG) resulted in myocyte swelling and reduced contractility that was prevented by diazoxide. Tertiapin Q prevented the cardioprotection afforded by diazoxide (volume homeostasis and maintenance of contractility) (Figure).
Conclusions: Tertiapin Q did not alter diazoxide - induced mitochondrial swelling, but it did inhibit myocyte cardioprotection provided by diazoxide during stress. Because Tertiapin 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 Kir 1.1, 3.1 or 3.4.
Author Disclosures: M.B. Janjua: None. E.M. Kanter: None. C.M. Makepeace: None. M.C. Henn: None. R.B. Schuessler: None. C.G. Nichols: None. J.S. Lawton: None.
- © 2014 by American Heart Association, Inc.