Abstract 11509: Adenosine Triphosphate - Sensitive Potassium Channel Opener Diazoxide Must Be Administered at the Onset of Stress to Provide Myocyte Protection During Metabolic Inhibition
Objective: Adenosine triphosphate sensitive (KATP) potassium channel opener diazoxide (DZX) maintains myocyte volume and contractility during stress via an unknown mechanism when administered at the onset of stress. These benefits are lost when DZX is administered after the onset of the stress of hypothermic hyperkalemic cardioplegia. The present study investigated the cardioprotective potential of diazoxide when added after the onset the stress of metabolic inhibition.
Methods: Isolated mouse ventricular or human atrial myocytes were exposed to control Tyrode’s solution (TYR) for 10 min, test solution for 30 min including: metabolic inhibition (MI) containing 2-deoxyglucose and NaCN or MI + 100uM diazoxide (MI+DZX) with DZX added after 10 or 20 min stress; followed by 20 min re-exposure to TYR (+/- DZX). Myocyte volume was compared.
Results: MI resulted in significant myocyte (human and mouse) swelling similar to that previously reported. DZX demonstrated only minor reduction in swelling when administered early (after 10 min of stress) and benefit was seen only after 5 min and after 20 min of DZX in mouse and human myocytes, respectively (Figure, Myocytes exposed to 10 min Tyrode’s (time 0-10min), 30 min stress (time 10-40), and 20 min re-exposure to Tyr (time 40-60min). Mean change in myocyte (mouse = top, human = bottom) volume from baseline, SEM omitted for clarity, * indicates only time points during stress NOT different (p>0.05) from Tyrode’s control). DZX provided no benefit when administered during re-exposure only. Human myocytes demonstrated prolongation of return to baseline volume in the MI group following re-exposure to TYR.
Conclusions: To maintain myocyte volume homeostasis during metabolic inhibition, KATP channel opener diazoxide requires administration at the onset of stress. These data have implications for any future clinical use of diazoxide as a cardioprotective adjunct.
- © 2013 by American Heart Association, Inc.