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| Diazoxide Mediated Maintenance of Myocyte Volume Homeostasis During Stress Requires KATP Channel Subunit SUR1 |
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Angela Sellitto, Haixia Zhang, Richard B. Schuessler, Colin Nichols, Jennifer S. Lawton; Surgery, Washington University School of Medicine, Saint Louis, MO Objective: Adenosine triphosphate - sensitive potassium (KATP) channel opener diazoxide is cardioprotective and mimics ischemic preconditioning in animal models. Diazoxide also inhibits the detrimental cell swelling and reduced contractility observed in animal and human myocytes during exposure to three stresses (metabolic inhibition, hyposmotic stress, and hyperkalemic cardioplegia) via an unknown mechanism. The sarcolemmal KATP channel in mouse myocytes is composed of SUR2A/Kir6.2 subunits in the ventricle and SUR1/Kir6.2 subunits in the atria. This study evaluated the effect of diazoxide on SUR1 knockout mice in an effort to determine diazoxide's mechanism of action. Methods: Isolated ventricular myocytes from SUR1 knockout (KO) and wild type (WT) mice underwent volume measurement at baseline during exposure to Tyrode’s solution (Ctr) at 37 deg C for 5 min, after 5 min of exposure to test solution (Ctr at 37 deg C, St Thomas hyperkalemic cardioplegia (CPG) at 9 deg C, or CPG + 100uM diazoxide (CPG+DZX) at 9deg C), and after 5 min of re-exposure to Ctr. Results: Data are represented as mean myocyte volume change normalized to baseline ± SEM (Figure 1). Myocyte volume remained unchanged in all groups during exposure to Ctr (time 5 min on Figure 1). Wild type myocytes demonstrated significant volume derangement during exposure to CPG that was prevented by DZX (time 10 min on Figure 1). SUR1 KO myocytes similarly swelled in response to CPG (6%); however, DZX had no effect on swelling. Re-exposure to Ctr is represented at time 15 min on Figure 1. Conclusion: Diazoxide provides volume homeostasis via an SUR1 - dependent pathway in ventricular myocytes. Because SUR1 is not expressed on the sarcolemma of mouse ventricular myocytes, these data support that the mechanism of action of DZX is via a non - sarcolemmal KATP channel location.  Figure 1 Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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