TY - JOUR
T1 - Inhibition of succinate dehydrogenase by diazoxide is independent of the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor
AU - Anastacio, Melissa M.
AU - Kanter, Evelyn M.
AU - Keith, Angela D.
AU - Schuessler, Richard B.
AU - Nichols, Colin G.
AU - Lawton, Jennifer S.
N1 - Funding Information:
This study was supported by American Heart Association Grant in Aid 09GRNT202045 (JSL), Thoracic Surgery Foundation for Research and Education Nina Starr Braunwald Career Award (JSL), NIH RO 1HL098182-01A1 (JSL), and NIH5T32 HL007776 (MMA).
PY - 2013/6
Y1 - 2013/6
N2 - Background: Diazoxide maintains myocyte volume and contractility during stress via an unknown mechanism. The mechanism of action may involve an undefined (genotype unknown) mitochondrial ATP-sensitive potassium channel and is dependent on the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor (SUR1). The ATP-sensitive potassium channel openers have been shown to inhibit succinate dehydrogenase (SDH) and a gene for a portion of SDH has been found in the SUR intron. Diazoxide may be cardioprotective via inhibition of SDH, which can form part of an ATP-sensitive potassium channel or share its genetic material. This study investigated the role of inhibition of SDH by diazoxide and its relationship to the SUR1 subunit. Study Design: Mitochondria were isolated from wild-type and SUR1 knockout mice. Succinate dehydrogenase activity was measured by spectrophotometric analysis of 2,6-dichloroindophenol reduction for 20 minutes as the relative change in absorbance over time. Mitochondria were treated with succinate (20 mM), succinate + 1% dimethylsulfoxide, succinate + malonate (8 mM) (competitive inhibitor of SDH), or succinate + diazoxide (100 μM). Results: Both malonate and diazoxide inhibit SDH activity in mitochondria of wild-type mice and in mice lacking the SUR1 subunit (p < 0.05 vs control). Conclusions: The ability of DZX to inhibit SDH persists even after deletion of the SUR1 gene. Therefore, the enzyme complex SDH is not dependent on the SUR1 gene. The inhibition of SDH by DZX can play a role in the cardioprotection afforded by DZX; however, this role is independent of the ATP-sensitive potassium channel subunit SUR1.
AB - Background: Diazoxide maintains myocyte volume and contractility during stress via an unknown mechanism. The mechanism of action may involve an undefined (genotype unknown) mitochondrial ATP-sensitive potassium channel and is dependent on the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor (SUR1). The ATP-sensitive potassium channel openers have been shown to inhibit succinate dehydrogenase (SDH) and a gene for a portion of SDH has been found in the SUR intron. Diazoxide may be cardioprotective via inhibition of SDH, which can form part of an ATP-sensitive potassium channel or share its genetic material. This study investigated the role of inhibition of SDH by diazoxide and its relationship to the SUR1 subunit. Study Design: Mitochondria were isolated from wild-type and SUR1 knockout mice. Succinate dehydrogenase activity was measured by spectrophotometric analysis of 2,6-dichloroindophenol reduction for 20 minutes as the relative change in absorbance over time. Mitochondria were treated with succinate (20 mM), succinate + 1% dimethylsulfoxide, succinate + malonate (8 mM) (competitive inhibitor of SDH), or succinate + diazoxide (100 μM). Results: Both malonate and diazoxide inhibit SDH activity in mitochondria of wild-type mice and in mice lacking the SUR1 subunit (p < 0.05 vs control). Conclusions: The ability of DZX to inhibit SDH persists even after deletion of the SUR1 gene. Therefore, the enzyme complex SDH is not dependent on the SUR1 gene. The inhibition of SDH by DZX can play a role in the cardioprotection afforded by DZX; however, this role is independent of the ATP-sensitive potassium channel subunit SUR1.
KW - DZX
KW - Kir
KW - SDH
KW - SUR1
KW - WT
KW - diazoxide
KW - mK
KW - mitochondrial ATP-sensitive potassium
KW - potassium inward rectifying subunit
KW - sK
KW - sarcolemmal ATP-sensitive potassium
KW - succinate dehydrogenase
KW - sulfonylurea type 1 receptor
KW - wild-type
UR - http://www.scopus.com/inward/record.url?scp=84878106886&partnerID=8YFLogxK
U2 - 10.1016/j.jamcollsurg.2013.01.048
DO - 10.1016/j.jamcollsurg.2013.01.048
M3 - Article
C2 - 23535164
AN - SCOPUS:84878106886
SN - 1072-7515
VL - 216
SP - 1144
EP - 1149
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 6
ER -