Cardioprotective mechanism of diazoxide involves the inhibition of succinate dehydrogenase.
Ann Thorac Surg
; 95(6): 2042-50, 2013 Jun.
Article
en En
| MEDLINE
| ID: mdl-23642436
ABSTRACT
BACKGROUND:
The adenosine triphosphate-sensitive potassium (KATP) channel opener, diazoxide, preserves myocyte volume homeostasis and contractility during stress via an unknown mechanism. Pharmacologic overlap has been suggested between succinate dehydrogenase (SDH) activity and KATP channel modulators. Diazoxide may be cardioprotective due to the inhibition of SDH which may form a portion of the mitochondrial KATP channel. To determine the role of inhibition of SDH in diazoxide's cardioprotection, this study utilized glutathione to prevent the inhibition of SDH.METHODS:
SDH activity was measured in isolated mitochondria exposed to succinate (control), malonate (inhibitor of succinate dehydrogenase), diazoxide, and varying concentrations of glutathione alone or in combination with diazoxide. Enzyme activity was measured by spectrophotometric analysis. To evaluate myocyte volume and contractility, cardiac myocytes were superfused with Tyrode's physiologic solution (Tyrode's) (20 minutes), followed by test solution (20 minutes), including Tyrode's, hyperkalemic cardioplegia (stress), cardioplegia + diazoxide, cardioplegia + diazoxide + glutathione, or glutathione alone; followed by Tyrode's (20 minutes). Myocyte volume and contractility were recorded using image grabbing software.RESULTS:
Both malonate and diazoxide inhibited succinate dehydrogenase. Glutathione prevented the inhibition of succinate dehydrogenase by diazoxide in a dose-dependent manner. The addition of diazoxide prevented the detrimental myocyte swelling due to cardioplegia alone and this benefit was lost with the addition of glutathione. However, glutathione elicited an independent cardioprotective effect on myocyte contractility.CONCLUSIONS:
The ability of diazoxide to provide beneficial myocyte homeostasis during stress involves the inhibition of succinate dehydrogenase, which may also involve the opening of a purported mitochondrial adenosine triphosphate sensitive potassium channel.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Succinato Deshidrogenasa
/
Cardiotónicos
/
Canales de Potasio
/
Miocitos Cardíacos
/
Diazóxido
/
Mitocondrias Musculares
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Ann Thorac Surg
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos