Myocyte stress in the form of exposure to hyperkalemic cardioplegic solutions, hyposmotic stress, or metabolic inhibition results in significant myocyte swelling that is directly linked to a significant reduction in myocyte contractility. Myocyte structural derangement is therefore hypothesized to be one mechanism of myocardial stunning. These structural and functional derangements may be eliminated by the addition of an adenosine triphosphate -sensitive potassium (KATP) channel opener diazoxide which is known to mimic ischemic preconditioning and provide cardioprotection in multiple models by an unknown mechanism. This application will investigate the role of the sarcolemmal KATP channel in volume derangement and the efficacy of diazoxide as a cardioprotective agent when administered during ischemia or reperfusion on the cellular and whole organ levels by the following specific aims:
Specific Aim #1 To determine the role of the sarcolemmal KATP channel in myocyte volume homeostasis (and resultant functional preservation) during stress, Specific Aim #2 To determine the effectiveness of KATP channel opener diazoxide as a cardioprotective agent during ongoing stress at the myocyte level, and Specific Aim #3 To establish the usefulness of KATP channel opener diazoxide as a cardioprotective agent during ongoing myocardial ischemia at the whole organ level. Increasing the level of understanding of this intrinsically protective ion channel and the effects of channel opener drugs will allow for direct pharmacologic targeting in the future that could lessen the myocardial stunning seen in hundreds of thousands of patients each year.

Public Health Relevance

This proposal will seek to expand the knowledge of the cardiac myocyte's response to stress and to increase the knowledge of a unique set of medications that activate an ion channel in the heart that serves as one of the heart's intrinsic cardioprotective mechanisms. This knowledge could lead to improvement in the treatment of any person suffering a heart attack or any form of heart injury. This is extremely important as coronary heart disease is the single largest killer of both American men and women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098182-04
Application #
8450769
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lathrop, David A
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$253,232
Indirect Cost
$86,632
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Janjua, M Burhan; Makepeace, Carol M; Anastacio, Melissa M et al. (2014) Cardioprotective benefits of adenosine triphosphate-sensitive potassium channel opener diazoxide are lost with administration after the onset of stress in mouse and human myocytes. J Am Coll Surg 219:803-13
Anastacio, Melissa M; Kanter, Evelyn M; Makepeace, Carol et al. (2013) Cardioprotective mechanism of diazoxide involves the inhibition of succinate dehydrogenase. Ann Thorac Surg 95:2042-50
Anastacio, Melissa M; Kanter, Evelyn M; Makepeace, Carol M et al. (2013) Relationship between mitochondrial matrix volume and cellular volume in response to stress and the role of ATP-sensitive potassium channel. Circulation 128:S130-5
Anastacio, Melissa M; Kanter, Evelyn M; Keith, Angela D et al. (2013) Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor. J Am Coll Surg 216:1144-9
Zhang, Hai Xia; Akrouh, Alejandro; Kurata, Harley T et al. (2011) HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal K ATP channels. J Mol Cell Cardiol 50:552-60
Sellitto, Angela D; Al-Dadah, Ashraf S; Schuessler, Richard B et al. (2011) An open sarcolemmal adenosine triphosphate-sensitive potassium channel is necessary for detrimental myocyte swelling secondary to stress. Circulation 124:S70-4
Sellitto, Angela D; Maffit, Sara K; Al-Dadah, Ashraf S et al. (2010) Diazoxide maintenance of myocyte volume and contractility during stress: evidence for a non-sarcolemmal K(ATP) channel location. J Thorac Cardiovasc Surg 140:1153-9
Lawton, Jennifer S (2010) Edema does matter. J Thorac Cardiovasc Surg 139:510; author reply 510-1