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.
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.
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