Previous studies supported by this grant have defined alterations of mitochondrial protein expression in the failing heart that are associated with abnormalities of myocardial energy metabolism, including loss of high energy phosphates (HEP), decreased myocardial oxygen consumption (MV02), and impaired maximal oxidative capacity. Since little information is available regarding ATP-sensitive potassium channel (KATP) function in the failing heart, the goal of this proposal is to determine whether maladaptive changes involving KATP channels during the response to cardiac stress contribute to the development of congestive heart failure (CHF). Pacing-induced tachycardia will be used to produce CHF in dogs;animals will be chronically instrumented for measurement of left ventricular (LV) function and MVO2. An initial study will determine whether the decreased MVO2 in the failing heart is the result of tonic opening of mitochondrial KATP channels, and whether this is triggered by superoxide (O2~). A second study will determine .whether activation of KATP channels during modest reductions of coronary blood flow triggers a fundamental but poorly understood response by which decreased mitochondrial respiration is able to depress contractile function without the usual signs of ischemia. An additional study will determine whether nicorandil, which acts as a preferential mitochondrial KATP channel opener, can protect the heart from the developments of progressive CHF during the stress of rapid ventricular pacing. This study will employ closed chest 31P NMR spectroscopy to evaluate the effect of nicorandil on myocardial HEP and LV function during the evolution of pacing-induced CHF. To further assess the importance of KATP on the response to chronic overload, mice expressing mutated Kir6.2 or SUR that result in ATP-insensitive KATP channels will be subjected to transverse aortic constriction to determine whether lack of KATP channel activity exacerbates myocardial hypertrophy and LV dysfunction, or causes increased mortality. We will determine whether loss of KATP channel function results in depressed myocardial respiration, increased cytosolic free [ADP] and decreased free energy of ATP hydrolysis either during basal conditions or with increased work in the overloaded and sham hearts. These studies will characterize responses of myocardial KATP channels that may contribute to the development of CHF in the chronically overloaded heart.
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