MEDIATORS OF CONTRACTILE FAILURE DURING CARDIAC ISCHEMIA

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The overall goal of this proposal is to determine the mechanisms responsible for the myocardial contractile failure of acute low flow ischemia. Specifically, this proposal is designed to ascertain the respective roles of intracellular free calcium ([Ca2+]i), inorganic phosphate ([P-i]i), acidosis ((H+]i), free magnesium ([Mg2+]i), and vascular pressure in mediating ischemic contractile dysfunction. Health Relatedness: Low flow ischemic contractile failure frequently results in congestive heart failure in patients with coronary artery disease. Elucidating the mechanisms of this contractile failure will aid the development of therapeutic modalities to reduce the morbid consequences of low flow ischemia. Experimental Design: Perfused rat heart studies will be performed to i) verify that decreased [Ca2+]i is not responsible for ischemic contractile dysfunction; ii) quantitatively define the [Ca2+]i-pressure relationship in whole hearts during graded coronary flow reductions; and iii) examine the role of potential mediators of ischemic contractile dysfunction through their effect on the [Ca2+]i-pressure relationship. Methods: Indo-1 fluorescence will be used to measure [Ca2+]i, and 31P-NMR to measure [P-i]i, [H+]i, and [Mg2+]i, in perfused rat hearts. The [Ca2+]i-pressure relationship will be quantitatively defined during control conditions and graded coronary flow reductions. The respective roles of [P-i]i, [H+]i, (Mg2+]i, and vascular pressure in altering the [Ca2+]i-pressure relationship will be examined quantitatively, isolating each as an independent variable. Additional fluorescence and NMR techniques will be used to confirm findings. Finally, techniques to define the [Ca2+]i-pressure relationship in open-chest pigs will be developed to determine the relevance of the previous perfused heart findings in vivo.