The cellular and molecular basis for the electrophysiological and mechanical abnormalities of adult mammalian myocardium with dysfunctional hypertrophy resulting from chronic pressureoverloading have not been studied in detail to date. Therefore a rational basis for medical manipulation of dysfuctionally hypertrophied myocardium has not been developed. The relative paucity of information in this regard arises primarily from the fact that standard multicellular cardiac muscle preparations are not well suited for experiments which address these issues because of complications arising from diffusion limiting extracellular spaces and neurohormonal influences. Single isolated mycoytes which retain the basic electromechanical properties of myocardium from which they are ioslated are free of these complications however and can serve as a powerful preparation to examine these issues for the first time. The long term objectives are to use these isolated myocyte preparations 1) to define cellular and molecular basis for the basic electrophysiological and contractile properties of normal adult mammalian myocardium and 2) to define the specific changes in these systems that play key roles in the myocardial response to pressure overload and/or the transition from compensatory hypertrophy to heart failure. The present proposal describes further work in this regard.
The specific aims of this project are to determine if and by what mechanism 1) calcium currents and 2) the systolic """"""""calcium transient"""""""" are altered in dysfunctionally hypertrophied myocytes. In addition the research seeks 3) to determine if the relationships between calcium influx through calcium channels, the calcium transient and contraction are altered in these myocytes and if so how do they explain the electromechanical alterations of dysfunctionally hypertrophied myocardium. In these experiments calcium currents will be recorded with suctiontype pipettes, calcium transients with a recently developed fluorescent dye, Indo1, and cell contraction with a recently developed photodiode technique. Therefore a unique collection of novel experimental techniques will be used simultaneously in order to gain a better understanding of the cellular basis for the electrophysiological and mechanical derangements of dysfunctionally hypertrophied myocardial cells. It is expected that future studies will address the subcellular basis for the changes defined in these experiments.
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