Adult mammalian myocardium adapts to chronic hemodynamic over loading by increasing the size of its constituent myocytes (hypertrophy). Previous studies have shown that functional electrophysiological and contractile alterations are associated with the (pressure-overload induced) hypertrophy process. The cellular basis for these changes have not been clearly defined to date because standard multicellular cardiac preparations are not well suited for experiments addressing these issues. Isolated single myocytes however (disaggregated from intact ventricular muscle with techniques developed recently) should serve as a useful model preparation for studies of this nature. In this regard, myocytes isolated from normal and hypertrophied feline right ventricles will serve as the experimental preparation in the present research. The long term objectives of this research is to elucidate changes in the excitation-contraction coupling process that might play a key role in the compensatory myocardial response to pressure and volume loading and/or the transition from compensated hypertrophy to heart failure. The hypothesis to be tested is that processes involved in Ca++ homeostasis are modified during hypertrophy and lead to the functional electrophysiological and contractile alterations of hypertrophied myocardium.
The specific aims of this research are 1. to determine if the Ca++ buffering capacity (and therefore free Ca++i) of hypertrophied feline myocytes is abnormal. 2. To determine if the electrophysiological and contractile alterations of hypertrophied myocytes are related to abnormalities in process involved in Ca++ homeostasis. 3. To determine if alterations in sarcolemmal Na/Ca exchange and/or sarcoplasmic reticular Ca++ release and/or uptake are specific factors leading to abnormal Ca++ handling by hypertrophied myocytes. To achieve these aims Ca++i and total cell Ca++ will be measured with Quin-2 and atomic absorbtion spectrophotometry respectively. Myocyte electrophysiological and contractile properties will be measured with microelectrode and photodiode techniques. The combined use of isolated myocytes and recetnly developed experimental techniques should provide significant new insight into the E-C coupling process in normal myocytes as well as the changes in this process that occur in hypertrophied myocardium.
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