The broad, long-term objectives of this application are to gain a better understanding of the interrelationship between Ca ion homeostasis and energy metabolism as determinants of contractile function in isolated cells from normal and failing hearts. Ca ions are known to play a key role in the control of contractile function, but the control of intracellular Ca even in normal hearts is not yet completely understood. The Na/Ca exchanger is known to play an important role in this control. Recent 22Na flux measurements indicate that the Na/Ca exchanger is switched off in cells at rest, and becomes activated by Cai when the cells beat, by Ca binding at a regulatory site. This regulation could give the heart a means to control its strength of contraction, in addition to the other known inotropic mechanisms. The focus of this application is to further elucidate this control of the Na/Ca exchanger, and how that control is altered in failing hearts. Heart failure is the end-point of both ischemic heart disease and idiopathic cardiomyopathy, and is a common cause of death. Evidence suggests that a contributory factor in the etiology of failure could be a defect in Ca regulation. In a rat model of inherited hypertensive cardiomyopathy, SHHF/Mcc-cp, preliminary evidence indicates that the exchanger may be active even at rest.
Our specific aims are: first, to develop and implement a new technique for measurement of isotope efflux from a small sample of cells with high time resolution, to determine if the regulation of the exchanger is on a beat-to-beat basis or if the activation responds to the mean level of Cai; second, to measure the dependence of activation of the exchanger on Cai concentration and pool of origin, and also the ATP concentration dependence; third, to determine the [Nao], [Cao], and [Nai] dependence of Ca uptake by the exchanger in intact cells; fourth, to investigate the effect of general anesthetics on those kinetics; and fifth, to investigate the cause of the apparent activation of the exchanger in cells from cardiomyopathic rats, and to similarly investigate the properties of Na/Ca exchange in cells isolated from hearts of transplant recipients.
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