One of the remarkable characteristics of heart muscle is its ability to change its force of contraction (inotropic responses) over a wide range under normal physiological conditions. The long-term objectives of our research are to elucidate the mechanisms by which intracellular Ca and Na ions are regulated and the ionic basis underlying inotropic responses in cardiac muscle. A Na-Ca exchange process operating across the surface membrane of cells is considered to be one of the most important factors in the regulation of intracellular Ca ion activity (a-1-Ca) and hence of the contractile force (T) in cardiac muscle. Na-Ca exchange is assumed to depend primarily on the transmembrane Na ion activity gradient (a-o-Na/a-i-Na: the ratio of extra- and intracellular Na ion activities) that, in turn, depends on Na-K pump. The objectives of this proposed research are to define the roles of Na-Ca exchange and Na-K pump in the regulation of intracellular Ca and contractile force in canine cardiac Purkinje fibers. To define their roles, the following specific aims are set: (1) to test the hypothesis that the ratio of a-o-Na/a-i-Na is the major factor for operating Na-Ca exchange and hence plays an important role in the control of a-i-Ca and T; (2) to test dependence of the quantitative relationship between T and a-i-Na on the levels of a-i-Na, a-i-Ca and membrane potential; (3) to test the hypothesis that a decrease of Ca influx by calcium antagonists (D-600 and Mn2+) depresses the inotropic response induced by strophanthidin; (4) to examine how an inhibition of Ca accumulation into sarcoplasmic reticulum by caffein and ryanodine influences the inotropic response; (5) to test the hypothesis that Ca influx and exchangeable Ca pool play a role in the positive inotropic action of strophanthidin; (6) to test the hypothesis that a decrease of Na influx by ladocaine, quinidine and tetrodotoxin depresses the inotropic response induced by strophanthidin. To test the hypotheses proposed, intracellular ion activity a-i-Na or a-i-Ca), contractile force and action potential of cardiac Purkinje fibers stimulated at a constant rate of 1.0 Hz are measured simultaneously and continuously under a variety of experimental conditions. The a-i-Na and a-i-Ca will be measured with Na+- and Ca2+ selective microelectrodes respectively. It is hoped that the proposed study on the ionic mechanism of cardiac inotropic responses may provide useful information for management of weak heart as well as about normal function of the heart.
