Ⅰ. Positive Inotropic Effects Of Na～+-Ca～(2+) Exchange Activators Potentiates The Cardiotonic Effect Of Ouabain In The Rat Hearts Ⅱ. Effects Of Neuropeptide Y On Ion Channels In The Rat Ventricular Myocytes

Partâ… Positive inotropic effects of Na⁺-Ca²⁺ exchange activators potentiates the cardiotonic effect of ouabain in the rat heartsSodium-calcium exchange is a bidirectional and electrogenic ion exchange in the plasma membrane of cardiomyocytes and plays a major role in maintaining intercellular calcium homeostasis. Na⁺-Ca²⁺ exchange operates in two modes: in forward-mode, Ca²⁺ efflux is coupled with Na⁺ influx, which occurs during the most of cardiac cycle, decreasing internal Ca²⁺ and contributing to myocardial diastole; on the other hand, in reverse-mode, Ca²⁺ influx is coupled with Na⁺ efflux, which occurs during the initial stage of the action potential. Recent study has indicated that Ca²⁺ influx via reverse-mode of Na⁺-Ca²⁺ exchange participated in the excitation-contraction coupling of cardiac muscle, playing a similar role to the L-type Ca²⁺ channel. Theoretically, an increase in the activity of Na⁺-Ca²⁺ exchange, including forward-mode and reverse-mode, may promote the cardiac function of both contraction and relaxation and provides a pathway to affect the cardiac performance. In our previous study, we have evaluated the effects of E-4031 and dofetilide, highly selective activators of IK channel, on Na⁺-Ca²⁺ exchange in the guinea pig and the rat cardiomyocytes. Since there is no IK channel in the rat myocardium, E-4031 and dofetilide can be used as selective activators of Na⁺-Ca²⁺ exchange. It should be emphasized that the cardiotonic effect of cardiac glycosides was coupled with Na⁺-Ca²⁺ exchange activity. In addition, recent studies showed that Na⁺ -K+ pump and Na⁺-Ca²⁺ exchanger are colocalized at sites of sarcolemmal diffusion restricted region in cardiomyocytes and that they influence each other via the cytoplasmic Na⁺ , suggesting the combination of Na⁺-Ca²⁺ exchange activator and Na⁺-K+ pump inhibitor may promote myocardial inotropism. However, it has never been studied that how the Na⁺-Ca²⁺ exchange activators change the behavior of cardiac glycosides. Obviously, this is a subject that has great clinical prospect. In the present study, therefore, we first investigated the inotropic effect of Na⁺-Ca²⁺ exchange activators in the rat papillary muscles and isolated hearts. Then, we observed the effect of Na⁺-Ca²⁺ exchange activator on cardiotonic effect of Na⁺-K+ pump inhibitor. In order to analyze the mechanism of the possible change of inotropism and electrical activity, we investigated the effects of drug interference on calcium transient and cell shortening synchronously in the rat cardiomyocytes using ionic imaging technique, and the effects on action potential and membrane current using patch clamp technique.