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Potential Therapeutic Effects of Na+/Ca2+ Exchanger Inhibition in Cardiac Diseases

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The Na+/Ca2+ exchanger (NCX) has a pivotal role in cardiac Na+ and Ca2+ homeostasis and is an essential pathway for Ca2+ extrusion from cardiomyocytes. Altered NCX function may result in abnormal Ca2+ release from the sarcoplasmic reticulum (SR) and impaired cardiac electrical activity and contractility in several diseases, like arrhythmias, ischemia/reperfusion injury, hypertrophy and heart failure. This review focuses on the role of the exchanger and the major effects of partial NCX blockade in normally functioning and diseased hearts. In healthy cardiac cells consequences of a partial NCX blockade were found to be moderate and species dependent. In rabbit and dog practically no change in the magnitude of the calcium transients and mechanical activity was observed, while elevation of systolic calcium levels and a concomitant positive inotropic action were demonstrated in rat and murine hearts. On the other hand, NCX inhibition represents a novel potential therapeutic strategy in case of a variety of cardiac dysfunctions. Partial NCX blockade was shown to have beneficial effects in animal models of ischemia/reperfusion injury and also antiarrhythmic and positive inotropic actions in the failing heart. Further progress in this field is seriously hampered by the absence of really selective NCX inhibitors. KB-R7943 and SEA0400 are widely used NCX blockers, both drugs, however, have limited selectivity and efficacy, properties required to initiate relevant clinical trials. In summary, there is an increasing demand by both researchers and clinicians for new NCX inhibitors with significantly enhanced selectivity and functionality.
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Keywords: Arrhythmia; Heart failure; Ischemia-reperfusion; KB-R794; NCX inhibition; SEA0400

Document Type: Research Article

Affiliations: Department of Physiology, University of Debrecen, Hungary.

Publication date: 2009-09-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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