sea-0400 and Heart-Diseases

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.

Topics: Aniline Compounds; Animals; Heart Diseases; Humans; Molecular Structure; Phenyl Ethers; Sodium-Calcium Exchanger; Stereoisomerism; Structure-Activity Relationship; Thiourea

The Na(+)/Ca(2+) exchanger (NCX), a surface membrane antiporter, is the primary pathway for Ca(2+) efflux from the cardiac cell and a determinant of both the electrical and contractile state of the heart. Enhanced expression of NCX has recently been recognised as one of the molecular mechanisms that contributes to reduced Ca(2+) release, impaired contractility and an increased risk of arrhythmias during the development of cardiac hypertrophy and failure. The NCX has also been implicated in the mechanism of arrhythmias and cellular injury associated with ischaemia and reperfusion. Hence, NCX blockade represents a potential therapeutic strategy for treating cardiac disease, however, its reversibility and electrogenic properties must be taken into consideration when predicting the outcome. NCX inhibition has been demonstrated to be protective against ischaemic injury and to have a positive inotropic and antiarrhythmic effect in failing heart cells. However, progress has been impaired by the absence of clinically useful agents. Two drugs, KB-R7943 and SEA-0400, have been developed as NCX blockers but both lack specificity. Selective peptide inhibitors have been well characterised but are active only when delivered to the intracellular space. Gene therapy strategies may circumvent the latter problem in the future. This review discusses the effects of NCX blockade, supporting its potential as a new cardiovascular therapeutic strategy.

Topics: Aniline Compounds; Calcium; Heart; Heart Diseases; Heart Failure; Humans; Ion Transport; Models, Biological; Oligopeptides; Phenyl Ethers; Sodium; Sodium-Calcium Exchanger; Thiourea; Ventricular Fibrillation