The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease.
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.
Hobai
Ion A
IA
Department of Medicine and Institute of Cardiobiology, Johns Hopkins University, Baltimore, MD 21205, USA.
O'Rourke
Brian
B
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D017136:Ion Transport; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000814:Aniline Compounds; D009842:Oligopeptides; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; C477158:phenylalanyl-arginyl-cysteinyl-arginyl-seryl-phenylalaninamide; D012964:Sodium; D013890:Thiourea; D002118:Calcium