Sodium-calcium exchange inhibitors: therapeutic potential in cardiovascular diseases.
Intracellular calcium ions (Ca2+) are the key regulators in cardiac and arterial functions during the contraction-relaxation cycle. Myocyte Ca2+ imbalance thus produces mechanical dysfunction, electrical instability (arrhythmia) and muscle remodeling. The sodium-calcium exchanger (NCX) is one of the major Ca(2+)-handling proteins in myocytes. Evidence is currently accumulating to suggest that NCX1 is upregulated in various cardiovascular diseases. Recently developed benzyloxyphenyl NCX inhibitors effectively prevent myocardial ischemia/reperfusion injury and salt-sensitive hypertension in animal models. Furthermore, several experiments with genetically engineered mice provide compelling evidence that these diseases are triggered by pathologic Ca2+ entry through NCX1 in cardiac and arterial myocytes, respectively. Thus, NCX inhibitors may have therapeutic potential as novel cardiovascular drugs for myocardial reperfusion injury and salt-sensitive hypertension. However, the efficacy of NCX inhibitors, as well as the role of NCX1, in heart failure or arrhythmias requires more detailed study.
Fukuoka University, Department of Pharmacology, School of Medicine, Jonan-ku, Fukuoka 814-0180, Japan. tiwamoto@cis.fukuoka-u.ac.jp
Takahiro
T
Iwamoto