The effects of
KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
methanesulfonate) on major ion transporters were studied in canine cardiac sarcolemmal and sarcoplasmic reticular vesicles.
KB-R7943 inhibited the Na+/Ca2+ exchange more potently than the Na+/H+ exchange, the Na+/K(+)-
ATPase and the Ca2(+)-
ATPase. The effects of
KB-R7943 on
ischemia/reperfusion-induced injury were studied in isolated rat perfused hearts in comparison with those of
diltiazem and
lidocaine. In normal hearts,
diltiazem (10 microM) and
lidocaine (100 microM) markedly reduced contractile function, but
KB-R7943 (1, 10 microM) had no such effect. In the hearts subjected to 25-min
ischemia and 30-min reperfusion,
KB-R7943 concentration-dependently and significantly improved post-ischemic recovery of left ventricular developed pressure, left ventricular dP/dtmax and left ventricular end-diastolic pressure by pre-ischemic treatment (5 min) or post-ischemic treatment (10 min).
Diltiazem and
lidocaine showed similar improvement of recovery by pre-ischemic treatment, but they had no effect by post-ischemic treatment. Furthermore, the effect of
KB-R7943 on
arrhythmia was studied in anesthetized rats subjected to 5-min cardiac ischmeia and 10-min reperfusion.
KB-R7943 (1, 10 mg/kg, i.v.) dose-dependently reduced the incidence and the duration of
ventricular fibrillation. These results indicate that
KB-R7943, a selective Na+/Ca2+ exchange inhibitor, has beneficial effects against
myocardial ischemia/
reperfusion injury and suggest that activation of the Na+/Ca2+ exchange mainly occurs immediately after reperfusion in the pathophysiological process of
myocardial ischemia/
reperfusion injury.