A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective 
effects against isoproterenol-induced myocardial injury. We investigated the 
effects of JTV on Ca2+ overload and on functional recovery during 
ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes 
of reperfusion following 30 min of global ischemia, the % recovery of LV 
developed pressure was improved in a concentration-dependent manner when JTV 
(0.3-3.0 microM) was administered either 5 min before induction of ischemia or 
for 5 min at the time of reperfusion only JTV showed a negative inotropic effect 
only at concentrations above 3.0 microM. In indol-loaded isolated heart 
preparations, 0.3 microM JTV did not affect the preischemic systolic or 
diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 
2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the 
increase in the ratio in the postischemic reperfusion period (% change of 
R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 
0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, 
we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). 
The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p 
= n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM 
(p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not 
be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ 
influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent 
that has been demonstrated for the first time to have clinical potential for the 
treatment of acute coronary syndrome by its efficacy in administration at the 
time of reperfusion, by its suppression of reperfusion-related intracellular 
Ca2+ overload with no significant interaction with I(Ca), and by its subsequent 
ability of strong myocardial protection.