The Cardioprotective Effects of a New 1,4-Benzothiazepine Derivative, JTV519, on Ischemia/Reperfusion-Induced Ca2+ Overload in Isolated Rat Hearts

Abstract

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 μM) 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 μM. In indol-loaded isolated heart preparations, 0.3 μM 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 μM (p = n.s.), 22.0 ± 3.3% at 1.0 μM (p < 0.05), and 59.6 ± 1.4% at 3.0 μM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 μM 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.