Ranolazine delays Ca2+‐induced mitochondrial permeability transition pore opening and membrane potential depolarization in guinea pig heart mitochondria

Abstract

Ranolazine (RAN) is an antianginal drug that may block a late Na+ current in cardiac cells during ischemia. We showed previously that RAN improved cardiac function and reduced ROS emission during ischemia and reperfusion (IR). Here we tested if these effects of RAN are associated with delay in opening of the mitochondrial (m) permeability transition pore (PTP) and membrane potential (ΔΨm) depolarization induced by incrementally adding buffer CaCl2 to mitochondrial suspension. Guinea pig hearts were perfused with RAN (5 μM) for 1 min followed by 30 min ischemia and 120 min reperfusion to assess m[Ca2] and infarct size (IS) in intact hearts, or reperfused for only 10 min to isolate mitochondria. ΔΨm and matrix Ca2+ uptake were measured using fluorescence spectrophotometry with rhodamine 123 and indo‐1. We found that m[Ca2+] increased less during early ischemia in RAN (296±25 nM) vs control hearts (436±34 nM), and m[Ca2+] was less in RAN treated (280±39 nM) vs control hearts (429±45 nM) during early reperfusion. RAN reduced IS (24±3%) vs control (37±3%). More buffer CaCl2 (20–25%) was required to open PTP and to induce full ΔΨm depolarization in RAN vs control hearts. Reduced ROS emission during ischemia may delay cytosolic Na+, Ca2+ loading, and consequently mCa2+ loading. The delay in PTP opening by Ca2+ in RAN treated hearts could result from improved mitochondrial bioenergetics with increased capacity to extrude Ca2+.This work was supported in part by the American Heart Association [0355608Z, 0855940G to D.F. Stowe]; the National Institutes of Health [K01 HL73246 to A.K.S. Camara, R01 HL089514 to D.F. Stowe]