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Ranolazine delays Ca 2+ ‐induced mitochondrial permeability transition pore opening and membrane potential depolarization in guinea pig heart mitochondria
Author(s) -
Aldakkak Mohammed,
Camara Amadou K.S.,
Heisner James S.,
Gadicherla Ashish K.,
Boelens Age D.,
Yang Meiying,
Dash Ranjan K.,
Stowe David F.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.601.9
Subject(s) - mitochondrial permeability transition pore , depolarization , membrane potential , chemistry , mitochondrion , ischemia , uniporter , rhodamine 123 , biophysics , inner mitochondrial membrane , cytosol , medicine , biochemistry , biology , programmed cell death , apoptosis , multiple drug resistance , enzyme , antibiotics
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 (ΔΨ m ) depolarization induced by incrementally adding buffer CaCl 2 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[Ca 2 ] and infarct size (IS) in intact hearts, or reperfused for only 10 min to isolate mitochondria. ΔΨ m and matrix Ca 2+ uptake were measured using fluorescence spectrophotometry with rhodamine 123 and indo‐1. We found that m[Ca 2+ ] increased less during early ischemia in RAN (296±25 nM) vs control hearts (436±34 nM), and m[Ca 2+ ] 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 CaCl 2 (20–25%) was required to open PTP and to induce full ΔΨ m depolarization in RAN vs control hearts. Reduced ROS emission during ischemia may delay cytosolic Na + , Ca 2+ loading, and consequently mCa 2+ loading. The delay in PTP opening by Ca 2+ in RAN treated hearts could result from improved mitochondrial bioenergetics with increased capacity to extrude Ca 2+ . 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]