Premium
Ranolazine inhibits hypoxia‐stimulated late sodium current
Author(s) -
Ma Jihua,
Song Yejia,
Hu Liangkun,
Yan Xisheng,
Zhang Peihua,
Shryock John C,
Belardinelli Luiz
Publication year - 2008
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.22.1_supplement.971.3
Subject(s) - ranolazine , hypoxia (environmental) , sodium channel , tetrodotoxin , chemistry , sodium , depolarization , medicine , endocrinology , sodium channel blocker , biophysics , oxygen , biology , organic chemistry
Ranolazine (Ran) has been suggested to attenuate cardiac arrhythmic activity associated with hypoxia. The objective of this study was to determine whether Ran inhibits hypoxia‐induced, arrhythmogenic late sodium current (I Na ). Both whole‐cell and single‐channel recordings were performed on guinea pig ventricular myocytes exposed to normoxic or hypoxic medium. Late I Na was measured 200 ms after the onset of a 500‐ms depolarizing pulse. Hypoxia (PO 2 = 3 KPa) caused an increase of the amplitude of inward late I Na from −0.47±0.01 to −3.99±0.07 pA/pF. The stimulatory effect of H 2 O 2 on late I Na was attenuated by Ran in a concentration‐dependent manner. Ran at 3 and 9 μmol/L significantly reduced the hypoxia‐induced late I Na by 16±3% and 55±3%, respectively, without altering the voltage‐dependence of the current. Hypoxia increased the mean open probability and open time of late sodium‐channel openings from 0.016±0.001 to 0.063±0.006 and from 0.693±0.042 to 1.081±0.097 ms, respectively. Ran at 3 and 9 μmol/L significantly attenuated the increase of open probability by 19±7% and 61±1%, and the increase of open time by 26±19% and 74±21%, respectively. The effects of hypoxia on whole‐cell and single‐channel properties of late I Na were also significantly inhibited in the presence of tetrodotoxin (2 μmol/L). In conclusion, Ran significantly inhibits hypoxia‐stimulated late I Na . The decrease by Ran of late I Na is due to reduction of the open probability and open time of late channel openings. The inhibitory effect of Ran on late I Na may provide cardiac protection in hypoxia.