Ranolazine attenuates hypoxia- and hydrogen peroxide-induced increases in sodium channel late openings in ventricular myocytes.
Ranolazine attenuates cardiac arrhythmic activity associated with hypoxia and hydrogen peroxide (H2O2) by inhibition of late sodium current (late INa). The mechanism of ranolazine's action on Na channels was investigated using whole-cell and single-channel recording from guinea pig isolated ventricular myocytes. Hypoxia increased whole-cell late INa from -0.48 ± 0.02 to -3.99 ± 0.07 pA/pF. Ranolazine at 3 and 9 μmol/L reduced the hypoxia-induced late INa by 16% ± 3% and 55% ± 3%, respectively. Hypoxia increased the mean open probability and open time of Na-channel late openings from 0.016 ± 0.001 to 0.064 ± 0.007 milliseconds and from 0.693 ± 0.043 to 1.081 ± 0.098 milliseconds, respectively. Ranolazine at 3 and 9 μmol/L attenuated the hypoxia-induced increase of open probability by 19% ± 7% and 61% ± 1%, and increase of open time by 26% ± 19% and 74 ± 21%, respectively. H2O2 increased the mean open probability and open time of Na-channel late openings from 0.013 ± 0.002 to 0.107 ± 0.015 milliseconds and from 0.689 ± 0.075 to 1.487 ± 0.072 milliseconds, respectively. Ranolazine at 3 and 6 μmol/L reduced the H2O2-induced increase of mean open probability by 60% ± 7% and 95% ± 2%, and the increase of mean open time by 31% ± 21% and 82% ± 8%. In conclusion, the inhibition by ranolazine of hypoxia- and H2O2-stimulated late INa is due to reduction of both the open probability and open time of Na-channel late openings.
*Cardio-Electrophysiological Research Laboratory, Wuhan University of Science and Technology, Wuhan, China; †Division of Cardiovascular Medicine, University of Florida, Gainesville, FL; and ‡Gilead Sciences, Foster City, CA.
Jihua
J
Ma
Yejia
Y
Song
John C
JC
Shryock
Liangkun
L
Hu
Weiping
W
Wang
Xisheng
X
Yan
Peihua
P
Zhang
Luiz
L
Belardinelli
D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015687:Cell Hypoxia; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D000069458:Ranolazine; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D015222:Sodium Channels; D000069458:Ranolazine; D006861:Hydrogen Peroxide