© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Reduced repolarization reserve in ventricular myocytes from female mice
aDepartment of Medicine, 315 Preston Research Building II, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA
bDepartment of Pharmacology, Vanderbilt University, Nashville, TN 37232-6300, USA
* Corresponding author. Tel.: +1-615-936-1873; fax: +1-615-936-1872 mark.anderson{at}mcmail.vanderbilt.edu
Objective: Cardiac repolarization is prolonged and repolarization reserve (RR) is diminished in female rabbits and humans, compared to males. Reduced RR is evidenced by the relatively greater increase in ventricular action potential duration (APD) in myocytes from females in response to drugs that block repolarizing K+ currents. Mice are an increasingly important experimental model animal for cardiovascular research, but gender-dependent differences have not been reported for repolarization in murine ventricular myocytes. Methods: APD and repolarizing K+ currents were measured in isolated ventricular myocytes from adult littermate male and female mice. Repolarizing K+ currents were dissected into transient (Ito) and sustained (Isus) components and the selective Isus antagonist FK506 was used to probe for differences in RR. Results: Under control conditions APD at 50% (APD50) and at 90% (APD90) repolarization was significantly longer in females (APD50=15±3 ms, n=6 and APD90=63±6 ms, n=6) compared to males (APD50=8±2 ms, n=7 and APD90=42±9 ms, n=7) at 1.0 Hz. At 0.3 Hz stimulation frequency APD90, but not APD50, was significantly longer in females (APD50=12±2 ms and APD90=54±5 ms, n=10) compared to males (APD50=11±2 ms and APD90=47±7 ms, n=10). FK506 treatment (25 µM) selectively and equally inhibited Isus in all cells, and significantly increased APD50 and APD90 in males and females at 0.3 and 1.0 Hz. However, increases in APD50 and APD90 (0.3 and 1.0 Hz) in response to FK506 were significantly greater in myocytes from females compared to males. Voltage clamp measurement of Ito and Isus revealed that males had a relatively more prominent Ito while females exhibited a more prominent Isus. Conclusions: Ventricular action potential repolarization is prolonged in myocytes from female compared to male mice. Female mice have reduced RR that is unmasked by FK506. These findings suggest that gender is an important variable for cardiovascular studies using mice.
KEYWORDS Gender; K-channel; Membrane potential; Myocytes; Repolarization
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