Reduced repolarization reserve in ventricular myocytes from female mice

Yuejin Wu; Mark E. Anderson

doi:10.1016/S0008-6363(01)00387-X

Reduced repolarization reserve in ventricular myocytes from female mice

Yuejin Wu, Mark E. Anderson

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

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 (I_to) and sustained (I_sus) components and the selective I_sus 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 I_sus 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 I_to and I_sus revealed that males had a relatively more prominent I_to while females exhibited a more prominent I_sus. 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.

Original language	English (US)
Pages (from-to)	763-769
Number of pages	7
Journal	Cardiovascular research
Volume	53
Issue number	3
DOIs	https://doi.org/10.1016/S0008-6363(01)00387-X
State	Published - Feb 15 2002
Externally published	Yes

Keywords

Gender
K-channel
Membrane potential
Myocytes
Repolarization

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1016/S0008-6363(01)00387-X

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@article{5a6515b0895946e3b8a324b879807656,

title = "Reduced repolarization reserve in ventricular myocytes from female mice",

abstract = "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",

author = "Yuejin Wu and Anderson, {Mark E.}",

note = "Funding Information: This study was supported by NIH grants HL03727, HL62494 and an American Heart Association (SE Affiliate) Grant-in-Aid. The authors wish to thank Drs Jeff Balser and Dan Roden for helpful discussion.",

year = "2002",

month = feb,

day = "15",

doi = "10.1016/S0008-6363(01)00387-X",

language = "English (US)",

volume = "53",

pages = "763--769",

journal = "Cardiovascular research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "3",

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T1 - Reduced repolarization reserve in ventricular myocytes from female mice

AU - Wu, Yuejin

AU - Anderson, Mark E.

N1 - Funding Information: This study was supported by NIH grants HL03727, HL62494 and an American Heart Association (SE Affiliate) Grant-in-Aid. The authors wish to thank Drs Jeff Balser and Dan Roden for helpful discussion.

PY - 2002/2/15

Y1 - 2002/2/15

N2 - 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.

AB - 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.

KW - Gender

KW - K-channel

KW - Membrane potential

KW - Myocytes

KW - Repolarization

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DO - 10.1016/S0008-6363(01)00387-X

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C2 - 11861046

AN - SCOPUS:0037084197

SN - 0008-6363

VL - 53

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JO - Cardiovascular research

JF - Cardiovascular research

IS - 3

ER -

Reduced repolarization reserve in ventricular myocytes from female mice

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