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Inhibition of big-conductance Ca2+-activated K+ channels in cerebral artery (vascular) smooth muscle cells is a major novel mechanism for tacrolimus-induced hypertension

  • Ion channels, receptors and transporters
  • Published:
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Abstract

Tacrolimus (TAC, also called FK506), a common immunosuppressive drug used to prevent allograft rejection in transplant patients, is well known to alter the functions of blood vessels. In this study, we sought to determine whether chronic treatment of TAC could inhibit the activity of big-conductance Ca2+-activated K+ (BK) channels in vascular smooth muscle cells (SMCs), leading to hypertension. Our data reveal that the activity of BK channels was inhibited in cerebral artery SMCs (CASMCs) from mice after intraperitoneal injection of TAC once a day for 4 weeks. The voltage sensitivity, Ca2+ sensitivity, and open time of single BK channels were all decreased. In support, BK channel β1-, but not α-subunit protein expression was significantly decreased in cerebral arteries. In TAC-treated mice, application of norepinephrine induced stronger vasoconstriction in both cerebral and mesenteric arteries as well as a larger [Ca2+]i in CASMCs. Chronic treatment of TAC, similar to BK channel β1-subunit knockout (KO), resulted in hypertension in mice, but did not cause a further increase in blood pressure in BK channel β1-subunit KO mice. Moreover, BK channel activity in CASMCs was negatively correlated with blood pressure. Our findings provide novel evidence that TAC inhibits BK channels by reducing the channel β1-subunit expression and functions in vascular SMCs, leading to enhanced vasoconstriction and hypertension.

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Abbreviations

BK:

Big-conductance Ca2+-activated K+

BSA:

Bovine serum albumin

CA:

Cerebral artery

V 1/2 :

Half-maximum current activation

NPo:

Open probability

τ o :

Open time constant

PSS:

Physiological saline solution

SMCs:

Smooth muscle cell

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Funding

This paper was supported by the American Heart Association (AHA) Scientist Development Grant 0630236N (Y.-M.Z.), National Natural Science Foundation of China Young Scientist Grant 81102439 (Q.T.), and AHA Established Investigator Award 0340160N, American Diabetes Association Research Award 1-11-BS-171, as well as NIH R01HL64043 and R01HL108232 (Y.-X.W.).

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Author notes

  1. Qiang Tang, Yun-Min Zheng and Tengyao Song contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA

    Qiang Tang, Yun-Min Zheng, Tengyao Song, Jorge Reyes-García & Yong-Xiao Wang

  2. Department of Pharmacology, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Qiang Tang & Chen Wang

Authors
  1. Qiang Tang
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Contributions

YXW, YMZ, QT and TS conceived and planned the experiments. QT, TS, CW and YMZ conducted the experiments. QT, YMZ, TS, JRG, CW and YXW contributed to data analysis and interpretation. QT, YMZ, JRG and YXW took the lead in writing the manuscript.

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Correspondence to Yun-Min Zheng or Yong-Xiao Wang.

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The experiments conducted in this work were approved by the Institutional Animal Care and Use Committee of Albany Medical College and in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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Tang, Q., Zheng, YM., Song, T. et al. Inhibition of big-conductance Ca2+-activated K+ channels in cerebral artery (vascular) smooth muscle cells is a major novel mechanism for tacrolimus-induced hypertension. Pflugers Arch - Eur J Physiol 473, 53–66 (2021). https://doi.org/10.1007/s00424-020-02470-6

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  • DOI: https://doi.org/10.1007/s00424-020-02470-6

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