Open AccessInhibition of big-conductance Ca2+-activated K+ channels in cerebral artery (vascular) smooth muscle cells is a major novel mechanism for tacrolimus-induced hypertension
Author(s) -
Qiang Tang,
YunMin Zheng,
Tengyao Song,
Jorge ReyesGarcía,
Chen Wang,
Yong-Xiao Wang
Publication year - 2020
Publication title -
pflügers archiv für die gesamte physiologie des menschen und der tiere/pflügers archiv
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.428
H-Index - 129
eISSN - 0365-267X
pISSN - 0031-6768
DOI - 10.1007/s00424-020-02470-6
Subject(s) - vasoconstriction , bk channel , vascular smooth muscle , tacrolimus , blood pressure , medicine , mesenteric arteries , endocrinology , pharmacology , chemistry , artery , potassium channel , smooth muscle , transplantation
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 Ca 2+ -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, Ca 2+ 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 [Ca 2+ ] 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.