Inhibition of big-conductance Ca 2+ -activated K + channels in cerebral artery (vascular) smooth muscle cells is a major
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ION CHANNELS, RECEPTORS AND TRANSPORTERS
Inhibition of big-conductance Ca2+-activated K+ channels in cerebral artery (vascular) smooth muscle cells is a major novel mechanism for tacrolimus-induced hypertension Qiang Tang 1,2 & Yun-Min Zheng 1 & Tengyao Song 1 & Jorge Reyes-García 1 & Chen Wang 2 & Yong-Xiao Wang 1 Received: 10 July 2020 / Revised: 17 September 2020 / Accepted: 30 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 β1subunit knockout (KO), resulted in hypertension in mice, but did not cause a further increase in blood pressure in BK channel β1subunit 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. Keywords Big-conductance Ca2+-activated K+ channels . Hypertension . Neurotransmitter . Tacrolimus . Vascular smooth muscle cells
Abbreviations BK Big-conductance Ca2+-activated K+ BSA Bovine serum albumin CA Cerebral artery V1/2 Half-maximum current activation NPo Open probability τo Open time constant PSS Physiological saline solution Qiang Tang, Yun-Min Zheng and Tengyao Song contributed equally to this work. * Yun-Min Zheng [email protected] * Yong-Xiao Wang [email protected] 1
Department of Molecular and Cellular Physiology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
2
Department of Pharmacology, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
SMCs
Smooth muscle cell
Introduction Tacrolimus (TAC), also known as FK506, is a potent immunosuppressive drug commonly used to prevent allograft rejection in transplant patients. It is well recognized that this drug often causes (systemic) hypertension, with an incidence up to 70% [4, 20]; however, the exact mechanisms are not understood. Rats following intraperitoneal injections of TAC (1 mg/kg) once a day for 8 days show increased norepinephrine (NE)induce
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