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.

他克莫司（TAC，也称为 FK506）是一种常见的免疫抑制药物，用于预防移植患者的同种异体移植排斥反应，众所周知可以改变血管的功能。在这项研究中，我们试图确定 TAC 的长期治疗是否可以抑制血管平滑肌细胞 (SMC)中大电导 Ca ²⁺激活的 K ⁺ (BK) 通道的活性，从而导致高血压。我们的数据显示，每天一次腹腔注射 TAC 4 周后，小鼠脑动脉 SMC (CASMC) 中 BK 通道的活性受到抑制。电压灵敏度，Ca ²⁺单个 BK 通道的灵敏度和开放时间均降低。作为支持，BK 通道β1-而非α-亚基蛋白在脑动脉中的表达显着降低。在 TAC 治疗的小鼠中，去甲肾上腺素的应用在大脑和肠系膜动脉中诱导更强的血管收缩以及更大的 [Ca ²⁺ ] _i在 CASMC 中。TAC 的慢性治疗，类似于 BK 通道 β1 亚基敲除 (KO)，导致小鼠高血压，但不会导致 BK 通道 β1 亚基 KO 小鼠血压进一步升高。此外，CASMCs 中的 BK 通道活性与血压呈负相关。我们的研究结果提供了新的证据，表明 TAC 通过降低血管 SMC 中通道 β1 亚基的表达和功能来抑制 BK 通道，导致血管收缩和高血压增强。