Takeda Y, Miyamori I, Wu P, Furukawa K, Inaba S, Takeda R, Mabuchi H
Second Department of Internal Medicine, School of Medicine, Kanazawa University, Japan.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S290-2.
Tacrolimus (FK 506) is a new, more powerful immunosuppressant and is more effective in the prevention and treatment of allograft rejection in humans than cyclosporine (CysA). The present study was conducted to determine whether FK 506 increases ET(A) receptor mRNA in blood vessels in rats. FK 506 5 mg/kg/day for 4 weeks increased blood pressure and expression of ET(A) receptor mRNA in mesenteric arteries of Wistar-Kyoto rats. However, 0.5 mg/kg/day of FK 506 did not increase blood pressure or ET(A) mRNA levels in the vasculature. The dose of 0.1 microM CysA used in clinical practice induced expression of ET(A) receptor mRNA in cultured rat vascular smooth-muscle cells (VSMCs). A clinical dose (0.01 microM) of FK 506 did not increase expression of ET(A) receptor mRNA in VSMCs. However, 0.1 microM FK 506 increased the levels of ET(A) receptor mRNA in VSMCs. These results indicate that the upregulating effect of FK 506 on the ET(A) receptor in the vasculature may contribute to the genesis of FK 506-induced hypertension. The lower incidence of complications seen with FK 506 may be due in part to its use at a lower clinical dose compared to that of CysA.
他克莫司（FK 506）是一种新型、效力更强的免疫抑制剂，在预防和治疗人类同种异体移植排斥反应方面比环孢素（CysA）更有效。本研究旨在确定FK 506是否会增加大鼠血管中ET(A)受体mRNA的含量。给Wistar - Kyoto大鼠每日注射5 mg/kg的FK 506，持续4周，可使大鼠血压升高，并增加肠系膜动脉中ET(A)受体mRNA的表达。然而，每日注射0.5 mg/kg的FK 506并不会使血管系统中的血压或ET(A) mRNA水平升高。临床实践中使用的0.1 microM CysA剂量可诱导培养的大鼠血管平滑肌细胞（VSMC）中ET(A)受体mRNA的表达。临床剂量（0.01 microM）的FK 506不会增加VSMC中ET(A)受体mRNA的表达。然而，0.1 microM的FK 506可增加VSMC中ET(A)受体mRNA的水平。这些结果表明，FK 506对血管系统中ET(A)受体的上调作用可能与FK 506诱导的高血压的发生有关。与CysA相比，FK 506并发症发生率较低可能部分归因于其临床使用剂量较低。
