Ghatta Srinivas, Tunstall Radhika R, Kareem Sohail, Rahman Mohamed, O'Rourke Stephen T
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
J Pharmacol Exp Ther. 2007 Mar;320(3):1204-8. doi: 10.1124/jpet.106.115329. Epub 2006 Dec 12.
Little is known about the vasomotor effects of sirolimus, and preliminary studies using animal models have provided conflicting results. The present study was designed to determine the effects of sirolimus on vasomotor tone in human blood vessels. Human radial artery segments were cut into rings, denuded of endothelium, and placed into organ chambers for isometric tension recording. Sirolimus (10(-10) to 10(-6) M) caused concentration-dependent relaxation of human arteries contracted with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha); 10(-8) M) [-log (M) EC(50) (pD(2)) = 7.28 +/- 0.1; E(max) = 57 +/- 6%] or phenylephrine (10(-6) M) (pD(2) = 7.16 +/- 0.4; E(max) = 45 +/- 9%). Sirolimus-induced relaxation was unaffected by treatment with indomethacin (10(-5) M) but was nearly abolished in tissues contracted by depolarization with elevated K(+) (60 mM). In U46619-contracted rings, the response to sirolimus was markedly inhibited in the presence of the specific ATP-sensitive potassium (K(ATP)) channel blocker, glyburide (10(-6) M), but was unaffected by treatment with blockers of large conductance, calcium-activated potassium channel (iberiotoxin, 10(-7) M), small conductance, calcium-activated potassium channel (apamin, 10(-6) M), or voltage-gated potassium channel (4-aminopyridine, 10(-3) M). The K(ATP) channel opener, aprikalim (10(-7) to 10(-5) M), caused concentration-dependent relaxations that were inhibited by glyburide (10(-6) M) and abolished in tissues contracted with elevated K(+) (60 mM), thus confirming that K(ATP) channel opening causes relaxation of these arteries. These data suggest that sirolimus, at concentrations attained in vivo, causes relaxation of human arteries, and this effect is mediated by opening of K(ATP) channels in vascular smooth muscle. Reduced vasomotor tone is a heretofore unrecognized action of sirolimus that could potentially contribute to its efficacy in drug-eluting stents.
西罗莫司的血管舒缩作用鲜为人知，此前利用动物模型进行的初步研究结果相互矛盾。本研究旨在确定西罗莫司对人体血管血管舒缩张力的影响。将人桡动脉段切成环状，去除内皮，放入器官浴槽中进行等长张力记录。西罗莫司（10⁻¹⁰至10⁻⁶ M）可使由U46619（9,11 - 二脱氧 - 11α,9α - 环氧甲叉 - 前列腺素F₂α；10⁻⁸ M）[ - log (M) EC₅₀（pD₂） = 7.28 ± 0.1；Eₘₐₓ = 57 ± 6%]或去氧肾上腺素（10⁻⁶ M）（pD₂ = 7.16 ± 0.4；Eₘₐₓ = 45 ± 9%）收缩的人体动脉产生浓度依赖性舒张。西罗莫司诱导的舒张不受吲哚美辛（10⁻⁵ M）处理的影响，但在用高钾（60 mM）去极化收缩的组织中几乎完全被消除。在U46619收缩的环中，在存在特异性ATP敏感性钾（Kₐₜₚ）通道阻滞剂格列本脲（10⁻⁶ M）的情况下，对西罗莫司的反应明显受到抑制，但不受大电导钙激活钾通道阻滞剂（iberiotoxin，10⁻⁷ M）、小电导钙激活钾通道阻滞剂（蜂毒明肽，10⁻⁶ M）或电压门控钾通道阻滞剂（4 - 氨基吡啶，10⁻³ M）处理的影响。Kₐₜₚ通道开放剂阿普卡林（10⁻⁷至10⁻⁵ M）可产生浓度依赖性舒张，该舒张受到格列本脲（10⁻⁶ M）抑制，并在高钾（60 mM）收缩的组织中被消除，从而证实Kₐₜₚ通道开放可使这些动脉舒张。这些数据表明，在体内达到的浓度下，西罗莫司可使人体动脉舒张，且这种作用是通过血管平滑肌中Kₐₜₚ通道的开放介导的。血管舒缩张力降低是西罗莫司此前未被认识的一种作用，这可能有助于其在药物洗脱支架中的疗效。
