Department of Life Sciences, University of Siena, Siena, Italy.
Department of Pharmacy-Pharmaceutical Sciences, University of Bari "A. Moro" Bari, Italy.
J Cardiovasc Pharmacol. 2017 Dec;70(6):405-410. doi: 10.1097/FJC.0000000000000536.
The P-glycoprotein (P-gp) substrate MC225, at concentrations ≤10 nM, is a valuable radiotracer for positron emission tomography imaging of P-gp function in rats and mice. The aim of this study was to evaluate its potential toxic hazard toward the cardiovascular system through an in-depth analysis of its effects on rat aorta rings, on CaV1.2 channel current (ICa1.2) of A7r5 cells and on Langendorff-perfused rat heart. In aortic rings, MC225 relaxed phenylephrine-induced contraction in a concentration-dependent and endothelium-independent manner, with an IC50 value of about 1 μM. At concentrations ≥3 μM, it antagonized the response to cumulative concentrations of K. MC225, 1 and 10 μM, inhibited ICa1.2 by 15% and 31%, respectively, without affecting either current activation or inactivation kinetics. In Langendorff-perfused rat hearts, only 10 μM MC225 significantly decreased left ventricular pressure and increased coronary perfusion pressure while reducing heart rate and prolonging the cardiac cycle length as well as the atrioventricular conduction time (PQ interval) on the electrocardiogram. Lower concentrations of the drug were ineffective. These findings demonstrate that MC225-induced cardiovascular effects took place at concentrations that are at least 2 orders of magnitude higher than those allowing in vivo measurement of P-gp function. Therefore, MC225 represents a promising positron emission tomography tool for in vivo straightforward P-gp quantification.
P-糖蛋白（P-gp）底物 MC225 的浓度≤10 nM 时，是一种用于大鼠和小鼠 P-gp 功能正电子发射断层扫描成像的有价值的示踪剂。本研究旨在通过深入分析 MC225 对大鼠主动脉环、A7r5 细胞 CaV1.2 通道电流（ICa1.2）和 Langendorff 灌注大鼠心脏的影响，评估其对心血管系统的潜在毒性危害。在主动脉环中，MC225 以浓度依赖性和非内皮依赖性方式松弛去氧肾上腺素诱导的收缩，IC50 值约为 1 μM。在≥3 μM 的浓度下，它拮抗了对累积浓度 K 的反应。MC225 1 和 10 μM 分别抑制 ICa1.2 15%和 31%，而不影响电流激活或失活动力学。在 Langendorff 灌注的大鼠心脏中，只有 10 μM 的 MC225 显著降低左心室压力，增加冠状动脉灌注压，同时降低心率并延长心脏周期长度以及心电图上的房室传导时间（PQ 间期）。较低浓度的药物无效。这些发现表明，MC225 诱导的心血管效应发生在至少比允许体内测量 P-gp 功能高 2 个数量级的浓度下。因此，MC225 代表了一种有前途的正电子发射断层扫描工具，可用于体内直接 P-gp 定量。
