Reis F, Parada B, Teixeira de Lemos E, Garrido P, Dias A, Piloto N, Baptista S, Sereno J, Eufrásio P, Costa E, Rocha-Pereira P, Santos-Silva A, Figueiredo A, Mota A, Teixeira F
Therapeutics Unit, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra University, Coimbra, Portugal.
Transplant Proc. 2009 Apr;41(3):868-73. doi: 10.1016/j.transproceed.2009.02.005.
The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.
本研究的目的是比较西罗莫司（SRL）与环孢素（CsA）对可能导致高血压发生的心血管机制的影响。研究了三组大鼠：对照组（赋形剂）、CsA组（5mg/kg/d）和SRL组（1mg/kg/d）。治疗7周后评估以下参数：血压（BP）和心率（HR；尾套法）、血脂谱、血液学指标、血浆和血小板5-羟色胺及儿茶酚胺（高效液相色谱-电化学检测法）以及氧化平衡（血清丙二醛[MDA]和总抗氧化状态[TAS]）。与对照组（115.9±3.3和99.1±2.0mmHg）相比，CsA组（146.2±4.5和124.9±4.5mmHg）和SRL组（148.9±4.8和126.4±6.0mmHg）的收缩压（SBP）和舒张压（DBP）值均更高（P<.001）。然而，CsA组动物的HR值升高，而SRL组动物未升高。SRL组中CsA的血脂异常模式更为明显，与CsA组相比，低密度脂蛋白胆固醇（LDL-c）和甘油三酯（TG）水平显著更高（P<.05）；与CsA组相比，SRL组的红细胞、血细胞比容、血红蛋白浓度、平均血小板体积和血小板分布宽度显著更高（P<.05）。SRL组未再现CsA组的促氧化特征（MDA/TAS升高）。虽然SRL大鼠的血浆和血小板5-羟色胺升高，但CsA组动物的儿茶酚胺含量更高。总之，本研究表明CsA和SRL产生相同的高血压效应。然而，CsA促进氧化应激和交感神经激活，而SRL主要干扰血脂谱和血液学参数。因此，钙调神经磷酸酶抑制剂CsA和雷帕霉素靶蛋白抑制剂SRL的高血压效应与不同心血管途径的损害有关。
