环孢素和他克莫司与新型免疫抑制剂霉酚酸酯和雷帕霉素对冠状动脉内皮功能影响的比较研究

Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function.

作者信息

Jeanmart Hugues, Malo Olivier, Carrier Michel, Nickner Caroline, Desjardins Nathalie, Perrault Louis P

机构信息

Research Center and Department of Surgery, Montreal Heart Institute, Quebec, Canada.

出版信息

J Heart Lung Transplant. 2002 Sep;21(9):990-8. doi: 10.1016/s1053-2498(02)00429-1.

DOI:10.1016/s1053-2498(02)00429-1

PMID:12231370

Abstract

BACKGROUND

Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function.

METHODS

An in vitro model of drug incubation in Krebs-bicarbonate solution (4(o)C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4), 10(-7) mol/liter), tacrolimus (10(-4), 10(-7) mol/liter), mycophenolate mofetil (10(-4), 10(-7) mol/liter), rapamycin (10(-7), 10(-11) mol/liter), and their vehicles to assess effects on G-protein-mediated vasorelaxations leading to the release of nitric oxide.

RESULTS

Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists.

CONCLUSIONS

These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.

摘要

背景

内皮功能障碍通过降低内皮源性一氧化氮的保护作用，促使移植心脏内膜增生的发展。免疫抑制药物可能会增加由排斥反应引起的功能障碍，并进一步加速移植冠状动脉病变的发展。本研究比较了环孢素和他克莫司与两种新型免疫抑制药物霉酚酸酯和雷帕霉素对冠状动脉内皮功能的影响。

方法

建立了在 Krebs - 碳酸氢盐溶液（4℃，48 小时）中使用猪心外膜冠状动脉进行药物孵育的体外模型。在用环孢素（10⁻⁴、10⁻⁷ 摩尔/升）、他克莫司（10⁻⁴、10⁻⁷ 摩尔/升）、霉酚酸酯（10⁻⁴、10⁻⁷ 摩尔/升）、雷帕霉素（10⁻⁷、10⁻¹¹ 摩尔/升）及其溶媒孵育后，在器官腔实验中进行冠状动脉内皮功能研究，以评估对 G 蛋白介导的血管舒张导致一氧化氮释放的影响。

结果

暴露于环孢素和霉酚酸酯与对血清素（一种与 Gi 蛋白偶联的 5 - HT1D 受体结合的激动剂）的内皮依赖性舒张呈剂量依赖性降低相关，但对缓激肽（一种与 Gq 蛋白偶联的 B2 受体结合的激动剂）的舒张无损害。暴露于他克莫司和雷帕霉素导致对血清素的舒张严重受损，对缓激肽的舒张受损程度较小。在暴露于霉酚酸酯和雷帕霉素后，我们观察到对钙离子载体 A23187 的舒张改变。暴露于雷帕霉素和霉酚酸酯溶媒会损害对所有激动剂的舒张。