Fischer Dieter, Landmesser Ulf, Spiekermann Stephan, Hilfiker-Kleiner Denise, Hospely Marian, Müller Maja, Busse Rudi, Fleming Ingrid, Drexler Helmut
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Eur J Heart Fail. 2007 Aug;9(8):770-5. doi: 10.1016/j.ejheart.2007.05.005. Epub 2007 Jun 15.
Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans.
FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery.
FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.
人体传导动脉的血流介导的血管舒张（FMD）部分与剪切应力诱导的内皮源性一氧化氮（NO）释放有关。然而，NO合酶抑制剂并不能完全消除这种FMD反应。最近，2C家族的细胞色素P450（CYP）环氧合酶与传导动脉的非NO和前列环素依赖性舒张有关。因此，我们评估了CYP 2C9对人体FMD的作用。
通过高分辨率超声测定12名健康志愿者桡动脉的FMD，并在动脉内输注特异性CYP 2C9抑制剂磺胺苯吡唑、L-NMMA（NO合酶抑制剂）以及两者联合输注前后进行分析。在动脉内输注硝普钠后对非内皮依赖性血管舒张进行表征。磺胺苯吡唑输注后FMD降低（11.5±0.87%对7.4±0.95%，p<0.01），L-NMMA输注后降低（6.0±0.71%；p<0.01），联合输注后降低至3.9±0.73%（与L-NMMA相比p<0.05；与磺胺苯吡唑相比p<0.01）。磺胺苯吡唑对非内皮依赖性血管舒张无影响。在慢性心力衰竭患者中，磺胺苯吡唑阻断的FMD部分未受影响。通过免疫组织化学在接受冠状动脉搭桥手术患者的桡动脉样本中检测到CYP 2C。
抑制CYP 2C9后人体传导动脉的FMD降低，支持CYP 2C代谢产物在体内有助于外周传导动脉内皮介导的血管舒张这一概念。在心力衰竭患者中，CYP依赖性FMD似乎得以保留。
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