Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Br J Clin Pharmacol. 2012 Jul;74(1):141-6. doi: 10.1111/j.1365-2125.2012.04189.x.
• Angiotensin II receptor blockers improve endothelial cell-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide synthase (eNOS) function.
• The key finding from this study is that angiotensin II receptor blockers (ARBs) differentially enhanced nitric oxide (NO) release in a manner influenced by certain genetic variants of eNOS. This finding provides new insights into the effects of ARBs on endothelial cell-dependent vasodilation and eNOS function that are of high importance in vascular medicine and clinical pharmacology. AIM Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk.
The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism. RESULTS All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n= 4-5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n= 4-5 in all eNOS variants) than increases observed with other ARBs.
The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.
血管紧张素 II 受体阻滞剂（ARB）通过抑制血管紧张素 II 型 1 受体改善高血压患者的内皮细胞（EC）依赖性血管舒张，但可能对内皮型一氧化氮合酶（eNOS）功能具有额外的和不同的影响。为了研究这个问题，我们测试了各种 ARB 对来自多个供体的 EC 中 NO 释放的影响，包括与心血管风险增加相关的 eNOS 遗传变异。
用纳米传感器测量 18 名供体来源的人脐静脉内皮细胞中 1 µm 浓度的 ARB（氯沙坦、奥美沙坦、替米沙坦、缬沙坦）对 NO 释放的影响。用钙离子载体（1 µm）刺激 NO 释放，并将其最大浓度与 eNOS 变异体相关联。通过启动子区域（T-786C）和外显子 7（G894T）中的单核苷酸多态性来确定 eNOS 变异体，这些变异体与 NO 代谢的变化有关。
与未处理的样本相比，所有 ARB 均导致 NO 释放增加（P < 0.01，n=4-5，所有 eNOS 变异体）。然而，最大的 NO 生成受到 eNOS 基因型的不同影响。奥美沙坦使最大 NO 释放增加了 30%，与其他 ARB 观察到的增加相比，这一增加显著更大（P < 0.01，n=4-5，所有 eNOS 变异体）。
ARB 以受 eNOS 单核苷酸多态性影响的方式差异增强了 EC 中的 NO 释放。这些发现为 ARB 对 EC 依赖性血管舒张和 eNOS 功能的影响提供了新的见解。
