Losartan increases bradykinin levels in hypertensive humans
Losartan increases bradykinin levels in hypertensive humans
复制标题
DOI：
10.1161/01.cir.0000153269.07762.3b
复制
发表时间：
2005-01-25
期刊：
影响因子：
37.8
通讯作者：
Esler, MD
中科院分区：
文献类型：
--
作者：
Campbell, DJ;Krum, H;Esler, MD
背景 - 对动物和人类的研究表明激肽在 1 型血管紧张素 (AT(1)) 受体阻滞剂的作用中发挥作用。然而，这些化合物对人体激肽水平的影响尚不清楚。 方法和结果 - 我们在双盲、3 个周期、3 个治疗中以随机顺序测量了原发性高血压受试者的血管紧张素 (Ang)、缓激肽 (BK) 和激肽，这些受试者服用安慰剂、氯沙坦 (50 mg OD) 和依普罗沙坦 (600 mg OD)， 交叉试验。使用基于高效液相色谱的放射免疫测定法测量动脉血中的肽。氯沙坦使 BK-(1 - 9) 和羟基化 BK-( 1 - 9) 的血液水平增加约 2 倍，并使 BK-( 1 - 7)/BK-(1- 9) 比率降低 55%。依普罗沙坦有导致缓激肽水平产生类似变化的趋势。血液激肽水平没有变化。氯沙坦和依普罗沙坦均可增加血浆 Ang I、Ang II 和 Ang-(2-8) 水平，而依普罗沙坦则增加 Ang-(3 - 8) 水平。 Ang-( 1 - 7) 和Ang-( 1 - 9) 水平没有变化。 Ang II/Ang I 比率相应降低 30% 至 35%，Ang-(1-7)/Ang I 比率降低 63% 至 69%。血浆 ACE 活性未改变。结论 - 氯沙坦增加缓激肽水平。 BK-( 1 - 7)/BK-( 1 - 9)、Ang II/Ang I 和 Ang(1 - 7)/Ang I 比率的降低表明缓激肽水平增加是 ACE 和中性内肽酶代谢减少的结果。缓激肽水平升高可能代表 AT1 受体阻滞剂的类效应，有助于其治疗作用，也可能导致伴随该治疗的血管性水肿。
Background - Studies in animals and humans indicate a role for kinins in the actions of angiotensin type 1 (AT(1)) receptor blockers. However, the effect of these compounds on kinin levels in humans is unknown.Methods and Results - We measured angiotensin (Ang), bradykinin (BK), and kallidin peptides in subjects with essential hypertension administered placebo, losartan (50 mg OD), and eprosartan (600 mg OD) in randomized order in a double-blind, 3-period, 3-treatment, crossover trial. Peptides were measured in arterial blood using high-performance liquid chromatography - based radioimmunoassays. Losartan increased blood levels of BK-(1 - 9) and hydroxylated BK-( 1 - 9) by approximate to2-fold and reduced the BK-( 1 - 7)/BK-(1- 9) ratio by 55%. There was a trend for eprosartan to produce similar changes in bradykinin levels. There were no changes in blood kallidin levels. Both losartan and eprosartan increased plasma levels of Ang I, Ang II, and Ang-(2-8), and eprosartan increased Ang-( 3 - 8) levels. Ang-( 1 - 7) and Ang-( 1 - 9) levels were unchanged. There was an associated 30% to 35% reduction in Ang II/Ang I ratio and 63% to 69% reduction in Ang-( 1 - 7)/Ang I ratio. Plasma ACE activity was unchanged.Conclusions - Losartan increases bradykinin levels. The reductions in BK-( 1 - 7)/BK-( 1 - 9), Ang II/Ang I, and Ang( 1 - 7)/Ang I ratios suggest that the increased bradykinin levels were the result of reduced metabolism by ACE and neutral endopeptidase. Increased bradykinin levels may represent a class effect of AT1 receptor blockers that contributes to their therapeutic actions and may also contribute to the angioedema that may accompany this therapy.