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Losartan Increases Bradykinin Levels in Hypertensive Humans

Background—Studies in animals and humans indicate a role for kinins in the actions of angiotensin type 1 (AT1) 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 ≈2-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.