ABSTRACT This study tested the hypothesis that endogenous bradykinin contributes to the effects of angiotensin AT 1 receptor blockade in humans. The effect of the bradykinin B 2 receptor antagonist D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg (HOE-140) (18 g/kg/h i.v. for 6 h) on hemodynamic and endocrine responses to acute and chronic (1-month) treatment with valsartan (160 mg/day) was determined in 13 normotensive and 12 hypertensive salt-deplete subjects. Acute valsartan increased plasma renin activity (PRA) from 5.3 Ϯ 9.9 to 15.6 Ϯ 19.8 ng of angiotensin (Ang) I/ml/h (P Ͻ 0.001) and decreased aldosterone from 18.3 Ϯ 10.5 to 12.0 Ϯ 9.6 ng/dl (P Ͻ 0.001). Chronic valsartan significantly increased baseline PRA (10.5 Ϯ 15.5 ng of Ang I/ml/h; P ϭ 0.004) but did not affect baseline angiotensinconverting enzyme activity or aldosterone. HOE-140 tended to increase the PRA response to valsartan, and it attenuated the decrease in aldosterone following chronic valsartan (P ϭ 0.03). Acute valsartan decreased mean arterial pressure 12.7 Ϯ 6.9% (from 100.2 Ϯ 8.4 to 87.5 Ϯ 9.8 mm Hg in hypertensives and from 82.4 Ϯ 8.6 to 70.3 Ϯ 8.4 mm Hg in normotensives). HOE-140 did not affect the blood pressure response to either acute (effect of valsartan, P Ͻ 0.001; effect of HOE-140, P ϭ 0.98) or chronic (valsartan, P ϭ 0.01; HOE-140, P ϭ 0.84) valsartan. Plasma cGMP was increased significantly during chronic valsartan (P ϭ 0.048) through a bradykinin receptorindependent mechanism (effect of HOE-140, P ϭ 0.13). Both acute (P Ͻ 0.001) and chronic (P Ͻ 0.001) valsartan increased heart rate. HOE-140 augmented the heart rate response to chronic valsartan (P ϭ 0.04). These data suggest that endogenous bradykinin does not contribute significantly to the blood pressure-lowering effect of valsartan through its B 2 receptor. The availability of the specific bradykinin B 2 receptor antagonist D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg (HOE-140) as well as the combined B 1 and B 2 antagonist D-Arg-Arg-ProHyp-Gly-Thi-Ser-D-Igl-Oic-Arg (B9340) has allowed investigators to determine the contribution of endogenous bradykinin to the effects of angiotensin-converting enzyme (ACE) inhibitors in animals and humans. For example, In congestive heart failure patients treated chronically with ACE inhibitor, combined B 1 and B 2 inhibition, but not B 2 inhibition alone, caused vasoconstriction Whether bradykinin contributes to the blood pressure-lowering effect of AT 1 receptor blockade remains to be determined. Unlike ACE inhibition, acute AT 1 receptor blockade does not potentiate the vasodilator effects of exogenous bradykinin in the human forearm vasculatur
