Bradykinin B 2 Receptor Does Not Contribute to Blood Pressure Lowering during AT 1 Receptor Blockade

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

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R-/-) have increased thrombosis risk. Paradoxically, the BKB2R-/- mice have long bleeding times and delayed carotid artery thrombosis, 78 ± 6.7 minutes, versus 31 ± 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R-/- plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R-/- mice have elevated BK 1-5 (160 ± 75 fmol/mL, vs 44 ± 29 fmol/mL in controls) and angiotensin II (182 ± 41 pg/mL, vs 49 ± 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R-/- mice have elevated plasma 6-keto-PGF1α (666 ± 232 ng/mL, vs 23 ± 5.3 ng/mL in controls) and serum nitrate (61 ± 5.3 μM, vs 24 ± 1.8 μMin controls). Treatment with L-NAME (NG-mono-methyl-l-arginine ester) or nimesulide shortens the thrombosis time. BKB2R-/- mice have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1α. The long bleeding times in BKB2R-/- mice also correct with L-NAME and nimesulide therapy. In BKB2R-/- mice, angiotensin II binding to an overexpressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems. (Blood. 2006;108:192-199