Bradykinin B(2) receptor does not contribute to blood pressure lowering during AT(1) receptor blockade.
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 microg/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 +/- 9.9 to 15.6 +/- 19.8 ng of angiotensin (Ang) I/ml/h (P < 0.001) and decreased aldosterone from 18.3 +/- 10.5 to 12.0 +/- 9.6 ng/dl (P < 0.001). Chronic valsartan significantly increased baseline PRA (10.5 +/- 15.5 ng of Ang I/ml/h; P = 0.004) but did not affect baseline angiotensin-converting 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 = 0.03). Acute valsartan decreased mean arterial pressure 12.7 +/- 6.9% (from 100.2 +/- 8.4 to 87.5 +/- 9.8 mm Hg in hypertensives and from 82.4 +/- 8.6 to 70.3 +/- 8.4 mm Hg in normotensives). HOE-140 did not affect the blood pressure response to either acute (effect of valsartan, P < 0.001; effect of HOE-140, P = 0.98) or chronic (valsartan, P = 0.01; HOE-140, P = 0.84) valsartan. Plasma cGMP was increased significantly during chronic valsartan (P = 0.048) through a bradykinin receptor-independent mechanism (effect of HOE-140, P = 0.13). Both acute (P < 0.001) and chronic (P < 0.001) valsartan increased heart rate. HOE-140 augmented the heart rate response to chronic valsartan (P = 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.
LeFebvre
Jean
J
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6602, USA.
Shintani
Ayumi
A
Gebretsadik
Tebeb
T
Petro
Jeffery R
JR
Murphey
Laine J
LJ
Brown
Nancy J
NJ
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000097:blood; D004039:Diet, Sodium-Restricted; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D043782:Receptor, Bradykinin B2 / Q000502:physiology*; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; C065679:icatibant; D000068756:Valsartan; D012964:Sodium; D012083:Renin; D006152:Cyclic GMP; D014633:Valine; D001920:Bradykinin