Abstract
This study tested the hypothesis that endogenous bradykinin contributes to the effects of angiotensin AT1 receptor blockade in humans. The effect of the bradykinin B2 receptor antagonist d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-Oic-Arg (HOE-140) (18 μg/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 B2 receptor.
Footnotes
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This work was funded by a grant from Novartis and by Grants R01HL060906, R01HL065193, R01HL067308, K23HL004445, and M01RR000095 from the National Institutes of Health. N.J.B. received grant funding from Novartis for this study and consults for Novartis.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.117259.
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ABBREVIATIONS: HOE-140, d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-Oic-Arg; B9340, d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Igl-Oic-Arg; ACE, angiotensin-converting enzyme; Ang, angiotensin; PAH, para-aminohippurate; PRA, plasma renin activity; BK1–5, Arg-Pro-Pro-Gly-Phe; RVR, renal vascular resistance; MAP, mean arterial pressure; bpm, beats per minute.
- Received November 21, 2006.
- Accepted December 19, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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