(Hypertension. 2000;35:1074.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin Type 2 Receptor Mediates Valsartan-Induced Hypotension in Conscious Rats
From the Department of Medicine (H.M.S., R.M.C.), University of Virginia Health System, Charlottesville, and Novartis Pharma (M.d.G.), Basel, Switzerland.
Correspondence to Helmy M. Siragy, MD, Department of Internal Medicine, Box 482, University of Virginia Health System, Charlottesville, VA 22908. E-mail hms7a{at}virginia.edu
Abstract—Inhibition of the renin-angiotensin system is associated with vasodilation and reduction in blood pressure. We hypothesized that angiotensin type 1 (AT1) receptor (AT1R) blockade is associated with increased production of renal nitric oxide (NO) mediated by release of bradykinin (BK). By use of a microdialysis technique, changes in renal interstitial fluid (RIF) BK, NO end products nitrite and nitrate (NOX), and cGMP were monitored in response to intravenous infusion of the AT1R blocker valsartan (10 mg/kg), the angiotensin type 2 (AT2) receptor (AT2R) blocker PD123319 (50 µg · kg-1 · min-1), and the BK B2 receptor blocker icatibant (10 µg · kg-1 · min-1) in conscious rats (n=10) during low sodium intake. RIF BK, NOX, and cGMP significantly increased during valsartan treatment, whereas AT2R blockade caused a significant decrease in these autacoids. During icatibant infusion, RIF NOX and cGMP decreased by 64% and 40%, respectively, whereas BK increased. Combined administration of valsartan and icatibant, of valsartan and PD123319, or of valsartan, PD123319, and icatibant prevented the increase in RIF cGMP and NOX in response to valsartan alone. These data demonstrate that AT1R blockade with valsartan is associated with release of renal BK, which in turn mediates NO production. The results suggest that increased angiotensin II, in response to sodium restriction and valsartan infusion, stimulates AT2R, which mediates a BK and NO cascade.
Key Words: receptors, angiotensin II • bradykinin • nitric oxide • cyclic GMP • valsartan
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