Angiotensin type 2 receptor mediates valsartan-induced hypotension in conscious rats.
Inhibition of the renin-angiotensin system is associated with vasodilation and reduction in blood pressure. We hypothesized that angiotensin type 1 (AT(1)) receptor (AT(1)R) 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 AT(1)R blocker valsartan (10 mg/kg), the angiotensin type 2 (AT(2)) receptor (AT(2)R) blocker PD123319 (50 microg x kg(-1) x min(-1)), and the BK B(2) receptor blocker icatibant (10 microg x kg(-1) x min(-1)) in conscious rats (n=10) during low sodium intake. RIF BK, NOX, and cGMP significantly increased during valsartan treatment, whereas AT(2)R 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 AT(1)R 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 AT(2)R, which mediates a BK and NO cascade.
Siragy
H M
HM
Department of Medicine, University of Virginia Health System, Charlottesville 22908, USA. hms7a@virginia.edu
de Gasparo
M
M
Carey
R M
RM
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology*; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014664:Vasodilation / Q000502:physiology
D000959:Antihypertensive Agents; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine