Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model.
We evaluated the role of the renal angiotensin II type 2 (AT2) receptor in blood pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and cGMP were higher in the contralateral intact kidney than in the wrapped kidney. In rats with Grollman hypertension, losartan normalized SBP and increased renal function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD 123319, a specific AT2-receptor antagonist, significantly increased SBP and decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK, NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys similar to that observed during administration of PD 123319. In rats that underwent sham operation, RIF BK increased in response to angiotensin II, an effect that was blocked by PD 123319. These data demonstrate that angiotensin II mediates renal production of BK, which, in turn, releases nitric oxide and cGMP via stimulation of AT2 receptors. The increase in blood pressure and the decrease in renal BK, nitric oxide, and cGMP during AT2-receptor blockade suggests that the AT2 receptor mediates counterregulatory vasodilation in Grollman hypertension and prevents a further increase in blood pressure.
Siragy
H M
HM
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, 22908, USA. hms7a@virginia.edu
Carey
R M
RM
D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000378:metabolism; D065168:Bradykinin Receptor Antagonists; D006152:Cyclic GMP / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D065168:Bradykinin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073402:PD 123319; D009569:Nitric Oxide; D006152:Cyclic GMP; D019808:Losartan; D001920:Bradykinin