Angiotensin II AT1 receptor blockade improves renal perfusion in hypercholesterolemia.
BACKGROUND
Hypercholesterolemia (HC) is a risk factor for renal disease that may activate the angiotensin II type 1 (AT1) receptor and accelerate renal damage. Early diet-induced HC impairs renal perfusion responses, but it is yet unknown whether the AT1 receptor is involved. This study tested the hypothesis that AT1 receptor blockade improved renal perfusion and functional responses in hypercholesterolemic pigs.


METHODS
Regional renal hemodynamics and function in vivo were quantified bilaterally in pigs, at baseline and during vasoactive challenge (acetylcholine or sodium nitroprusside), using electron beam computed tomography after 12 weeks of normal (n = 6) or HC diet (n = 6), or HC diet supplemented (100 mg/d) with the AT1-receptor antagonist irbesartan (HC + AT1, n = 6).


RESULTS
Basal cortical and medullary perfusion was similar among the groups. Basal tubular function was similar on normal and HC diets, whereas HC + AT1 showed decreased proximal and distal fluid reabsorption. Hypercholesterolemic pigs had blunted cortical perfusion (P = .22) and augmented tubular responses to acetylcholine, whereas on HC + AT1 diet, cortical perfusion (P = .002) and tubular function were similar to normal animals. This was associated with decreased systemic levels of the oxidative stress markers thiobarbituric acid reactive substances.


CONCLUSIONS
The AT1 receptor blockade in HC improves renal perfusion and tubular functional responses to endothelium-dependent vasodilators, in association with a decrease in oxidative stress. These results imply involvement of the renin-angiotensin system in the blunted renal cortical perfusion responses observed in HC, and suggest a potential role for these agents in preservation of intrarenal hemodynamics and function in HC.
Chade
Alejandro R
AR
Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Rodriguez-Porcel
Martin
M
Rippentrop
Steven J
SJ
Lerman
Amir
A
Lerman
Lilach O
LO
D000109:Acetylcholine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000503:physiopathology*; D000077405:Irbesartan; D007668:Kidney / Q000000981:diagnostic imaging; D007684:Kidney Tubules / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1; D012079:Renal Circulation / Q000187:drug effects*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed; D014665:Vasodilator Agents / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014665:Vasodilator Agents; D000077405:Irbesartan; D000109:Acetylcholine