Low-dose candesartan improves renal blood flow and kidney oxygen tension in rats with endotoxin-induced acute kidney dysfunction.
Sepsis is associated with an activation of the renin-angiotensin system and causes acute kidney injury. The aim was to examine the effects of a low, nondepressor dose of the selective angiotensin II type 1 receptor antagonist candesartan on renal hemodynamics and function in endotoxemic rats. Endotoxemia was induced in Sprague-Dawley rats by a dose of LPS (Escherichia coli O127:B8; 7.5 mg kg(-1), i.p.). At 16 h after endotoxin administration, renal clearance experiments were performed in thiobutabarbital anesthetized rats. Study groups (1) sham-saline, (2) LPS-saline, and (3) LPS-candesartan received isotonic saline or candesartan (10 microg kg(-1), i.v.) after baseline measurements. Kidney function, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (P(O2); Clark-type microelectrodes) were analyzed during 2 h after drug administration. At baseline, endotoxemic rats showed an approximately 50% reduction in glomerular filtration rate and RBF (P < 0.05), a decline in cortical and outer medullary perfusion, and Po2 (P < 0.05), but no significant alterations in MAP compared with saline-injected controls. Candesartan treatment significantly improved RBF (+40% +/- 6% vs. baseline), cortical perfusion (+18% +/- 3% vs. baseline), and cortical (+19% +/- 7% vs. baseline) and outer medullary (+22% +/- 10% vs. baseline) P(O2) in endotoxemic rats (P < 0.05 vs. LPS-saline). Candesartan did not significantly influence MAP or glomerular filtration rate, whereas filtration fraction was reduced by 27% +/- 5% vs. baseline (P < 0.05 vs. LPS-saline). In conclusion, candesartan, in a dose that did not significantly decrease MAP, caused renal vasodilation and markedly improved RBF and intrarenal P(O2) in endotoxemic rats. These findings suggest renoprotective effects of candesartan in sepsis.
Nitescu
Nicoletta
N
Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska University Hospital, Göteborg, Sweden. nicoletta.nitescu@vgregion.se
Grimberg
Elisabeth
E
Guron
Gregor
G
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D010100:Oxygen / Q000097:blood*; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D013777:Tetrazoles; D010100:Oxygen; C081643:candesartan