Endothelin B receptors preserve renal blood flow in a normotensive model of endotoxin-induced acute kidney dysfunction.
The aim was to investigate the role of endothelin 1 receptor subtypes in the early renal response to lipopolysaccharide (LPS) during normotensive endotoxemia with acute kidney dysfunction. Endotoxemia was induced in thiobutabarbital-anesthetized rats (n = 9 per group) by infusion of LPS (dosage, 1 mg/kg per hour i.v.). The study groups (1) sham-saline, (2) LPS-saline, (3) LPS-BQ123, (4) LPS-BQ788 and (5) LPS-BQ123 + BQ788 received isotonic saline, the ETA receptor antagonist BQ-123 (dosage, 30 nmol/kg per minute i.v.), and/or the ETB receptor antagonist BQ-788 (dosage, 30 nmol/kg per minute i.v.) before and during 2 h of LPS infusion. Renal clearance measurements, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark-type microelectrodes) were analyzed throughout. Before LPS administration, there were no significant differences between groups in glomerular filtration rate (GFR), RBF, or in cortical (CLDF) and outer medullary perfusion. However, mean arterial pressure (MAP) was elevated in LPS-BQ788 group compared with LPS-BQ123 + BQ788 group (P < 0.05). In saline-treated rats, endotoxin induced an approximate 35% reduction in GFR (P < 0.05), without significant effects on MAP, RBF, or on CLDF and cortical PO2. In addition, LPS increased outer medullary perfusion and PO2 (P < 0.05). The fractional urinary excretion rates of sodium, potassium, and water were not significantly different in LPS-saline group compared with sham-saline group. Neither selective nor combined ETA and ETB receptor blockade improved GFR. In BQ-788-infused rats, endotoxin produced marked reductions in RBF (-18% +/- 4% [P < 0.05]) and CLDF (-18% +/- 2% [P < 0.05]). Similarly, endotoxin decreased RBF (-14% +/- 3% [P < 0.05]) and CLDF (-10% +/- 2% [P < 0.05]) in LPS-BQ123 + BQ788 group. Endotoxin reduced MAP (-22% +/- 4% [P < 0.05]) in BQ-123-treated rats but did not significantly influence MAP in other groups. We conclude that in early normotensive endotoxemia, ETB receptors exert a renal vasodilator influence and contribute to maintain normal RBF.
Nitescu
Nicoletta
N
Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, The Sahlgrenska Academy at Göteborg University, Sweden. nicoletta.nitescu@vgregion.se
Grimberg
Elisabeth
E
Ricksten
Sven-Erik
SE
Herlitz
Hans
H
Guron
Gregor
G
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D004731:Endotoxins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004731:Endotoxins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044023:Receptor, Endothelin B; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)