title: Endotoxin-mediated changes in plasma endothelin concentrations, renal endothelin receptor and renal function.
abstract: The purpose of these studies was to examine the changes in renal endothelin (ET) receptor, renal function and plasma ET (ET-1) concentration in male Sprague-Dawley rats injected with nonlethal doses of Escherichia coli endotoxin (LPS). Prior to the injection of LPS, kidney ET receptor density was 59 +/- 5 fmol/mg protein (n = 20). At 24 h after the injection of 1 or 3 mg/kg LPS, [125I]ET-1 binding to kidney membranes was increased by 70% in both LPS groups (p < 0.001). Scatchard analysis of the saturation binding experiments confirmed that the increase in [125I]ET-1 binding was due to an increase in receptor density with no change in affinity (202 pmol/l at baseline and 168 pmol/l and 246 pmol/l at 24 h after the injection of 1 and 3 mg/kg LPS, respectively). At 7 days after the injection of LPS, kidney ET-1 receptor density was still increased by 30 +/- 5% and 58 +/- 16%, respectively (p < 0.05, compared to the baseline value). Baseline values for Na+ and K+ excretion were approximately 115 muEq/h and 214 +/- mu/Eq/h respectively, and were decreased with LPS. Maximal decreases in Na+ and K+ excretion occurred at 48 h (-85%) and 30 h (-82%), respectively, following the injection of 3 mg/kg LPS and returned to baseline levels in 7 days. Following the injection of 3 mg/kg LPS, plasma immunoreactive ET-1, as measured by radioimmunoassay, increased in a time-dependent manner: the maximal increase of 60% occurred within 1 h after the injection of LPS (p < 0.05), and thereafter returned to baseline levels. Kidney tissue levels of ET-1 increased from baseline values of 2.6 fmol/mg protein to a peak of 4.6 fmol/mg protein 1 h after the injection of LPS. Tissue ET-1 levels were still significantly elevated at 6 h but not 24 h after LPS injection. These studies suggest that ET-1, either by increases in plasma concentration and/or altered receptor density, may be involved in the LPS-induced impairment of renal function.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Department of Renal Pharmacology, King of Prussia, PA 19406-0939.
authors.forename: P
authors.initials: P
authors.lastname: Nambi
authors.forename: M
authors.initials: M
authors.lastname: Pullen
authors.forename: M J
authors.initials: MJ
authors.lastname: Slivjak
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: B
authors.initials: B
authors.lastname: Storer
authors.forename: E F
authors.initials: EF
authors.lastname: Smith
mesh_terms: D000818:Animals; D001665:Binding Sites; D016232:Endothelins / Q000032:analysis / Q000097:blood*; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D007668:Kidney / Q000502:physiology*; D008297:Male; D009994:Osmolar Concentration; D011188:Potassium / Q000652:urine; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*; D012964:Sodium / Q000652:urine
chemical_list: D016232:Endothelins; D004731:Endotoxins; D017466:Receptors, Endothelin; D012964:Sodium; D011188:Potassium