Endotoxin-mediated changes in plasma endothelin concentrations, renal endothelin receptor and renal function.
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.
Nambi
P
P
SmithKline Beecham Pharmaceuticals, Department of Renal Pharmacology, King of Prussia, PA 19406-0939.
Pullen
M
M
Slivjak
M J
MJ
Ohlstein
E H
EH
Storer
B
B
Smith
E F
EF
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
D016232:Endothelins; D004731:Endotoxins; D017466:Receptors, Endothelin; D012964:Sodium; D011188:Potassium