Nambi P, Pullen M, Slivjak M J, Ohlstein E H, Storer B, Smith E F
SmithKline Beecham Pharmaceuticals, Department of Renal Pharmacology, King of Prussia, PA 19406-0939.
Pharmacology. 1994 Mar;48(3):147-56. doi: 10.1159/000139174.
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.
