Modulation of circulating endothelin levels in hypertension and endotoxemia in rats.
We have developed separate radioimmunoassays to measure circulating ET-1 and ET-3 levels in normotensive and different hypertensive rat models so that the role of endothelin in the regulation of vasomotor function can be studied. We also assessed the stimulatory effects of endotoxin on plasma and liver lymph ET-1 and ET-3 levels. The circulating ET-1 levels in normotensive rats, SHRs, and DOCA-salt hypertensive rats were 2.3 +/- 0.5, 2.1 +/- 0.4, and 2.1 +/- 0.9 pg/ml, respectively. Similarly, the plasma ET-3 levels in normotensive and different hypertensive rats were similar, ranging from 19.7 +/- 1.5 to 24.7 +/- 2.2 pg/ml. The data indicate that steady-state circulating levels of endothelins are a poor correlate of the hypertensive state. Endotoxin (30 mg/kg i.v. over 15 min) reduced blood pressure significantly and augmented plasma ET-1 levels by sevenfold (29.1 +/- 3.7 vs. 4.1 +/- 0.6 pg/ml in the vehicle group; p less than 0.05) and ET-3 levels by twofold (47.7 +/- 7.0 vs. 22.7 +/- 4.0 pg/ml in the vehicle group; p less than 0.05). Human TNF-alpha (30 ng/kg/min x 30 min), a putative mediator of endotoxin shock, enhanced plasma ET-1 (18.3 +/- 1.0 vs. 2.7 +/- 0.4 pg/ml in the vehicle group; p less than 0.05) by sevenfold and ET-3 levels by twofold (45.7 +/- 2.0 vs. 27.1 +/- 4.0 pg/ml in the vehicle group; p less than 0.05) without affecting blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Vemulapalli
S
S
Department of Pharmacology, Schering-Plough Research, Bloomfield, New Jersey 07003.
Chiu
P J
PJ
Rivelli
M
M
Foster
C J
CJ
Sybertz
E J
EJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016232:Endothelins / Q000032:analysis / Q000097:blood*; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D006973:Hypertension / Q000097:blood*; D007213:Indomethacin / Q000494:pharmacology; D008196:Lymph / Q000737:chemistry; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D011918:Rats, Inbred SHR; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016232:Endothelins; D004731:Endotoxins; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin