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 < 0.05) and ET-3 levels by twofold (47.7 +/- 7.0 vs. 22.7 +/- 4.0 pg/ml in the vehicle group; p < 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 < 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 < 0.05) without affecting blood pressure. In contrast, PAF (50 ng/kg/min x 30 min), another mediator liberated during endotoxin shock, exerted a similar hypotensive response to endotoxin but did not alter either plasma ET-1 or ET-3 levels. In a separate study, endotoxin augmented plasma and liver lymph ET-1 levels by eight- and twofold, respectively. In comparison, endotoxin caused a twofold increase in both plasma and lymph ET-3 levels. Pretreatment with indomethacin (10 mg/kg p.o.) significantly attenuated the endotoxin-induced increases in plasma ET-1 and ET-3 levels without affecting the depressor responses to endotoxin. The endotoxin-induced increase in ET-1 levels in the plasma and liver lymph is most likely derived from the endothelial cells. However, since ET-3 is not produced by endothelial cells, the source of endotoxin-induced increases in plasma and liver lymph ET-3 levels remains to be identified. The data suggest that the endotoxin-stimulated release of ET-1 and ET-3 can be dissociated from blood pressure changes. Eicosanoids may also be involved in the release of endothelins due to endotoxin.