Relationship between Eicosanoids and Endothelin-1 in the Pathogenesis of Erythropoietin-induced Hypertension in Uremic Rats

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Abstract
Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A2 and prostacyclin (PGI2) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ETA receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB2 and 6-keto-PGF1α, stable metabolites of TXA2 and PGI2), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB2 in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF1α was not significantly changed. Ridogrel significantly decreased tissue TXB2 concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA2 and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA2 probably serves as a mediator of the vascular effect of ET-1.