title: Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats.
abstract: We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.
authors.affiliation: Research Centre and Division of Nephrology, CHUQ, L'Hôtel-Dieu de Québec Hospital and Department of Medicine, Laval University, Quebec, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Rodrigue
authors.forename: Sonia
authors.initials: S
authors.lastname: Lacasse-M
authors.forename: Richard
authors.initials: R
authors.lastname: Larivière
authors.forename: Marcel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D004921:Erythropoietin / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013929:Thromboxane B2 / Q000378:metabolism; D014511:Uremia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D011994:Recombinant Proteins; D004921:Erythropoietin; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D001241:Aspirin