Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats

Authors: Rodrigue, Marie-Ève; Lacasse-M, Sonia; Larivière, Richard; Lebel, Marcel

Source: Canadian Journal of Physiology and Pharmacology, Volume 83, Number 6, June 2005 , pp. 467-475(9)

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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·kg^–1·day^–1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA₂- and prostacyclin (PGI₂)-stable metabolites (TXB₂ and 6-keto-PGF₁, 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-PGF₁ (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-PGF₁ 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-PGF₁ 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.Key words: hypertension, erythropoietin, renal failure, acetylsalicilic acid, prostacyclin, thromboxane, endothelin-1.

Nous avons déjà indiqué que le blocage des récepteurs et de la synthèse de la thromboxane (TX)A₂ prévient l'hypertension causée par l'érythropoïétine humaine recombinante (rhEPO) chez des rats en insuffisance rénale chronique. La présente étude a eu pour objectif d'examiner l'effet d'un inhibiteur des cyclooxygénases, l'acide acétylsalicylique (ASA), sur la pression artérielle, la fonction rénale et la concentration d'éicosanoïdes et d'endothéline-1 (ET-1) dans les tissus rénaux et vasculaires de rats urémiques traités ou non avec la rhEPO. L'insuffisance rénale a été induite par ablation de masse rénale 5/6 en deux temps. Les rats ont été divisés en 4 groupes : véhicule, rhEPO (100 U/kg, s.c., trois fois par semaine), ASA (100 mg·kg^–1·day^–1) et rhEPO + ASA x 3 semaines. Les métabolites stables de la TXA₂ et de la prostacycline (PGI₂) (TXB₂ et 6-céto-PGF_1a, respectivement) ainsi que l'ET-1 ont été mesurés dans le cortex rénal et dans l'aorte thoracique ou dans le lit artériel mésentérique. Les rats urémiques ont développé une anémie, une urémie et une hypertension. Ils ont aussi présenté une augmentation significative des concentrations vasculaires et rénales de TXB₂ (p < 0,01) et de 6-céto-PGF_1a (p < 0,01). Le traitement à la rhEPO (p < 0,05) a corrigé l'anémie mais aggravé l'hypertension (p < 0,05). Les taux de TXB₂et d'ET-1 (p < 0,05) tissulaires ont augmenté davantage, alors que les taux 6-céto-PGF_1asont demeurés stables chez les rats traités à la rhEPO comparativement à ceux des rats urémiques ayant reçu le véhicule. Le traitement à l'ASA n'a pas prévenu l'augmentation de pression artérielle systolique ni la progression de la maladie rénale chez les rats urémiques traités ou non traités à la rh

Document Type: Research article

Publication date: 2005-06-01

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Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats

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