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Leukotrienes, But Not Angiotensin II, Are Involved in the Renal Effects Elicited by the Prolonged Cyclooxygenase-2 Inhibition When Sodium Intake Is Low

Salazar, Francisco PhD*; Salazar, F. Javier PhD*; Saez, Fara PhD*; Reverte, Virginia PhD*; Zweifel, Ben; Dufield, Dawn PhD; Radabaugh, Melissa; Graneto, Matt PhD; Llinas, Maria T. PhD*; Masferrer, Jaime L. PhD

Journal of Cardiovascular Pharmacology: April 2013 - Volume 61 - Issue 4 - p 329–336
doi: 10.1097/FJC.0b013e31828399ae
Original Article

Abstract: It is known that cyclooxygenase-2 (COX-2) inhibition elicits significant renal hemodynamics alterations when sodium intake is low. However, the mechanisms involved in these renal changes are not well known. Our objective was to evaluate the role of angiotensin II and 5-lipooxygenase-derived metabolites in the renal effects induced by prolonged COX-2 inhibition when sodium intake is low. Conscious dogs were treated during 7 days with a COX-2 inhibitor (1 mg·kg−1·d−1, SC75416), and either a vehicle, an AT1 receptor antagonist (0.4 mg·kg−1·d−1, candesartan) or a selective 5-lipooxygenase inhibitor (PF-150, 20 and 60 mg·kg−1·d−1). The administration of SC75416 alone induced significant changes in renal blood flow (219 ± 14 to 160 ± 10 mL/min), glomerular filtration rate (51 ± 2 to 42 ± 3 mL/min), and plasma potassium (pK) (4.3 ± 0.1 to 4.6 ± 0.1 mEq/L). Similar decrements in renal blood flow (27%) and glomerular filtration rate (20%) and a similar increment in pK (7%) were found when SC75416 was administered in candesartan-pretreated dogs. However, SC75416 administration did not elicit significant changes in renal hemodynamics and pK in dogs pretreated with each dose of PF-150. Our data suggest that leukotrienes but not angiotensin II are involved in the renal effects induced by COX-2 inhibition when sodium intake is low.

*Department of Physiology, School of Medicine, University of Murcia, Murcia, Spain

Pfizer Inc., St Louis, MO.

Reprints: F. Javier Salazar, PhD, Department of Physiology, School of Medicine, University of Murcia, 30100 Murcia, Spain (e-mail: salazar@um.es).

Supported by grants from Dirección General de Educación y Ciencia of Ministerio de Educación y Ciencia (SAF2007-64498) and by the Red Temática de Investigación Cooperativa on Aging from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo in Spain (RD06/0013/1020). Part of this work was also supported by a grant from Pfizer Inc.

B. Zweifel, D. Dufield, M. Radabaugh, and M. Graneto were Pfizer Inc. employees in St Louis, MO. J. L. Masferrer is a Pfizer Inc. employee in Cambridge, MA. F. Salazar, F. J. Salazar, F. Saez, V. Reverte, and M. T. Llinas have no disclosures to declare.

F. J. Salazar and J. L. Masferrer share senior authorship.

Received October 22, 2012

Accepted December 17, 2012

© 2013 Lippincott Williams & Wilkins, Inc.