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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1751.)
© 2001 American Heart Association, Inc.

Vascular Biology

Cysteinyl Leukotrienes Modulate Angiotensin II Constrictor Effects on Aortas From Streptozotocin-Induced Diabetic Rats

Gaëlle Hardy; Franfcoise Stanke-Labesque; Michel Peoc’h; Ahmed Hakim; Philippe Devillier; Françoise Caron; Sandrine Morel; Patrice Faure; Serge Halimi; Germain Bessard

From the Laboratory of Pharmacology (G.H., F.S.-L., A.H., F.C., G.B.), University of Medicine, LSCPA EA2937, La Tronche, France; the Laboratory of Pathological Anatomy (M.P.), Albert Michallon Hospital, Grenoble, France; the Laboratory of Pharmacology (P.D.), IFR 53, Faculty of Medicine, Reims, France; and LSCPA EA 2937 (S.M., P.F., S.H.), La Tronche, France.

Correspondence to Françoise Stanke-Labesque, Laboratory of Pharmacology, University of Medicine, LSCPA EA 2937, 38706 La Tronche cedex, France. E-mail Francoise.Stanke{at}ujf-grenoble.fr

Abstract—— Angiotensin II (Ang II) is a vasopressor peptide involved in the pathogenesis of cardiovascular diseases associated with diabetes mellitus. We have previously reported that the 5-lipoxygenase-derived products, particularly the cysteinyl leukotrienes (CysLTs), are involved in Ang II-induced contraction. In this study, we demonstrated that CysLTs contribute to the contraction elicited by Ang II in isolated aortas from streptozotocin-induced diabetic (SS) rats but not from insulin-treated diabetic rats, fructose-fed rats, or control rats. In an organ bath, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 µmol/L) reduced by 37.6±8.2% and 30.1±10.9% the Ang II-induced contractions in intact and endothelium-denuded aortic rings, respectively, from SS rats. In contrast, the CysLT₁ receptor antagonist (MK571, 1 µmol/L) or the dual CysLT₁/CysLT₂ receptor antagonist (BAY-u9773, 0.1 µmol/L) did not affect Ang II-induced contraction. In addition, Ang II induced a 6.2±1.5-fold increase in CysLT release through the stimulation of the Ang II type 1 receptor. Furthermore, the urinary excretion of leukotriene E₄ was increased in SS rats (leukotriene E₄, 13.7±2.9 ng/24 h [SS rats, n=10] versus 1.5±0.5 ng/24 h [control rats, n=6]; P<0.0004). These data suggest the activation of the 5-lipoxygenase pathway in SS rats and the involvement of 5-lipoxygenase-derived products, particularly the CysLTs, in Ang II-induced contraction in aortas from SS rats through stimulation of CysLT receptors different from the well-characterized CysLT₁ or CysLT₂ receptor.

Key Words: angiotensin II • cysteinyl leukotrienes • diabetes • insulin • rat aortas

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