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

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 CysLT 1 receptor antagonist (MK571, 1 μmol/L) or the dual CysLT 1 /CysLT 2 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 E 4 was increased in SS rats (leukotriene E 4 , 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 CysLT 1 or CysLT 2 receptor.