Cysteinyl leukotrienes modulate angiotensin II constrictor effects on aortas from streptozotocin-induced diabetic rats

Angiotensin II (Ang II) is a vasopressor peptide involved in the pathogenes is of cardiovascular diseases associated with diabetes mellitus. We have pr eviously reported that the 5-lipoxygenase-derived products, particularly th e cysteinyl leukotrienes (CysLTs), are involved in Ang II-induced contracti on. In this study, we demonstrated that CysLTs contribute to the contractio n elicited by Ang II in isolated aortas from streptozotocin-induced diabeti c (SS) rats but not from insulin-treated diabetic rats, fructose-fed rats, or control rats. In an organ bath, pretreatment with the 5-lipoxygenase inh ibitor (AA861, 10 mu mol/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 mu mol/L) or the dual CysLT(1)/CysLT(2) receptor antagonist (BAY -u9773, 0.1 mu mol/L) did not affect Ang II-induced contraction. In additio n, 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 excreti on 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 pa thway in SS rats and the involvement of 5-lipoxygenase-derived products, pa rticularly the CysLTs, in Ang II-induced contraction in aortas from SS rats through stimulation of CysLT receptors different from the well-characteriz ed CysLT(1) or CysLT(2) receptor.