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 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 micromol/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 micromol/L) or the dual CysLT(1)/CysLT(2) receptor antagonist (BAY-u9773, 0.1 micromol/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.
Hardy
G
G
Laboratory of Pharmacology, University of Medicine, LSCPA EA2937, La Tronche, France.
Stanke-Labesque
F
F
Peoc'h
M
M
Hakim
A
A
Devillier
P
P
Caron
F
F
Morel
S
S
Faure
P
P
Halimi
S
S
Bessard
G
G
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016227:Benzoquinones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology* / Q000652:urine; D007328:Insulin / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017999:Leukotriene E4 / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013189:SRS-A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C071435:BAY u9773; D016227:Benzoquinones; D007328:Insulin; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011804:Quinolines; D013189:SRS-A; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C059141:verlukast; D011189:Potassium Chloride; D017999:Leukotriene E4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone