Effect of 5-lipoxygenase blockade on blood pressure and acetylcholine-evoked endothelium-dependent contraction in aorta from spontaneously hypertensive rats.
OBJECTIVE
Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension.


METHODS
We investigated, in spontaneously hypertensive rats (SHR), the involvement of cysLT in the in-vivo regulation of blood pressure and the in-vitro endothelium-dependent contraction to acetylcholine in isolated aorta.


METHODS
SHR and Wistar-Kyoto rats (WKY) were orally treated for 3 weeks with either the cysLT biosynthesis inhibitor MK-886 (0.1 mg/ml) or vehicle. After mean arterial blood pressure (MABP) measurement, aortic ring preparations were removed from all groups of animals, and contractions and relaxations were monitored subsequent to stimulation with acetylcholine.


RESULTS
MABP was higher in SHR. Chronic treatment with MK-886 did not alter MABP in either SHR or WKY. In the presence of the N-nitro-L-arginine (L-NA, 100 micromol/l), and on prostaglandin F2alpha (PGF2alpha)-induced tone, acetylcholine evoked concentration-dependent contractions in intact aortic rings from SHR only. Pretreatment with either MK-886 (10 micromol/l), the 5-lipoxygenase (5-LO) inhibitor AA861 (10 micromol/l), or the cysLT1 receptor antagonist MK571 (1 micromol/l) reduced (P < 0.05) acetylcholine-induced contractions in intact aortic rings from SHR only. Acetylcholine-induced contractions were weaker (P < 0.01) in SHR chronically treated with MK-886 than in SHR. In the presence of L-NA, leukotriene (LT) D4 induced greater (P < 0.05) concentration-dependent contractions in aortic rings from SHR than from WKY. MK571 abolished LTD4-evoked contractions.


CONCLUSIONS
These data suggested that 5-LO-derived products, through the activation of cysLT1 receptors, could be involved in the endothelium-dependent contraction to acetylcholine in aorta from SHR but not in the regulation of MABP in SHR.
Lefebvre
Blandine
B
Laboratory of Pharmacology, University of Medicine, Laboratory HP2 INSERM-ESPRI EA 3745, 38706 La Tronche cedex, France.
Caron
Françoise
F
Bessard
Germain
G
Stanke-Labesque
Françoise
F
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology*; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018077:Receptors, Leukotriene / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D002722:Chlorobenzenes
D000109:Acetylcholine; D001094:Arachidonate 5-Lipoxygenase; D016227:Benzoquinones; D001708:Biopterins; D015237:Dinoprost; D007211:Indoles; D017998:Leukotriene D4; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D019335:Nitroarginine; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; C060893:MK-886; D002722:Chlorobenzenes; C059141:verlukast; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C003402:sapropterin; C083169:leukotriene D4 receptor