Inhibition of leukotriene synthesis with MK-886 prevents a rise in blood pressure and reduces noradrenaline-evoked contraction in L-NAME-treated rats.
(1) Long-term treatment of rats with Nomega-nitro-l-arginine methyl ester (l-NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with l-NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta. (2) Rats were randomly assigned to four groups and orally treated for 3 weeks with l-NAME (1 mg ml-1), l-NAME (1 mg ml-1) plus the leukotriene biosynthesis inhibitor MK-886 (0.1 mg ml-1), MK-886 (0.1 mg ml-1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid. (3) The mean arterial blood pressure (MABP) increased significantly in l-NAME-treated rats (173.3+/-9.4 mmHg (n=25)) vs Methocel-treated rats (110.7+/-4.8 mmHg (n=11), P<0.001). Chronic treatment with MK-886 prevented this rise in MABP. (4) Aortic rings with or without endothelium were suspended in organ baths for recording isometric changes in response to noradrenaline. Pretreatment with either MK-886 (10 microm), the CysLT1 receptor antagonist MK571 (1 microm) or the dual CysLT1/CysLT2 receptor antagonist BAY-u9773 (0.1 microm) reduced (P<0.05) noradrenaline-induced contractions in intact aortic rings from l-NAME-treated rats only. (5) Noradrenaline (0.3 microm) induced a two-fold increase in cysteinyl leukotriene (CysLT) release (measured by enzyme immunoassay) in intact aortic rings from l-NAME-treated rats only. (6) These data suggested (1) a role for the 5-lipoxygenase pathway in the regulation of blood pressure in l-NAME-treated rats and (2) the involvement of endothelial CysLTs in noradrenaline-induced contraction in aorta from l-NAME-treated rats.
Stanke-Labesque
Françoise
F
Laboratory of Pharmacology, University of Medicine, Laboratory HP2, 38706 La Tronche Cedex, France. FStanke@ujf-grenoble.fr
Hardy
Gaëlle
G
Caron
Françoise
F
Cracowski
Jean-Luc
JL
Bessard
Germain
G
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D002722:Chlorobenzenes
D007211:Indoles; D015289:Leukotrienes; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; C060893:MK-886; D002722:Chlorobenzenes