nitroarginine and verlukast

Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension.. 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.. 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.. 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.. 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.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arachidonate 5-Lipoxygenase; Benzoquinones; Biopterins; Blood Pressure; Body Weight; Dinoprost; Endothelium, Vascular; Hypertension; Indoles; Leukotriene D4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Nitroarginine; Propionates; Quinolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Leukotriene; Vasoconstriction

Two cysteinyl-leukotriene receptors, CysLT(1) and CysLT(2) receptors, have been cloned, but the contractions to cysteinyl-leukotrienes in the guinea pig lung parenchyma have been reported to be resistant to CysLT(2) receptor antagonism and to be only partially inhibited by CysLT(1) receptor antagonism. The receptor preferences of the individual cysteinyl-leukotrienes (leukotriene C(4), D(4) and E(4)) in the guinea pig lung parenchyma were studied in organ baths. CysLT(1) receptor antagonists competitively inhibited the contraction to leukotriene E(4), but exhibited only weak antagonism of contractions to leukotriene C(4) and D(4). In the presence of the cyclooxygenese inhibitor indomethacin and the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG), the CysLT(1) receptor antagonists did not further inhibit the leukotriene D(4)-induced contraction. These results suggest that leukotriene E(4) solely activates a CysLT(1) receptor, and that the CysLT(1) receptor antagonist-resistant contraction to leukotriene D(4) and C(4) is mediated via another CysLT receptor.

Topics: Animals; Bronchodilator Agents; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guinea Pigs; In Vitro Techniques; Indoles; Indomethacin; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lung; Male; Membrane Proteins; Muscle Contraction; Nitric Oxide Synthase; Nitroarginine; Phenylcarbamates; Propionates; Quinolines; Receptors, Leukotriene; Sulfonamides; Tosyl Compounds