l-663536 and Body-Weight

Previous studies revealed the presence of LTC(4) synthase in paraventricular vasopressinergic neurons, suggesting a role for leukotrienes (LTs) in certain neuroendocrine system functions. Our aim was to study the effect of an inhibitor of LT synthesis in the release of arginine vasopressin (AVP) following an osmotic stimulus in rats. Male Wistar rats received an intra-cerebroventricular injection of 2 μl of the LT synthesis inhibitor MK-886 (1, 2, or 4 μg/kg), or vehicle (DMSO 5%), 1h before an intraperitoneal injection of hypertonic saline (NaCl 2M) or isotonic saline (NaCl 0.01 M) in a volume corresponding to 1% of body weight. Thirty minutes after the osmotic stimulus, the animals were decapitated and blood was collected for determining hematocrit, plasma osmolality and plasma AVP levels. As expected, the injection of hypertonic saline significantly increased (P<0.05) the hematocrit, plasma osmolality and plasma AVP levels. While inhibiting LT synthesis by central administration of MK-886 did not cause any additional increase in hematocrit or osmolality, plasma AVP levels were augmented (P<0.05). We conclude that central leukotrienes may have a modulatory role in AVP secretion following an osmotic stimulus, this deserving future studies.

Topics: 5-Lipoxygenase-Activating Protein Inhibitors; 5-Lipoxygenase-Activating Proteins; Animals; Arginine Vasopressin; Body Weight; Glutathione Transferase; Hematocrit; Indoles; Leukotriene Antagonists; Leukotrienes; Male; Neurons; Osmolar Concentration; Radioimmunoassay; Rats; Rats, Wistar; Saline Solution, Hypertonic; Sodium Chloride

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

5-Lipoxygenase is a key enzyme in the metabolism of arachidonic acid to leukotrienes. The preventive efficacy of 5-lipoxygenase inhibitors against lung tumorigenesis was determined in A/J mice given the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in drinking water from week 0 to week +7. Groups of 25 mice were fed either: acetylsalicylic acid (ASA), a cyclooxygenase inhibitor; A-79175, a 5-lipoxygenase inhibitor; MK-886, an inhibitor of the 5-lipoxygenase activating-protein; a combination of ASA and A-79175 from weeks -2 to +23. ASA, A-79175 and MK-886 reduced lung tumor multiplicity by 44, 75 and 52% respectively. Furthermore, A-79175 reduced tumor incidence by 20%. Administration of A-79175 and MK-886 decreased the mean tumor volume by 64 and 44% respectively. Lung tumor multiplicity was directly proportional to tumor volume. The combination of ASA and A-79715 was the most effective preventive intervention and reduced lung tumor multiplicity by 87% and lung tumor incidence by 24%, demonstrating that inhibition of both 5-lipoxygenase and cyclooxygenase is more effective than inhibition of either pathway alone. NNK treatment increased plasma prostaglandin E2 levels from 49 to 260 pg/ml and plasma LTB4 levels from 29 to 71 pg/ml. Incubation of 82-132 and LM2 murine lung tumor cells with MK-886 and A-79715 decreased cell proliferation in a concentration-dependent manner. Soybean lipoxygenases with or without murine lung microsomal proteins metabolized NNK by alpha-carbon hydroxylation (9.5% of the metabolites) and N-oxidation (3.9%). Activation of NNK by alpha-carbon hydroxylation was inhibited by addition of arachidonic acid and A-79715. Possible mechanisms of action of 5-lipoxygenase inhibitors include inhibition of tumor growth and lipoxygenase-mediated activation of NNK. These studies suggest that inhibitors of 5-lipoxygenase may have benefits as preventive agents of lung tumorigenesis.

Topics: Animals; Anticarcinogenic Agents; Arachidonic Acid; Aspirin; Body Weight; Carcinogens; Drug Screening Assays, Antitumor; Female; Hydroxyurea; Indoles; Lipoxygenase Inhibitors; Lung Neoplasms; Mice; Mice, Inbred A; Neoplasms, Experimental; Nitrosamines

We measured daily food intake and body weight in rats before and after the induction of colitis by intrarectal administration of either 2,4,6-trinitrobenzenesulfonic acid in ethyl alcohol (TNBE) or 4% acetic acid (AA). Administration of TNBE or AA induced inflammation in the distal colon, which was reflected by a significant increase in myeloperoxidase (MPO) activity in the colon. On days 1, 2, and 3 after induction of colitis by TNBE, food intake fell by 80, 70, and 50%, respectively, compared with pretreatment values; food intake returned to normal by day 4. Body weight fell within 24 h after induction of colitis and remained 10% less than control for at least 5 days. Colitis induced by AA produced a similar pattern and degree of decreased food intake and weight loss. Treatment with the 5'-lipoxygenase inhibitor MK-886 significantly reduced concentrations of leukotriene B4 in the colon of TNBE-treated rats but did not affect food intake. In contrast, the cyclooxygenase inhibitor indomethacin decreased prostaglandin E2 concentrations in the colon but also attenuated the suppression of feeding by 52 and 64% on the first 2 days after induction of colitis by TNBE. These results identify a specific prostaglandin-mediated suppression of feeding in the rat with acute colitis induced by TNBE and illustrate the utility of this model for studying mechanisms underlying anorexia associated with inflammation of the gastrointestinal tract.

Topics: Acetates; Acetic Acid; Administration, Rectal; Animals; Body Weight; Colitis; Eating; Indoles; Indomethacin; Male; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid