Journal
JOURNAL OF PHARMACY AND PHARMACOLOGY
Volume 57, Issue 1, Pages 117-125Publisher
WILEY
DOI: 10.1211/0022357055137
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Eugenosedin-A has been demonstrated to possess alpha/beta-adrenoceptor and serotonergic receptor blocking activities. We have investigated by what mechanisms eugenosedin-A prevents lipopolysaccharide (LPS)-induced hypotension, vascular hyporeactivity, hyperglycaemia, oxidative injury of inflammatory cytokines formation in rats. Intravenous administration of eugenosedin-A, trazodone, yohimbine (1 mg kg(-1)), aminoguanicline or ascorbic acid (15 mg kg(-1)) normalized LPS (10mg kg(-1))induced hypotension. Pretreatment with eugenosedin-A or the other agents 30min before LPS injection reduced aortic hyporeactivity. LPS-induced increases in plasma interleukin-1beta (IL-beta), IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and blood glucose levels were significantly inhibited by eugenosedin-A (1 mg kg(-1), i.v.). The same dose of trazodone, a chloropiperazinylbenzene-type antidepressant, and yohimbine, an alpha(2)-adrenoceptor antagonist, reduced IL-1beta and TNW-alpha, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthaswe (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased Il-1beta, TNF-alpha contents and hyperglycaemiaEugenosedin-A and the other agents inhibited Fe2+-ascorbic acid-induced peroxidation in fat cortex, indicating that those agents had antioxidant effects, with the exception of aminoguanidine- in Free-radical scavenged experiments, eugenosedin-A and ascorbic acid eliminated peroxyl radicals. All test agents inhibited the LPS-induced increase of malondialdehyde (MDA) content in fat brain homogenates. When mice were administered an intraperitoneal injection of LPS alone, mortality occurred from 4 to 16 h, after which time all were dead. However, eugenosedin-A significantly prolonged the survival time after LPS injection, suggesting that eugenosedin-A protected against LPS-induced cardiovascular dysfunction, hyperglycaernia, tissue injury and inflammatory cytokine production. This was attributable mainly to the antioxidant and peroxyl radical scavenged effects of eugenosedin-A, and which may be, at least in part, due to its blockade on alpha/beta-adrenergic and serotonergic receptors.
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