| PHARMA & HYPERTENSION: -Pharmacological characterization of (3-Thienylidene)-3,4-methylenedioxybenzoylhydrazide: a novel muscarinic agonist with antihypertensive profile |
Several new bioactive compounds of the N-acylhydrazone class were developed from the safrole, a Brazilian natural product obtained from sassafras oil (Ocotea pretiosa). This work investigated the effects on cardiovascular system of LASSBio-897, a new analogue of the lead compound 3,4-methylenedioxybenzoyl-2-thienylhydrazone named LASSBio-294. MethodsThoracic aorta from Wistar–Kyoto (WKY) rats was prepared for isometric tension recording and for cGMP content determination.
LASSBio-897 (0.05–1 µmol/l) exhibited a potent vasodilatory activity in phenylephrine (Phe)-contracted aortic rings from WKY rats. This effect was abolished in endothelium-denuded aortic rings and after treatment with the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Also, LASSBio 897 (1 µmol/l) increased about 15 times the intracellular content of cGMP. LASSBio-897-induced vasodilation was totally inhibited by the muscarinic antagonist atropine and by the M3 subtype selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), indicating the involvement of M3 receptors. Intravenous administration of LASSBio-897 (1 mg/kg) produced significant hypotensive response in both WKY and SHR. The hypotensive effect of LASSBio-897 was also observed during the 14 days of oral administration. ConclusionsThe novel N-acylhydrazone derivative LASSBio-897 exhibited a potent vasodilatory activity in aortic rings mediated by the NO/cGMP pathway via activation of endothelial M3 receptors and was orally effective in reducing BP on SHR. American Journal of Hypertension 2010; doi:10.1038/ajh.2009.238 Keywords: blood pressure, hypertension, muscarinic receptor, N-acylhydrazone, vasodilationGisele Zapata-Sudo1, Sharlene L. Pereira1, Hellen J.V. Beiral1, Arthur E. Kummerle2,3, Juliana M. Raimundo1, Fernanda Antunes4, Roberto T. Sudo1, Eliezer J. Barreiro2,3 and Carlos A.M. Fraga2,3
Correspondence: Gisele Zapata-Sudo, (gsudo@farmaco.ufrj.br) |
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