title: Vasodilator and antihypertensive effects of a novel N-acylhydrazone derivative mediated by the inhibition of L-type Ca²⁺ channels.
abstract: New bioactive N-acylhydrazone derivatives synthesized from safrole previously have been found to promote intense vasodilation and antihypertensive activity. In this study, we describe the synthesis and the cardiovascular effects of the new N-acylhydrazone derivative (E)-N-methyl-N'-(thiophen-3-ylmethylene)benzo[d][1,3]dioxole-5-carbohydrazide (LASSBio-1289). Thoracic aorta and left papillary muscles from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. LASSBio-1289 promoted relaxation of endothelium-intact and denuded aortic rings with respective pIC₅₀ (-log IC₅₀) values of 5.07 ± 0.09 and 4.26 ± 0.09 (P < 0.001) for WKY rats and 5.43 ± 0.05 and 5.58 ± 0.07 (P > 0.05) for SHR. The vasodilator activity of LASSBio-1289 was increased in the KCl-contracted aorta. LASSBio-1289 attenuated the contracture elicited by Ca(2+) in depolarized aorta from both WKY rats and SHR. In endothelium-intact aorta from WKY rats, LASSBio-1289-induced relaxation was unchanged after incubation with propranolol, ZM 241385, atropine, diphenhydramine, and HOE140, but was significantly reduced by L-NAME and ODQ. LASSBio-1289 decreased papillary muscles contractility only at concentrations above 200 μm. Acute intravenous injection of LASSBio-1289 (3 mg/kg) produced a significant hypotensive response in SHR but not in WKY rats, suggesting its antihypertensive profile. The antihypertensive effect was also observed in SHR during 14 days of intraperitoneal and oral administration. In conclusion, our data demonstrated that LASSBio-1289 induces both endothelium-independent vasorelaxation involving the inhibition of Ca(2+) influx through L-type Ca(2+) channels in aorta from WKY rats and SHR, and endothelium-dependent relaxation mediated by the NO/cyclic GMP pathway in WKY rats.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-590, Brazil.
authors.forename: Sharlene Lopes
authors.initials: SL
authors.lastname: Pereira
authors.forename: Arthur Eugen
authors.initials: AE
authors.lastname: Kummerle
authors.forename: Carlos Alberto Manssour
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer Jesus
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Roberto Takashi
authors.initials: RT
authors.lastname: Sudo
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D052117:Benzodioxoles; D020746:Calcium Channels, L-Type; D006835:Hydrazones; C586082:N-methyl-N'-(thiophen-3-methylene)benzo(d)(1,3)dioxole-5-carbohydrazide; D014665:Vasodilator Agents; D011189:Potassium Chloride; D002118:Calcium