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.
Fundam Clin Pharmacol. 2014 Feb;28(1):29-41. doi: 10.1111/j.1472-8206.2012.01076.x. Epub 2012 Sep 7.
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.
先前的研究发现，从黄樟中合成的新型生物活性 N-酰腙衍生物可促进强烈的血管舒张和降压作用。在这项研究中，我们描述了新型 N-酰腙衍生物（E）-N-甲基-N'-(噻吩-3-亚甲基)苯并[d][1,3]二恶唑-5-甲酰肼（LASSBio-1289）的合成和心血管作用。Wistar-Kyoto（WKY）大鼠和自发性高血压大鼠（SHR）的胸主动脉和左乳头肌被制备用于等长张力记录。LASSBio-1289 促进内皮完整和去内皮的主动脉环松弛，WKY 大鼠的 pIC₅₀（-log IC₅₀）值分别为 5.07 ± 0.09 和 4.26 ± 0.09（P < 0.001），SHR 大鼠的 pIC₅₀ 值分别为 5.43 ± 0.05 和 5.58 ± 0.07（P > 0.05）。在 KCl 收缩的主动脉中，LASSBio-1289 的血管舒张活性增加。LASSBio-1289 减轻了 WKY 大鼠和 SHR 去极化主动脉中由 Ca（2+）引起的收缩。在 WKY 大鼠的内皮完整主动脉中，LASSBio-1289 诱导的松弛在与普萘洛尔、ZM 241385、阿托品、苯海拉明和 HOE140 孵育后无变化，但被 L-NAME 和 ODQ 显著减少。LASSBio-1289 仅在浓度高于 200 μm 时才降低乳头肌收缩性。LASSBio-1289（3 mg/kg）急性静脉注射可显著降低 SHR 的血压，但对 WKY 大鼠无影响，提示其具有降压作用。在腹腔内和口服给予 LASSBio-1289 14 天期间，也观察到 SHR 的降压作用。总之，我们的数据表明，LASSBio-1289 诱导 WKY 大鼠和 SHR 主动脉中的内皮非依赖性血管舒张，涉及通过 L 型钙（2+）通道抑制 Ca（2+）内流，以及 WKY 大鼠中的内皮依赖性舒张，由 NO/cGMP 途径介导。
