Lauro Figueroa-Valverde, Francisco Díaz-Cedillo, Elodia García-Cervera, Eduardo Pool-Gómez, Maria López-Ramos, Marcela Rosas-Nexticapa, Lenin Hau-Heredia, Bety Sarabia-Alcocer, Landy Campos-Ramos
Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche Av. Agustín Melgar s/n, Col Buenavista C.P.24039 Campeche Cam., México.
Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala s/n Col. Santo Tomas México, D.F. C.P. 11340.
Int J Clin Exp Med. 2014 May 15;7(5):1223-32. eCollection 2014.
There are studies which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, a new estradiol derivative was synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. The Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the estradiol derivative. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the OTBDS-estradiol-hexanoic acid derivative was evaluated by measuring left ventricular pressure in absence or presence of following compounds; tamoxifen, prazosin, metoprolol, indomethacin and nifedipine. The results showed that the OTBDS-estradiol-hexanoic acid derivative significantly increased the perfusion pressure and coronary resistance in comparison with the control conditions. Additionally, other data indicate that OTBDS-estradiol-hexanoic acid derivative increase left ventricular pressure in a dose-dependent manner (0.001 to 100 nM); nevertheless, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These data suggest that positive inotropic activity induced by the OTBDS-estradiol-hexanoic acid derivative is via activation of L-type calcium channel. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.
有研究表明，一些类固醇衍生物具有变力活性；然而，其在心血管水平的细胞作用位点和作用机制非常令人困惑。为了在本研究中阐明这些现象，合成了一种新的雌二醇衍生物，目的是评估其对左心室压力的生物学活性并表征其分子机制。采用Langendorff技术在离体大鼠心脏模型中，在不存在或存在雌二醇衍生物的情况下测量灌注压力和冠状动脉阻力的变化。此外，为了表征OTBDS-雌二醇-己酸衍生物诱导的变力活性所涉及的分子机制，在不存在或存在以下化合物的情况下测量左心室压力进行评估：他莫昔芬、哌唑嗪、美托洛尔、吲哚美辛和硝苯地平。结果表明，与对照条件相比，OTBDS-雌二醇-己酸衍生物显著增加了灌注压力和冠状动脉阻力。此外，其他数据表明，OTBDS-雌二醇-己酸衍生物以剂量依赖性方式（0.001至100 nM）增加左心室压力；然而，这种现象仅在1 nM剂量的硝苯地平作用下受到显著抑制。这些数据表明，OTBDS-雌二醇-己酸衍生物诱导的正性变力活性是通过L型钙通道的激活。这种现象特别有趣，因为这种类固醇衍生物诱导的正性变力活性涉及与其他正性变力药物不同的分子机制。
