Ragone María I, Bonazzola Patricia, Colareda Germán A, Lazarte María Lara, Bruno Fiorella, Consolini Alicia E
Cátedra de Farmacología, Grupo de Farmacología Experimental y Energética Cardíaca, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Instituto de Investigaciones Cardiológicas, Facultad de Medicina, Universidad de Buenos Aires (UBA-CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Phytomedicine. 2017 Nov 15;35:18-26. doi: 10.1016/j.phymed.2017.08.022. Epub 2017 Aug 24.
The sweetener and hypoglycemic properties of stevioside (STV) are well known, as the main component of the plant Stevia rebaudiana. Given its extensive use in diabetic patients, it was of interest to evaluate its effects on the most frequent cardiovascular disease, the coronary insufficiency.
To study whether STV could be cardioprotective against ischemia-reperfusion (I/R) in a model of "stunning" in rat hearts.
A preclinical study was performed in isolated hearts from rats in the following groups: non-treated rats whose hearts were perfused with STV 0.3 mg/ml and their controls (C) exposed to either moderate stunning (20 min I/45 min R) or severe stunning (30 min I/45 min R), and a group of rats orally treated with STV 25 mg/kg/day in the drink water during 1 week before the experiment of severe stunning in the isolated hearts were done.
The mechano-calorimetrical performance of isolated beating hearts was recorded during stabilization period with control Krebs perfusion inside a calorimeter, with or without 0.3 mg/ml STV before the respective period of I/R. The left ventricular maximal developed pressure (P) and total heat rate (Ht) were continuously measured.
Both, orally administered and perfused STV improved the post-ischemic contractile recovery (PICR, as % of initial control P) and the total muscle economy (P/Ht) after the severe stunning, but only improved P/Ht in moderate stunning. However, STV increased the diastolic pressure (LVEDP) during I/R in both stunning models. For studying the mechanism of action, ischemic hearts were reperfused with 10 mM caffeine-36 mM Na-Krebs to induce a contracture dependent on sarcorreticular Ca content, whose relaxation mainly depends on mitochondrial Ca uptake. STV at 0.3 mg/ml increased the area-under-curve of the caffeine-dependent contracture (AUC-LVP). Moreover, at room temperature STV increased the mitochondrial Ca uptake measured by Rhod-2 fluorescence in rat cardiomyocytes, but prevented the [Ca]m overload assessed by caffeine-dependent SR release.
Results suggest that STV is cardioprotective against I/R under oral administration or direct perfusion in hearts. The mechanism includes the regulation of the myocardial calcium homeostasis and the energetic during I/R in several sites, mainly reducing mitochondrial Ca overload and increasing the sarcorreticular Ca store.
甜菊糖苷（STV）作为甜叶菊的主要成分，其甜味剂和降血糖特性广为人知。鉴于其在糖尿病患者中的广泛应用，评估其对最常见的心血管疾病——冠状动脉供血不足的影响具有重要意义。
研究在大鼠心脏“顿抑”模型中，STV是否对缺血再灌注（I/R）具有心脏保护作用。
对大鼠离体心脏进行临床前研究，分组如下：未处理的大鼠心脏用0.3mg/ml STV灌注，其对照组（C）经历中度顿抑（20分钟缺血/45分钟再灌注）或重度顿抑（30分钟缺血/45分钟再灌注）；另一组大鼠在离体心脏重度顿抑实验前1周，每天经饮水口服25mg/kg STV。
在热量计内，用对照Krebs灌注液稳定离体搏动心脏期间，记录其机械量热性能，在各自的I/R期之前，灌注液中添加或不添加0.3mg/ml STV。连续测量左心室最大发展压力（P）和总热率（Ht）。
口服和灌注STV均可改善重度顿抑后的缺血后收缩恢复（PICR，以初始对照P的百分比表示）和总肌肉经济性（P/Ht），但仅改善中度顿抑后的P/Ht。然而，在两种顿抑模型中，STV均增加了I/R期间的舒张压（LVEDP）。为研究作用机制，用含10mM咖啡因 - 36mM Na - Krebs的溶液对缺血心脏进行再灌注，以诱导依赖于肌浆网Ca含量的挛缩，其舒张主要依赖于线粒体Ca摄取。0.3mg/ml的STV增加了咖啡因依赖性挛缩的曲线下面积（AUC - LVP）。此外，在室温下，STV增加了大鼠心肌细胞中用Rhod - 2荧光测量的线粒体Ca摄取，但阻止了通过咖啡因依赖性肌浆网释放评估的[Ca]m过载。
结果表明，口服或直接灌注STV对心脏I/R具有心脏保护作用。其机制包括调节心肌钙稳态以及I/R期间多个部位的能量代谢，主要是减少线粒体Ca过载并增加肌浆网Ca储存。
