Cardioprotection of stevioside on stunned rat hearts: A mechano-energetical study

Abstract

Background: The sweetener and hypoglycemic properties of stevioside (STV) are well known, as the main component of the plant <i>Stevia rebaudiana</i>. Given its extensive use in diabetic patients, it was of interest to evaluate its effects on the most frequent cardiovascular disease, the coronary insufficiency. Purpose: To study whether STV could be cardioprotective against ischemia-reperfusion (I/R) in a model of “stunning” in rat hearts. Study design: 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. Methods: 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. Results: 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 Ca²⁺ content, whose relaxation mainly depends on mitochondrial Ca²⁺ 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 Ca²⁺ uptake measured by Rhod-2 fluorescence in rat cardiomyocytes, but prevented the [Ca²⁺]m overload assessed by caffeine-dependent SR release. Conclusions: 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 Ca²⁺ overload and increasing the sarcorreticular Ca²⁺ store.