Effect of steviol glycosides on cardio-vascular systems
Apart from mild reduction of arterial blood pressure in hypertensive subjects, no effect of Stevioside in cardiovascular systems has been reported.
Boeckh and Humboldt (1981) reported that Stevia extracts reduced heart rate and mean arterial blood pressure in humans. Melis (1995) found that aqueous extracts fed to rats for 40–60 days produced hypotension, the mean arterial pressure falling from 110 mm Hg to 90 mm Hg over the 40- day-treatment period.
Lee et al (2001) showed that intraperitoneal injection of stevioside 25 mg/kg has antihypertensive effect in spontaneously hypertensive rats. In isolated aortic rings from normal rats, stevioside could dose-dependently relax the vasopressin-induced vasoconstriction in both the presence and absence of endothelium. However, stevioside had no effect on phenylephrine- and KCl-induced phasic vasoconstriction. In addition, stevioside lost its influence on vasopressin-induced vasoconstriction in Ca(2+)-free medium. The results indicate that stevioside caused vasorelaxation via an inhibition of Ca(2+) influx into the blood vessel.
Liu et al (2003) reported that after nasogastric administration of stevioside powder (200 mg/kg), the blood pressure of healthy mongrel dogs began to significantly decrease at 60 min and returned to baseline level at 180 min. The reduction of blood pressure was more rapid (at 5-10 min) and effective after intravenous injection. However, no significant change of blood pressure was noted after injection through left vertebral artery, implicating that the hypotensive effect is not related to the central nervous system. Stevioside also showed significant hypotensive effects in renal hypertensive dogs, in a dose-dependent manner. In cultured rat aortic smooth muscle cells (A7r5 cell line), stevioside can dose-dependently inhibit the stimulatory effects of vasopressin and phenylephrine on intracellular Ca(2+) in a calcium-containing medium. However, no intracellular Ca(2+) inhibitory effect was observed in calcium-free medium, implicating that stevioside may inhibit the Ca(2+) influx from extracellular fluid.
The interaction of aqueous solutions of stevioside and bile acids with cardioactive drugs was studied by Vasovic et al (2006) in rats by registering changes in their electrocardiograms (ECG). In their study, Wistar rats of both sexes received daily doses of 20 mg/kg (i.p.) of an aqueous solution of stevioside or physiological solution (controls), then were narcotized with urethane and connected to the ECG apparatus for the first recording. The jugular vein was prepared and connected to an infusion pump to administer one of the drugs: adrenaline (0.1 mg/ml), verapamil (2.5 mg/ml) or metoprolol (1 mg/ml) to rats in both groups, while recording their ECGs. In the second part of the study, the animals were treated in the same way but instead of the stevioside solution received a single dose of 4 mg/kg of monoketocholic acid methyl ester (ME) or sodium salt of the same bile acid (MKHNa), 30 minutes before cardioactive drug infusion. The infusion rate of cardioactive drugs was 0.2 ml/min, except for verapamil (0.1 ml/min). The events observed on ECG recordings were the first myocardial reaction to drug infusion, the second longer-lasting reaction (observed as more extended extrasystoles, decrease in intensity of the QRS complex, or changes in heart rate frequency), and toxicity effect. In the control animals, adrenaline induced a decrease in heart rate frequency at a dose of 0.094 mg/kg, while with stevioside-pretreated rats this effect appeared significantly earlier (at a dose of 0.018 mg/kg). No toxic effect of adrenaline was observed, either in control or stevioside-pretreated group. Bile acids caused no changes in myocardial reaction to adrenaline. Only in the group of animals that received MKHNa, a significant decrease in the QRS complex was observed. Finally, the infusion of stevioside to intact animals at doses of 45 and 55 mg/kg caused no significant changes in the ECG patterns. The myocardial reaction to metoprolol remained unchanged in rats of all groups when compared with controls except for a mild decrease in heart rate frequency. Stevioside induced/produced a significant increase in myocardial sensitivity to verapamil, but no toxic effect was observed in any of the cases. A similar conclusion also holds for the interaction with MKHNa, whereas ME caused an increase in the toxicity of verapamil.
Bornia (2008) et al reported that in endothelium-intact rat aortic ring preparations pre-contracted with norepinephrine or KCl, NG-nitro L-arginine (L-NOARG, 0.1 mM) and 1H-[1,2,4] oxidiazolo [4,3-a] quinoxalin-1-one (ODQ, 10 microM) antagonized the reduction of the vascular tone induced by stevioside, but this antagonism did not occur when the experiment was performed with endothelium-denuded aortic rings. The data indicates that the vasodilatation produced by stevioside is dependent on nitric oxide synthase and guanylate cyclase activities when the endothelium is not damaged.
Geeraertet (2010) al found that in mice model, Stevioside treatment improved adipose tissue maturation, and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a twofold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized low-density lipoprotein (ox-LDL) content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. The decrease in ox-LDL in the plaque was likely due to an increase in the antioxidant defense in the vascular wall, as evidenced by increased Sod1, Sod2 and Sod3. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice. Thus, Stevioside treatment was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, leading to inhibition of atherosclerotic plaque development and inducing plaque stabilization.
Yasmin et al (2013) demonstarted antihypertensive and antidiabetic effects of stevia in several human and animal models. Their study aimd to define stevia's role in modifying the electrophysiological and mechanical properties of cardiomyocytes, blood vessels, and gastrointestinal smooth muscle. Tissues from thoracic aorta, mesenteric arteries, ileum, and left ventricular papillary muscles were excised from 8-week-old healthy Wistar rats. The effects of stevia (1 × 10-9 M to 1 × 10-4 M) were measured on these tissues. Stevia's effects in the presence of verapamil, 4-AP, and L-NAME were also assessed. In cardiomyocytes, stevia attenuated the force of contraction, decreased the average peak amplitude, and shortened the repolarisation phase of action potential - repolarisation phase of action potential 25%, repolarisation phase of action potential50 by 34%, and repolarisation phase of action potential90 by 36%. Stevia caused relaxation of aortic tissues which was significantly potentiated in the presence of verapamil. In mesenteric arteries, incubation with L-NAME failed to block stevia-induced relaxation indicating the mechanism of action may not be fully via nitric oxide-dependent pathways. Stevia concentration-dependently reduced electrical field stimulated and carbachol-induced contractions in the isolated ileum. This study is the first to show the effectiveness of stevia in reducing cardiac action potential duration at 20%, 50%, and 90% of repolarisation. Stevia also showed beneficial modulatory effects on cardiovascular and gastrointestinal tissues via calcium channel antagonism, activation of the M2 muscarinic receptor function, and enhanced nitric oxide release.
Meta-analysis of published papers by Onakpoya and Heneghan (2015) revealed a non-significant difference in systolic blood pressure between steviol glycoside and placebo, mean difference (MD): -2.98 mm Hg (-6.23 to 0.27). Significant reductions in diastolic blood pressure and fasting blood glucose were observed. There was no significant effect on blood lipid profile. Heterogeneity was significant. Adverse events included abdominal fullness, epigastric pain, and dizziness. They concluded that stevioside may generate reductions in blood pressure and fasting blood glucose. The sizes of the effects are small, and the substantial heterogeneity limits the robustness of any conclusions. Rebaudioside A does not appear to have any significant effects on blood pressure or cardiovascular risk factors.
Boeckh, E.M.A. and Humboldt, G.: Cardio-circulatory effects of total water extract in normal persons and of stevioside in rats. Ciência e Cultura (São Paulo), 1981; 32, 208–210.
Melis, M.S. Chronic administration of aqueous extract of Stevia rebaudiana in rats: Renal effects, Journal of Ethnopharmacology, 1995; 47, 129–134.
Lee CN, Wong KL, Liu JC, Chen YJ, Cheng JT, Chan P., Inhibitory effect of stevioside on calcium influx to produce antihypertension.; Planta Med. 2001 Dec;67(9):796-9.
Liu JC, Kao PK, Chan P, Hsu YH, Hou CC, Lien GS, Hsieh MH, Chen YJ, Cheng JT, Mechanism of the antihypertensive effect of stevioside in anesthetized dogs.; Pharmacology. 2003 Jan;67(1):14-20.
Vasović V, Vukmirović S, Posa M, Mikov M, Rasković A, Jakovljević V., Effect of rat pretreatment with aqueous solutions of stevioside and bile acids on the action of certain cardioactive drugs.; Eur J Drug Metab Pharmacokinet. 2006 Oct-Dec;31(4):311-4.
Bornia EC, do Amaral V, Bazotte RB, Alves-Do-Prado W, The reduction of arterial tension produced by stevioside is dependent on nitric oxide synthase activity when the endothelium is intact.; J Smooth Muscle Res. 2008 Feb;44(1):1-8.
Geeraert B, Crombé F, Hulsmans M, Benhabilès N, Geuns JM, Holvoet P., Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice.; Int J Obes (Lond). 2010 Mar;34(3):569-77.
Yesmine S, Connolly K, Hill N, Coulson FR, Fenning AS. Electrophysiological, vasoactive, and gastromodulatory effects of stevia in healthy Wistar rats. Planta Med. 2013 Jul;79(11):909-15. doi: 10.1055/s-0032-1328706. Epub 2013 Jul 5.
Onakpoya IJ, Heneghan CJ. Effect of the natural sweetener, steviol glycoside, on cardiovascular risk factors: a systematic review and meta-analysis of randomised clinical trials. Eur J Prev Cardiol. 2015 Dec;22(12):1575-87. doi: 10.1177/2047487314560663. Epub 2014 Nov 20.
Yesmine, S 2013, The potential antihypertensive and antidiabetic activities of stevia in preventing chronic cardiovascular disease in rat models of hypertension and diabetes : comparison to the calcium channel antagonist verapamil, PhD thesis, CQUniversity, Rockhampton. http://hdl.cqu.edu.au/10018/1013648