Download PDF
Planta Med 2013; 79(11): 909-915
DOI: 10.1055/s-0032-1328706
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Electrophysiological, Vasoactive, and Gastromodulatory Effects of Stevia in Healthy Wistar Rats

Saquiba Yesmine
School of Medical & Applied Sciences, Faculty of Sciences, Engineering and Health, Central Queensland University, Rockhampton, Australia
,
Kylie Connolly
School of Medical & Applied Sciences, Faculty of Sciences, Engineering and Health, Central Queensland University, Rockhampton, Australia
,
Nicholas Hill
School of Medical & Applied Sciences, Faculty of Sciences, Engineering and Health, Central Queensland University, Rockhampton, Australia
,
Fiona R. Coulson
School of Medical & Applied Sciences, Faculty of Sciences, Engineering and Health, Central Queensland University, Rockhampton, Australia
,
Andrew S. Fenning
School of Medical & Applied Sciences, Faculty of Sciences, Engineering and Health, Central Queensland University, Rockhampton, Australia
› Author Affiliations
Further Information

Publication History

received 27 November 2012
revised 12 March 2013

accepted 16 May 2013

Publication Date:
05 July 2013 (online)

Also available at
    Permissions and Reprints

Abstract

Antihypertensive and antidiabetic effects of stevia, Stevia rebaudiana (Asteraceae), have been demonstrated in several human and animal models. The current study aims to define steviaʼs 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. Steviaʼs 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 potential20 by 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.

Key words

Stevia rebaudiana (Asteraceae) - Wistar rats - cardiovascular function - electrophysiology - action potential duration - gastrointestinal smooth muscle
 

  • References

  • 1 Jeppesen PB, Gregersen S, Alstrup KK, Hermansen K. Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the diabetic goto-kakizaki (GK) rats. Phytomedicine 2002; 9: 9-14
    CrossrefPubMedGoogle Scholar
  • 2 Jeppesen PB, Gregersena S, Poulsena CR, Hermansena K. Stevioside acts directly on pancreatic β cells to secrete insulin: actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitivie K+-channel activity. Metabolism 2000; 49: 208-214
    CrossrefPubMedGoogle Scholar
  • 3 Midmore DJ, Rank AH. A new rural industry – Stevia – to replace imported chemical sweeteners. A report for the Rural Industries Research and Development Corporation Australia. RIRDC web. Publication no. W02/022, RIRDC, project no. UCQ-16A; 2002. Available at:. http://owndoc.com/pdf/Stevia%2520new%2520rural%2520industry.pdf Accessed November 16, 2011.
    PubMedGoogle Scholar
  • 4 Bridel M, Lavielle R. The sweet principle of Kaa-he-e (Stevia rebaudiana) . J Clin Pharmacol 1931; 14: 154-161
    PubMedGoogle Scholar
  • 5 Meigs JB. Epidemiology of type 2 diabetes and cardiovascular disease: translation from population to prevention. Diabet Care 2010; 33: 1865-1871
    CrossrefPubMedGoogle Scholar
  • 6 Figlewicz DP, Ioannou G, Bennett Jay J, Kittleson S, Savard C, Roth CL. Effect of moderate intake of sweeteners on metabolic health in the rat. Physiol Behav 2009; 98: 618-624
    CrossrefPubMedGoogle Scholar
  • 7 Kelley GL, Allan G, Azhar S. High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation. Endocrinology 2004; 145: 548-555
    CrossrefPubMedGoogle Scholar
  • 8 Yodyingyuad V, Bunyawong S. Effect of stevioside on growth and reproduction. Hum Reprod 1991; 6: 158-165
    PubMedGoogle Scholar
  • 9 Paul C, Brian T, Yi-Jen C, Ju-Chi L, Ming-Hsiung H, Juei-Tang C. A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside in human hypertension. Br J Clin Pharmacol 2000; 50: 215-220
    PubMedGoogle Scholar
  • 10 Geuns JMC, Augustijns P, Mols R, Buyse JG, Driessen B. Metabolism of stevioside in pigs and intestinal absorption characteristics of stevioside, rebaudioside A and steviol. Food Chem Toxicol 2003; 41: 1599-1607
    PubMedGoogle Scholar
  • 11 Bloomgarden ZT. Nonnutritive sweeteners, fructose, and other aspects of diet. Diabet Care 2011; 34: e46-e51
    CrossrefPubMedGoogle Scholar
  • 12 Nabors LOB, Gelardi RC. Alternative sweeteners. 2nd. edition. Revised and expanded. New York: Marcel Dekker; 1991
    Google Scholar
  • 13 Kinghorn A, Soejarto D. Current status of stevioside as a sweetening agent for human use. Economic and medicinal plant research. London: Academic Press; 1985: 1-22
    CrossrefGoogle Scholar
  • 14 Geeraert B, Crombe F, Hulsmans M, Benhabiles N, Geuns JM, Holvoet P. Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice. Int J Obes 2010; 34: 569-577
    CrossrefPubMedGoogle Scholar
  • 15 Chatsudthipong V, Muanprasat C. Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther 2009; 121: 41-54
    CrossrefPubMedGoogle Scholar
  • 16 Kujur RS, Singh V, Ram M, Yadava HN, Singh KK, Kumari S, Roy BK. Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic rats. Pharmacognosy Res 2010; 2: 258-263
    CrossrefPubMedGoogle Scholar
  • 17 Jeppesen PB, Gregersen S, Rolfsen SE, Jepsen M, Colombo M, Agger A, Xiao J, Kruhoffer M, Orntoft T, Hermansen K. Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat. Metabolism 2003; 52: 372-378
    CrossrefPubMedGoogle Scholar
  • 18 Ferri LAF, Alves-Do-Prado W, Yamada SS, Gazola S, Batista MR, Bazotte RB. Investigation of the antihypertensive effect of oral crude stevioside in patients with mild essential hypertension. Phytother Res 2006; 20: 732-736
    CrossrefPubMedGoogle Scholar
  • 19 Chan P, Xu DY, Liu JC, Chen YJ, Tomlinson B, Huang WP, Cheng JT. The effect of stevioside on blood pressure and plasma catecholamines in spontaneously hypertensive rats. Life Sci 1998; 63: 1679-1684
    CrossrefPubMedGoogle Scholar
  • 20 Bornia ECS, 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; 44: 1-8
    CrossrefPubMedGoogle Scholar
  • 21 Shiozaki K, Fujii A, Nakano T, Yamaguchi T, Sato M. Inhibitory effects of hot water extract of the stevia stem on the contractile response of the smooth muscle of the guinea pig ileum. Biosci Biotechnol Biochem 2006; 70: 489-494
    CrossrefPubMedGoogle Scholar
  • 22 Takahashi K, Akiba Y, Nakano T, Yamaguchi T, Sato M, Sato N. Effect of dietary stevia (Stevia rebaudiana) extract on gizzard erosion and ulceration induced by dietary histamine in broiler chicks. J Poult Sci 2001; 38: 181-184
    CrossrefPubMedGoogle Scholar
  • 23 Shiozaki K, Nakano T, Yamaguchi T, Sato M, Sato N. The protective effect of stevia extract on the gastric mucosa of rainbow trout Oncorhynchus mykiss (Walbaum) fed dietary histamine. Aquacult Res 2004; 35: 1421-1428
    CrossrefPubMedGoogle Scholar
  • 24 Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney disease: causes and consequences. Heart 2010; 96: 817-823
    CrossrefPubMedGoogle Scholar
  • 25 Tedesco MA, Natale F, Salvo GD, Caputo S, Capasso M, Calabro R. Effects of coexisting hypertension and type II diabetes mellitus on arterial stiffness. J Hum Hypertens 2004; 18: 469-473
    CrossrefPubMedGoogle Scholar
  • 26 Stams TRG, Oros A, der Nagel RV, Beekman JDM, Chamberlin P, Dittrich HC, Vos MA. Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes . Eur J Pharmacol 2011; 672: 126-134
    CrossrefPubMedGoogle Scholar
  • 27 Milberg P, Pott C, Frommeyer G, Fink M, Ruhe M, Matsuda T, Baba A, Klocke R, Quang TH, Nikol S, Stypmann J, Osada N, Müller FU, Breithardt G, Noble D, Eckardt L. Acute inhibition of the Na+/Ca2+ exchanger reduces proarrhythmia in an experimental model of chronic heart failure. Heart Rhythm 2012; 9: 570-578
    CrossrefPubMedGoogle Scholar
  • 28 Milberg P, Fink M, Pott C, Frommeyer G, Biertz J, Osada N, Stypmann J, Mönnig G, Koopmann M, Breithardt G, Eckardt L. Blockade of ICa suppresses early afterdepolarizations and reduces transmural dispersion of repolarization in a whole heart model of chronic heart failure. Br J Pharmacol 2012; 166: 557-568
    CrossrefPubMedGoogle Scholar
  • 29 Wong KL, Chan P, Yang HY, Hsu FL, Liu IM, Cheng YW, Cheng JT. Isosteviol acts on potassium channels to relax isolated aortic strips of Wistar rat. Life Sci 2004; 74: 2379-2387
    CrossrefPubMedGoogle Scholar
  • 30 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; 67: 796-799
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Brown L, Fenning A, Shek A, Burstow D. Reversal of cardiovascular remodelling with candesartan. J Renin-Angio-Aldo S 2001; 2: S141-S147
    PubMedGoogle Scholar
  • 32 Thuraisingham RC, Raine AE. Maintenance of normal agonist-induced endothelium-dependent relaxation in uraemic and hypertensive resistance vessels. Nephrol Dial Transplant 1999; 14: 70-75
    PubMedGoogle Scholar
  • 33 Coulson FR, Jacoby DB, Fryer AD. Increased function of inhibitory neuronal M2 muscarinic receptors in trachea and ileum of diabetic rats. Br J Pharmacol 2002; 135: 1355-1362
    CrossrefPubMedGoogle Scholar
  • 34 Fenning A, Harrison G, Roseʼmeyer R, Hoey A, Brown L. L-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 2005; 289: H1408-H1416
    CrossrefPubMedGoogle Scholar
  • 35 Waldron GJ, Cole WC. Activation of vascular smooth muscle K+ channels by endothelium-derived relaxing factors. Clin Exp Pharmacol Physiol 1999; 26: 180-184
    CrossrefPubMedGoogle Scholar
  • 36 Berg T. Analysis of the pressor response to the K+ channel inhibitor 4-aminopyridine. Eur J Pharmacol 2002; 452: 325-337
    CrossrefPubMedGoogle Scholar
  • 37 Berg T. The vascular response to the K+ channel inhibitor 4-aminopyridine in hypertensive rats. Eur J Pharmacol 2003; 466: 301-310
    CrossrefPubMedGoogle Scholar
  • 38 Melis MS, Sainati AR. Effect of calcium and verapamil on renal function of rats during treatment with stevioside. J Ethnopharmacol 1991; 33: 257-262
    CrossrefPubMedGoogle Scholar
  • 39 Melis MS. Stevioside effect on renal function of normal and hypertensive rats. J Ethnopharmacol 1992; 36: 213-217
    CrossrefPubMedGoogle Scholar
  • 40 Abramochkin D, Tapilina S, Sukhova G, Nikolsky E, Nurullin L. Functional M3 cholinoreceptors are present in pacemaker and working myocardium of murine heart. Eur J Physiol 2012; 463: 1-7
    CrossrefPubMedGoogle Scholar
  • 41 Thaina P, Poonpanang P, Sawangjaroen K. Comparison of spasmolytic activities of Piper longum, P. Sarmentosum and Quercus infectoria extracts with loperamide and verapamil in rat and guinea pig intestinal tissues. Acta Hort 2005; 680: 183-189
    PubMedGoogle Scholar
  • 42 Hurwitz L, McGuffee LJ, Little SA, Blumberg H. Evidence for two distinct types of potassium-activated calcium channels in an intestinal smooth muscle. J Pharmacol Exp Ther 1980; 214: 574-580
    PubMedGoogle Scholar
  • 43 Coulson FR, Jacoby DB, Fryer AD. Insulin regulates neuronal M2 muscarinic receptor function in the ileum of diabetic rats. J Pharmacol Exp Ther 2004; 308: 760-766
    PubMedGoogle Scholar
  • 44 van Koppen CJ, Kaiser B. Regulation of muscarinic acetylcholine receptor signaling. Pharmacol Ther 2003; 98: 197-220
    CrossrefPubMedGoogle Scholar