Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration


1 Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Auraptene, a monoterpene coumarin from Citrus species, exhibits cardioprotective effects.In this study, the effects of auraptene administration were investigated on blood pressure of normotensive and desoxycorticosterone acetate (DOCA) salt induced hypertensive rats.
Materials and Methods: Five weeks administration of auraptene (2, 4, 8 and 16 mg/kg/day) and nifedipine (0.25, 0.5, 1, 2 and 4 mg/kg/day) in different groups of normotensive and hypertensive rats (at the end of 3 weeks treatment by DOCA salt) was carried out and their effects on mean systolic blood pressure (MSBP) and mean heart rate (MHR) were evaluated using tail cuff method.
Results: Our results indicated that chronic administration of auraptene (2, 4, 8 and 16 mg/kg/day) significantly reduced the MSBP in DOCA salt treated rats in a dose and time dependent manner. The percent of decreases in MSBP levels by the highest dose of auraptene (16 mg/kg) at the end of 4 th to 8 th weeks, were 7.00%, 10.78%, 16.07%, 21.28% and 27.54% respectively(P<0.001). Moreover the antihypertensive effect of auraptene was less than nifedipine (ED50 value of nifedipine = 0.7 mg/kg at 8th week and ED50 value of auraptene = 5.64 mg/kg at 8 week).
Conclusion: Auraptene considerably reduced MSBP in hypertensive rats, but not in normotensive (normal saline treated) rats. The results of MHR measurement showed that the increase in MHR was not significant in comparison with DOCA treated rats.


1. Veeramani C, Al-Numair K, Chandramohan G, Alsaif MA, Alhamdan AA, Pugalendi KV. Antihypertensive effect of Melothria maderaspatana leaf fractions on DOCA-salt-induced hypertensive rats and identification of compounds by GC-MS analysis. J Nat Med 2012; 66:302-310.

2. Krum H, Pellizzer AM. New and emerging drug treatments for hypertension. Aust Fam Physician 1998; 27:235-237.

3. Talha J, Priyanka MAA. Hypertension and herbal plants. Int Res J Pharm 2011; 2:26-30.

4. Mulero J, Bernabé J, Cerdá B, García-Viguera C, Moreno DA, Albaladejo MD, et al. Variations on cardiovascular risk factors in metabolic syndrome after consume of a Citrus-based juice. Clin Nutr 2012; 31:372-377.

5.Yamada T, Hayasaka S, Shibata Y, Ojima T, Saegusa T, Gotoh T, et al. Frequency of citrus fruit intake is associated with the incidence of cardiovascular disease: The Jichi medical school cohort study. J Epidemiol 2011; 21:169–175.

6. Perez YY, Jimenez-Ferrer E, Alonso D. Botello-Amaro CA, Zamilpa A. Citrus limetta leaves extract antagonizes the hypertensive effect of angiotensin II. J Ethnopharmacol 2010; 128:611-614.

7. Díaz-Juárez JA, Tenorio-López FA, Zarco-Olvera G, Valle-Mondragón LD, Torres-Narváez JC, Pastelín-Hernández G. Effect of Citrus paradisi extract and juice on arterial pressure both in vitro and in vivo. Phytother Res 2009; 23:948-954.

8. Gaziano JM. Antioxidant vitamins and cardiovascular disease. Proc Assoc Am Physicians1999; 111:2-9.

9. Roza JM, Xian-Liu Z, Guthrie N. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. Altern Ther Health Med 2007; 13:44-48.

10. Curini M, Cravotto G, Epifano F, Giannone G. Chemistry and biological activity of natural and synthetic prenyloxycoumarins. Curr Med Chem 2006; 13:199-222.

11. Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F, et al. Auraptene from Ferula szowitsiana protects human peripheral lymphocytes against oxidative stress. Phytother Res2010; 24:85-89.

12. Genovese S, Epifano F. Auraptene: A natural biologically active compound with multiple targets. Curr Drug Targets2011; 12:381-386.

13. Curini M, Epifano F, Messina F, Genovese S. Antibacterial properties of auraptene and oxyprenylated naturally occurring benzoic and cinnamic acids. Boletin Latinoamericano y del Caribe de Plantas Medicinales y Aromaticas 2012; 11:74–76.

14. Yamada Y, Okamoto M, Kikuzaki H, Nakatani N. Spasmolytic activity of auraptene analogs. Biosci Biotechnol Biochem 1997; 61:740-742.

15. Kakiuchi N, Senaratne LR, Huang SL, Yang XW, Hattori M, Pilapitiya U, Namba T. Effects of constituents of Beli (Aegle marmelos) on spontaneous beating and calcium-paradox of myocardial cells. Planta Med 1991; 57:43-46.

16. Imenshahidi M, Eghbal M, Sahebkar A, Iranshahi M. Hypotensive activity of auraptene, a monoterpene coumarin from Citrus spp. Pharm Biol 2013; 51:545-549.

17. Askari M, Sahebkar A, Iranshahi M. Synthesis and purification of 7-prenyloxycoumarins and herniarin as bioactive natural coumarins. Iran J Basic Med Sci 2009; 12: 63-69.

18. Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res 2010; 24:990-994.

19. Lorenz JN.A practical guide to evaluating cardiovascular, renal, and pulmonary function in mice. Am J Physiol Regul Integr Comp Physiol 2002; 282:R1565-1582.

20. Reshef N, Hayari Y, Goren C, Boaz M, Madar Z, Knobler H. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am J Hypertens 2005; 18:1360-1363.

21. Komatsu S, Tanaka S, Ozawa S. Biochemical studies on grape fruits, Citrus aurantium. Nippon Kagaku Kaishi 1930; 51:478-498.

22. Epifano F, Genovese S, Curini M. Auraptene: Phytochemical and pharmacological properties. In: Matsumoto T, editor. Phytochemistry Research Progressed. New York: Nova Science Publishers Inc; 2008.p.145–162.

23. Nagao K,  Yamano N, Shirouchi B, Inoue N, Murakami S, Sasaki T, et al. Effects of Citrus auraptene                                 (7-geranyloxycoumarin) on hepatic lipid metabolism            in vitro and in vivo. J Agric Food Chem 2010; 58:9028–9032.

24. Fusi F, Saponara S, Pessina F, Gorelli B, Sgaragli G. Effects of quercetin and rutin on vascular preparations: A comparison between mechanical and electrophysiological phenomena. Eur J Nutr2003;

25. Ari YN, Altan VM, Altinkurt O, Ozturk Y. Pharmacological effects of rutin. Phytother Res 2006; 5:19-23.

26. Xu YC, Leung SWS, Yeung DKY, Hu LH,  Chen  GH,  Che CM, et al. Structure–activity relationships of flavonoids for vascular relaxation in porcine coronary artery. Phytochemistry 2007; 68:1179-1188.

27. Athiroh N, Permatasari N, Sargowo D, Widodo MA. Effect of Scurrula atropurpurea on nitric oxide, endothelial damage, and endothelial progenitor cells of DOCA-salt hypertensive rats. Iran J Basic Med Sci 2014; 17: 622-625.