Antihypertensive Effects of Roselle-Olive Combination in L-NAME-Induced Hypertensive Rats

Rehab F Abdel-Rahman, Alyaa F Hessin, Marwan Abdelbaset, Hanan A Ogaly, Reham M Abd-Elsalam, Salah M Hassan, Rehab F Abdel-Rahman, Alyaa F Hessin, Marwan Abdelbaset, Hanan A Ogaly, Reham M Abd-Elsalam, Salah M Hassan

Abstract

This study aimed to evaluate the antihypertensive efficacy of a new combination therapy of Hibiscus sabdariffa and Olea europaea extracts (2 : 1; Roselle-Olive), using N(G)-nitro-L-arginine-methyl ester- (L-NAME-) induced hypertensive model. Rats received L-NAME (50 mg/kg/day, orally) for 4 weeks. Concurrent treatment with Roselle-Olive (500, 250, and 125 mg/kg/day for 4 weeks) resulted in a dose-dependent decrease in both systolic and diastolic blood pressure, reversed the L-NAME-induced suppression in serum nitric oxide (NO), and improved liver and kidney markers, lipid profile, and oxidative status. Furthermore, Roselle-Olive significantly lowered the elevated angiotensin-converting enzyme activity (ACE) and showed a marked genoprotective effect against oxidative DNA damage in hypertensive rats. Roselle-Olive ameliorated kidney and heart lesions and reduced aortic media thickness. Real-time PCR and immunohistochemistry showed an enhanced endothelial nitric oxide synthase (eNOS) gene and protein expression in both heart and kidney of Roselle-Olive-treated rats. To conclude, our data revealed that Roselle-Olive is an effective combination in which H. sabdariffa and O. europaea synergistically act to control hypertension. These effects are likely to be mediated by antioxidant and genoprotective actions, ACE inhibition, and eNOS upregulation by Roselle-Olive constituents. These findings provide evidences that Roselle-Olive combination affords efficient antihypertensive effect with a broad end-organ protective influence.

Figures

Figure 1
Figure 1
Effect of Roselle-Olive combination on MAP in L-NAME-induced hypertensive rats. Data were expressed as mean ± SE. of 5–7 experiments. Data were analyzed by one-way ANOVA followed by LSD for multiple comparison test, Ap < 0.05 versus normal control and Bp < 0.05 versus hypertensive rats.
Figure 2
Figure 2
Effect of Roselle-Olive combination on ECG parameters (a) PR interval, (b) heart rate, (c) QRs interval, and (d) PR interval in L-NAME-induced hypertensive rats. Data were expressed as mean ± SE. of 5–7 experiments. Data were analyzed by one-way ANOVA followed by LSD for multiple comparison test, Ap < 0.05 versus normal control and Bp < 0.05 versus hypertensive rats.
Figure 3
Figure 3
Effect of Roselle-Olive combination on ECG parameters (a) QT interval, (b) QTc interval, and (c) R amplitude in L-NAME-induced hypertensive rats. Data were expressed as mean ± SE. of 5–7 experiments. Data were analyzed by one-way ANOVA followed by LSD for multiple comparison test, Ap < 0.05 versus normal control and Bp < 0.05 versus hypertensive rats.
Figure 4
Figure 4
Effect of Roselle-Olive combination on kidney and myocardium lesion scoring in L-NAME-induced hypertensive rats. (a) Renal glomerular lesions; (b) renal tubular lesions; (c) renal interstitium lesions; (d) myocardium lesions. Values are presented as means ± SE. Mean values with different letters are significantly different (p < 0.05). Nec.: necrosis; P.l: protenious leakage; Thic: thickening of Bowman's capsule; B.di: Bowman's space dilation; Vac.: vacuolation; P.c: protein cast; Dil: tubular dilation; MNC: mononuclear cell; Myo. Deg.: myocardial degeneration; Myo. Nec.: myocardial necrosis; Inflam: inflammation.
Figure 5
Figure 5
Histopathological changes of the kidneys in different experimental groups (H&E ×400). (a) Control normotensive group showing normal histological features. (b) L-NAME group showing marked necrosis of glomerular tuft, adhesion of glomerular tuft to parietal layer of the Bowman's capsule, the dilation of Bowman's space, and proteinous leakage into the space (arrow) with marked necrobiotic changes of renal tubules. (c) L-NAME + lisinopril group (10 mg/kg) showing mild glomerular necrosis, dilation of Bowman's space, partial glomerular tuft adhesion, slight thickening of the parietal layer of the Bowman's capsule, and moderate medial hypertrophy of blood vessels (arrow) with mild necrobiotic changes of renal tubular epithelium. (d) L-NAME + Roselle-Olive (500 mg/kg) group showing moderate necrobiotic changes of renal tubules (arrow). (e) L-NAME + Roselle-Olive (250 mg/kg) group showing mild glomerular tuft necrosis, adhesion of glomerular tuft, dilation of Bowman's space, and proteinous leakage. (f) L-NAME + Roselle-Olive (125 mg/kg) group showing moderate glomerular changes marked necrobiotic changes of renal tubules (arrow).
Figure 6
Figure 6
Photomicrograph of heart stained with H&E stain (×200). (a) Control normotensive group showing normal histological features. (b) L-NAME group showing extensive myocardial fibrosis, myocardial loss, and mononuclear inflammatory cell infiltration. (c) L-NAME + lisinopril group (10 mg/kg) showing moderate myocardial degeneration. (d) L-NAME + Roselle-Olive (500 mg/kg) group and (e) L-NAME + Roselle-Olive (250 mg/kg) group showing mild myocardial degeneration. (f) L-NAME + Roselle-Olive (125 mg/kg) group showing moderate myocardial degeneration, necrosis, mononuclear inflammatory cell aggregation, and collagen fiber deposition.
Figure 7
Figure 7
Photomicrograph of the heart stained with MT stain (×200). (a) Control normotensive group showing normal collagen fiber deposition around coronary blood vessels (arrow). (b) L-NAME group showing extensive collagen fiber deposition (arrow). (c) L-NAME + lisinopril group (10 mg/kg) showing moderate collagen fiber deposition (arrow). (d) L-NAME + Roselle-Olive (500 mg/kg) group and (e) L-NAME + Roselle-Olive (250 mg/kg) group showing slight collagen fiber deposition (arrow) in the interstitial tissue. (f) L-NAME + Roselle-Olive (125 mg/kg) group showing moderate myocardial fibrosis (arrow).
Figure 8
Figure 8
Effect of different treatment on the heart. (a) Myocardial fibrosis; (b) aortic tunica media thickening. Values are presented as means ± SE. Mean values with different letters are significantly different (p < 0.05).
Figure 9
Figure 9
eNOS immunohistochemistry in the kidney tissues of different experimental groups (×400). The eNOS immunoreactivity was characteristically cytoplasmic and the cytoplasm was stained brown color (arrow), (a) control normotensive group moderate immunoreactivity. (b) L-NAME group showing very weak immunopositive reaction. (c) L-NAME + lisinopril group (10 mg/kg) showing moderate immunoreactivity. (d) L-NAME + Roselle-Olive (500 mg/kg) group showing strong immunoreactivity. (e) L-NAME + Roselle-Olive (250 mg/kg) group showing strong immunoreactivity. (f) L-NAME + Roselle-Olive (125 mg/kg) group showing moderate immunoreactivity. (g) Bar chart represents the eNOS immunopositivity expressed as area %. Mean values with different superscripts are significantly different (p < 0.05).
Figure 10
Figure 10
eNOS immunohistochemistry in the aorta of different experimental groups (×400). The eNOS immunoreactivity was in the endothelial lining blood vessels (arrow), (a) control normotensive group strong immunoreactivity. (b) L-NAME group showing very weak immunostaining. (c) L-NAME + lisinopril group (10 mg/kg) showing moderate immunoreactivity. (d) L-NAME + Roselle-Olive (500 mg/kg) group showing strong immunopositive reaction. (e) L-NAME + Roselle-Olive (250 mg/kg) and (f) L-NAME + Roselle-Olive (125 mg/kg) group showing moderate immunoreactivity. (g) Bar chart represents the eNOS immunopositivity expressed as area %. Mean values with different superscripts are significantly different (p < 0.05).
Figure 11
Figure 11
iNOS immunohistochemistry in the kidney tissues of different experimental groups (×400). (a) Control normotensive group showing very weak immunostaining. (b) L-NAME group showing strong immunostaining. (c) L-NAME + lisinopril group (10 mg/kg), (d) L-NAME + Roselle-Olive (500 mg/kg) group, (e) L-NAME + Roselle-Olive (250 mg/kg) group, and (f) L-NAME + Roselle-Olive (125 mg/kg) group showing strong immunostaining. (g) Bar chart represents the iNOS immunopositivity expressed as area %. Mean values with different superscripts are significantly different (p < 0.05).
Figure 12
Figure 12
DNA damage in the kidney detected by comet assay in the different experimental groups. (a) Normal control group, (b) hypertensive (L-NAME) group, (c) L-NAME + lisinopril-treated group (10 mg/kg), (d) L-NAME + Roselle-Olive-treated group (500 mg/kg), (e) L-NAME + Roselle-Olive-treated group (250 mg/kg), and (f) L-NAME + Roselle-Olive-treated group (125 mg/kg).
Figure 13
Figure 13
DNA damage in the heart detected by comet assay in the different experimental groups. (a) Normal control group, (b) hypertensive (L-NAME) group, (c) L-NAME + lisinopril-treated group (10 mg/kg), (d) L-NAME + Roselle-Olive-treated group (500 mg/kg), (e) L-NAME + Roselle-Olive-treated group (250 mg/kg), and (f) L-NAME + Roselle-Olive-treated group (125 mg/kg).

References

    1. Kahan T. Focus on blood pressure as a major risk factor. The Lancet. 2014;383(9932):1866–1868. doi: 10.1016/s0140-6736(14)60896-5.
    1. Staessen J. A. Hypertension: age-specificity of blood-pressure-associated complications. Nature Reviews Cardiology. 2014;11(9):499–501. doi: 10.1038/nrcardio.2014.109.
    1. World Health Organization. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. Journal of Hypertension. 2003;21(11):1983–1992. doi: 10.1097/00004872-200311000-00002.
    1. Jing P., Qian B., He Y., et al. Screening milk-derived antihypertensive peptides using quantitative structure activity relationship (QSAR) modelling and in vitro/in vivo studies on their bioactivity. International Dairy Journal. 2014;35(1):95–101. doi: 10.1016/j.idairyj.2013.10.009.
    1. Pruijm M. T., Maillard M. P., Burnier M. Patient adherence and the choice of antihypertensive drugs: focus on lercanidipine. Vascular Health and Risk Management. 2008;4(6):1159–1166. doi: 10.2147/vhrm.s3510.
    1. Obouayeba A. P., Djyh N. B., Diabate S., et al. Phytochemical and antioxidant activity of Roselle (Hibiscus sabdariffa L.) petal extracts. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2014;5:1453–1465.
    1. Anwar M. A., Al Disi S. S., Eid A. H. Anti-hypertensive herbs and their mechanisms of action: part II. Frontiers in Pharmacology. 2016;7 doi: 10.3389/fphar.2016.00050.
    1. Da-Costa-Rocha I., Bonnlaender B., Sievers H., Pischel I., Heinrich M. Hibiscus sabdariffa L. – a phytochemical and pharmacological review. Food Chemistry. 2014;165:424–443. doi: 10.1016/j.foodchem.2014.05.002.
    1. Dhar P., Kar C. S., Ojha D., Pandey S. K., Mitra J. Chemistry, phytotechnology, pharmacology and nutraceutical functions of kenaf (Hibiscus cannabinus L.) and roselle (Hibiscus sabdariffa L.) seed oil: an overview. Industrial Crops and Products. 2015;77:323–332. doi: 10.1016/j.indcrop.2015.08.064.
    1. Ajiboye T. O., Salawu N. A., Yakubu M. T., Oladiji A. T., Akanji M. A., Okogun J. I. Antioxidant and drug detoxification potentials of Hibiscus sabdariffa anthocyanin extract. Drug and Chemical Toxicology. 2011;34(2):109–115. doi: 10.3109/01480545.2010.536767.
    1. Mossalam H. H., Abd-El Aty O. A., Morgan E. N., Youssaf S. M., Mackawy A. M. Biochemical and ultra-structure studies of the antioxidant effect of aqueous extract of Hibiscus sabdariffa on the nephrotoxicity induced by organophosphorous pesticide (malathion) on the adult albino rats. Journal of American Science. 2011;7(12):561–572.
    1. Mohd-Esa N., Hern F. S., Ismail A., Yee C. L. Antioxidant activity in different parts of roselle (Hibiscus sabdariffa L.) extracts and potential exploitation of the seeds. Food Chemistry. 2010;122(4):1055–1060. doi: 10.1016/j.foodchem.2010.03.074.
    1. Jonadet M., Bastide J., Bastide P., Boyer B., Carnat A. P., Lamaison J. L. In vitro enzyme inhibitory and in vivo cardioprotective activities of hibiscus (Hibiscus sabdariffa L.) Journal de Pharmacie de Belgique. 1990;45(2):120–124.
    1. Falade O. S., Otemuyiwa I. O., Oladipo A., Oyedapo O. O., Akinpelu B. A., Adewusi S. R. The chemical composition and membrane stability activity of some herbs used in local therapy for anemia. Journal of Ethnopharmacology. 2005;102(1):15–22. doi: 10.1016/j.jep.2005.04.034.
    1. Peng C. H., Chyau C. C., Chan K. C., Chan T. H., Wang C. J., Huang C. N. Hibiscus sabdariffa polyphenolic extract inhibits hyperglycemia, hyperlipidemia, and glycation-oxidative stress while improving insulin resistance. Journal of Agricultural and Food Chemistry. 2011;59(18):9901–9909. doi: 10.1021/jf2022379.
    1. Laikangbam R., Damayanti Devi M. D. Inhibition of calcium oxalate crystal deposition on kidneys of urolithiatic rats by Hibiscus sabdariffa L. extract. Urological Research. 2012;40(3):211–218. doi: 10.1007/s00240-011-0433-3.
    1. Gunstone F., editor. Vegetable Oils in Food Technology: Composition, Properties and Uses. USA/Canada: Blackwell Publishing and CRC Press; 2002.
    1. Kumral A., Giriş M., Soluk-Tekkeşin M., et al. Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats. Pathophysiology. 2015;22(2):117–123. doi: 10.1016/j.pathophys.2015.04.002.
    1. Perrinjaquet-Moccetti T., Busjahn A., Schmidlin C., Schmidt A., Bradl B., Aydogan C. Food supplementation with an olive (Olea europaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins. Phytotherapy Research. 2008;22(9):1239–1242. doi: 10.1002/ptr.2455.
    1. Omar S. H. Cardioprotective and neuroprotective roles of oleuropein in olive. Saudi Pharmaceutical Journal. 2010;18(3):111–121. doi: 10.1016/j.jsps.2010.05.005.
    1. Carvajal-Zarrabal O., Barradas-Dermitz D. M., Orta-Flores Z., et al. Hibiscus sabdariffa L., roselle calyx, from ethnobotany to pharmacology. Journal of Experimental Pharmacology. 2012;4:p. 25. doi: 10.2147/jep.s27974.
    1. Susalit E., Agus N., Effendi I., et al. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril. Phytomedicine. 2011;18(4):251–258. doi: 10.1016/j.phymed.2010.08.016.
    1. Majithiya J. B., Parmar A. N., Trivedi C. J., Balaraman R. Effect of pioglitazone on L-NAME induced hypertension in diabetic rats. Vascular Pharmacology. 2005;43(4):260–266. doi: 10.1016/j.vph.2005.08.012.
    1. Meaney E., Alva F., Moguel R., Meaney A., Alva J., Webel R. Formula and nomogram for the sphygmomanometric calculation of the mean arterial pressure. Heart. 2000;84(1):p. 64. doi: 10.1136/heart.84.1.64.
    1. Kushikata T., Hirota K., Yoshida H., et al. Orexinergic neurons and barbiturate anesthesia. Neuroscience. 2003;121(4):855–863. doi: 10.1016/s0306-4522(03)00554-2.
    1. Reitman S., Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. American Journal of Clinical Pathology. 1957;28(1):56–63. doi: 10.1093/ajcp/28.1.56.
    1. Szasz G. A kinetic photometric method for serum gamma-glutamyl transpeptidase. Clinical Chemistry. 1969;15(2):124–136.
    1. Wills M. R., Savory J. O. Biochemistry of renal failure. Annals of Clinical & Laboratory Science. 1981;11(4):292–299.
    1. Kroll M. H., Roach N. A., Poe B., Elin R. J. Mechanism of interference with the Jaffé reaction for creatinine. Clinical Chemistry. 1987;33(7):1129–1132.
    1. Placer Z. A., Cushman L. L., Johnson B. C. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Analytical Biochemistry. 1966;16(2):359–364. doi: 10.1016/0003-2697(66)90167-9.
    1. Miranda K. M., Espey M. G., Wink D. A. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62–71. doi: 10.1006/niox.2000.0319.
    1. Beutler E., Duron O., Kelly B. M. Improved method for the determination of blood glutathione. The Journal of Laboratory and Clinical Medicine. 1963;61:882–888.
    1. Friedewald W. T., Levy R. I., Fredrickson D. S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry. 1972;18(6):499–502.
    1. Bancroft J. D., Gamble M. Theory and Practice of Histological Techniques. 6th. UK: Elsevier Health Sciences; 2008.
    1. Duarte C. G., Zhang J., Ellis S. The SHR as a small animal model for radiocontrast renal failure. Relation of nephrotoxicity to animal’s age, gender, strain, and dose of radiocontrast. Renal Failure. 1997;19(6):723–743. doi: 10.3109/08860229709037213.
    1. Kanda T., Araki M., Nakano M., et al. Chronic effect of losartan in a murine model of dilated cardiomyopathy: comparison with captopril. Journal of Pharmacology and Experimental Therapeutics. 1995;273(2):955–958.
    1. Ogaly H. A., Khalaf A. A., Ibrahim M. A., Galal M. K., Abd-Elsalam R. M. Influence of green tea extract on oxidative damage and apoptosis induced by deltamethrin in rat brain. Neurotoxicology and Teratology. 2015;50:23–31. doi: 10.1016/j.ntt.2015.05.005.
    1. Livak K. J., Schmittgen T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402–408. doi: 10.1006/meth.2001.1262.
    1. Guo J. S., Cho C. H., Wang W. P., Shen X. Z., Cheng C. L., Koo M. W. Expression and activities of three inducible enzymes in the healing of gastric ulcers in rats. World Journal of Gastroenterology. 2003;9(8):1767–1771. doi: 10.3748/wjg.v9.i8.1767.
    1. Mostafa R. E. Salama A. A. A., Abdel-Rahman R. F., Ogaly H. A. Hepato and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats. Canadian Journal of Physiology and Pharmacology. 2017;95(5):539–547. doi: 10.1139/cjpp-2016-0433.
    1. Eltablawy N. A., Ogaly H. A. Responsiveness of p53 expression and genetic mutation to CCl4-induced DNA damage in rat’s liver. International Journal of Genomics and Proteomics. 2014;5(1):99–105.
    1. Ramanathan V., Thekkumalai M. Role of chrysin on hepatic and renal activities of Nω-nitro-l-arginine-methylester induced hypertensive rats. International Journal of Nutrition, Pharmacology, Neurological Diseases. 2014;4:58–63. doi: 10.4103/2231-0738.124615.
    1. Pfeiffer S., Leopold E., Schmidt K., Brunner F., Mayer B. Inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME): requirement for bioactivation to the free acid, NG-nitro-L-arginine. British Journal of Pharmacology. 1996;118(6):1433–1440. doi: 10.1111/j.1476-5381.1996.tb15557.x.
    1. Hopkins A. L., Lamm M. G., Funk J. L., Ritenbaugh C. Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies. Fitoterapia. 2013;85:84–94. doi: 10.1016/j.fitote.2013.01.003.
    1. Jaarin K., Foong W. D., Yeoh M. H., et al. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats. Clinics. 2015;70(11):751–757. doi: 10.6061/clinics/2015(11)07.
    1. Akinyemi A. J., Thome G. R., Morsch V. M., et al. Effect of dietary supplementation of ginger and turmeric rhizomes on angiotensin-1 converting enzyme (ACE) and arginase activities in L-NAME induced hypertensive rats. Journal of Functional Foods. 2015;17:792–801. doi: 10.1016/j.jff.2015.06.011.
    1. Cardoso A. M., Abdalla F. H., Bagatini M. D., et al. Swimming training prevents alterations in acetylcholinesterase and butyrylcholinesterase activities in hypertensive rats. American Journal of Hypertension. 2014;27:522–529. doi: 10.1093/ajh/hpt030.
    1. Chillon J. M., Ghoneim S., Baumbach G. L. Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in rats. Hypertension. 1997;30(5):1097–1104. doi: 10.1161/01.hyp.30.5.1097.
    1. Baumbach G. L., Heistad D. D., Siems J. E. Effect of sympathetic nerves on composition and distensibility of cerebral arterioles in rats. The Journal of Physiology. 1989;416:123–140. doi: 10.1113/jphysiol.1989.sp017753.
    1. Ojeda D., Jiménez-Ferrer E., Zamilpa A., Herrera-Arellano A., Tortoriello J., Alvarez L. Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin-and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. Journal of Ethnopharmacology. 2010;127(1):7–10. doi: 10.1016/j.jep.2009.09.059.
    1. Hansen K., Adsersen A., Christensen S. B., Jensen S. R., Nyman U., Smitt U. W. Isolation of an angiotensin converting enzyme (ACE) inhibitor from Olea europaea and Olea lancea. Phytomedicine. 1996;2(4):319–325. doi: 10.1016/s0944-7113(96)80076-6.
    1. Aliyu B., Oyeniyi Y. J., Mojiminiyi F. B., Isezuo S. A., Alada A. R. The aqueous calyx extract of Hibiscus sabdariffa lowers blood pressure and heart rate via sympathetic nervous system dependent mechanisms. Nigerian Journal of Physiological Sciences. 2014;29(2):131–136.
    1. Micucci M., Malaguti M., Gallina Toschi T., et al. Cardiac and Vascular Synergic Protective Effect of Olea europaea L. Leaves and Hibiscus sabdariffa L. Flower Extracts. Oxidative Medicine and Cellular Longevity. 2015;2015:14. doi: 10.1155/2015/318125.318125
    1. Chaswal M., Das S., Prasad J., Katyal A., Mishra A. K., Fahim M. Effect of losartan, an angiotensin II type 1 receptor antagonist on cardiac autonomic functions of rats during acute and chronic inhibition of nitric oxide synthesis. Physiological Research. 2012;61(2):135–144.
    1. Silva V. J., Ferreira Neto E., Salgado H. C., Fazan Júnior R. Chronic converting enzyme inhibition normalizes QT interval in aging rats. Brazilian Journal of Medical and Biological Research. 2002;35(9):1025–1031. doi: 10.1590/s0100-879x2002000900003.
    1. Cohuet G., Struijker-Boudier H. Mechanisms of target organ damage caused by hypertension: therapeutic potential. Pharmacology and Therapeutics. 2006;111(1):81–98. doi: 10.1016/j.pharmthera.2005.09.002.
    1. Vardi N., Ozturk F., Fadillioglu E., Otlu A., Yagmurca M. Histological changes in the rat thoracic aorta after chronic nitric oxide synthase inhibition. Turkish Journal of Medical Sciences. 2003;33(3):141–147.
    1. Rossoni G., Manfredi B., Gennaro Colonna V., Berti M., Guazzi M., Berti F. Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat. British Journal of Pharmacology. 2007;150(5):567–576. doi: 10.1038/sj.bjp.0707131.
    1. Adaramoye O. A., Nwosu I. O., Farombi E. O. Sub-acute effect of NG-nitro-l-arginine methyl-ester (L-NAME) on biochemical indices in rats: protective effects of Kolaviron and extract of Curcuma longa L. Pharmacognosy Research. 2012;4(3):127–133. doi: 10.4103/0974-8490.99071.
    1. Talas Z. S., Gogebakan A., Orun I. Effects of propolis on blood biochemical and hematological parameters in nitric oxide synthase inhibited rats by Nω-nitro-L-arginine methyl ester. Pakistan Journal of Pharmaceutical Sciences. 2013;26(5):915–919.
    1. Barón V., Hernández J., Noyola M., Escalante B., Muriel P. Nitric oxide and inducible nitric oxide synthase expression are downregulated in acute cholestasis in the rat accompanied by liver ischemia. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology. 2000;127(3):243–249. doi: 10.1016/s0742-8413(00)00154-7.
    1. Cottart C. H., Nivet-Antoine V., Do L., et al. Hepatic cytoprotection by nitric oxide and the cGMP pathway after ischaemia–reperfusion in the rat. Nitric Oxide. 2003;9(2):57–63. doi: 10.1016/j.niox.2003.09.003.
    1. Lee C. H., Kuo C. Y., Wang C. J., et al. A polyphenol extract of Hibiscus sabdariffa L. ameliorates acetaminophen-induced hepatic steatosis by attenuating the mitochondrial dysfunction in vivo and in vitro. Bioscience, Biotechnology, and Biochemistry. 2012;76(4):646–651. doi: 10.1271/bbb.110579.
    1. Giannini E. G., Testa R., Savarino V. Liver enzyme alteration: a guide for clinicians. Canadian Medical Association Journal. 2005;172(3):367–379. doi: 10.1503/cmaj.1040752.
    1. Mount P. F., Power D. A. Nitric oxide in the kidney: functions and regulation of synthesis. Acta Physiologica. 2006;187(4):433–446. doi: 10.1111/j.1748-1716.2006.01582.x.
    1. Ali B. H., Wabel N. A., Blunden G. Phytochemical, pharmacological and toxicological aspects of Hibiscus sabdariffa L.: a review. Phytotherapy Research. 2005;19(5):369–375. doi: 10.1002/ptr.1628.
    1. Alarcón-Alonso J., Zamilpa A., Aguilar F. A., Herrera-Ruiz M., Tortoriello J., Jimenez-Ferrer E. Pharmacological characterization of the diuretic effect of Hibiscus sabdariffa Linn (Malvaceae) extract. Journal of Ethnopharmacology. 2012;139(3):751–756. doi: 10.1016/j.jep.2011.12.005.
    1. Nyadjeu P., Nguelefack-Mbuyo E. P., Atsamo A. D., Nguelefack T. B., Dongmo A. B., Kamanyi A. Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats. BMC Complementary and Alternative Medicine. 2013;13:27–37. doi: 10.1186/1472-6882-13-27.
    1. Chen C. C., Hsu J. D., Wang S. F., et al. Hibiscus sabdariffa extract inhibits the development of atherosclerosis in cholesterol-fed rabbits. Journal of Agricultural and Food Chemistry. 2003;51(18):5472–5477. doi: 10.1021/jf030065w.
    1. Onyenekwe P. C., Ajani E. O., Ameh D. A., Gamaniel K. S. Antihypertensive effect of roselle (Hibiscus sabdariffa) calyx infusion in spontaneously hypertensive rats and a comparison of its toxicity with that in Wistar rats. Cell Biochemistry and Function. 1999;17(3):199–206. doi: 10.1002/(sici)1099-0844(199909)17:3<199::aid-cbf829>;2-u.
    1. Atlas S. A. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. Journal of Managed Care Pharmacy. 2007;13(8) Supplement B:9–20. doi: 10.18553/jmcp.2007.13.s8-b.9.
    1. Ng K. K., Vane J. R. Conversion of angiotensin I to angiotensin II. Nature. 1967;216(5117):762–766. doi: 10.1038/216762a0.
    1. Singh P., Deng A., Weir M. R., Blantz R. C. The balance of angiotensin II and nitric oxide in kidney diseases. Current Opinion in Nephrology and Hypertension. 2008;17(1):51–56. doi: 10.1097/mnh.0b013e3282f29a8b.
    1. Giani J. F., Janjulia T., Kamat N., et al. Renal angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition. Journal of the American Society of Nephrology. 2014;25(12):2752–2763. doi: 10.1681/asn.2013091030.
    1. Mojiminiyi F. B., Dikko M., Muhammad B. Y., et al. Antihypertensive effect of an aqueous extract of the calyx of Hibiscus sabdariffa. Fitoterapia. 2007;78(4):292–297. doi: 10.1016/j.fitote.2007.02.011.
    1. Nekooeian A. A., Dehghani G. A., Mostafavi H., Khalili A. The effect of hydroalcoholic extract of olive leaves on blood pressure in rat model of two-kidney, one-clip goldblatt hypertension. International Cardivascular Research Journal. 2011;5(1):1–6.
    1. Khayyal M. T., El-Ghazaly M. A., Abdallah D. M., Nassar N. N., Okpanyi S. N., Kreuter M. H. Blood Pressure Lowering Effect of an Olive Leaf Extract (Olea europaea) in L-NAME Induced Hypertension in Rats. Arzneimittelforschung. 2002;52(11):797–802. doi: 10.1055/s-0031-1299970.
    1. Zhou M. S., Schulman I. H., Raij L. Nitric oxide, angiotensin II, and hypertension. Seminars in Nephrology. 2004;24(4):366–378. doi: 10.1016/j.semnephrol.2004.04.008.
    1. Montezano A. C., Dulak-Lis M., Tsiropoulou S., Harvey A., Briones A. M., Touyz R. M. Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. Canadian Journal of Cardiology. 2015;31(5):631–641. doi: 10.1016/j.cjca.2015.02.008.
    1. Forte M., Conti V., Damato A., et al. Targeting nitric oxide with natural derived compounds as a therapeutic strategy in vascular diseases. Oxidative Medicine and Cellular Longevity. 2016;2016:20. doi: 10.1155/2016/7364138.7364138
    1. Selemidis S., Dusting G. J., Peshavariya H., Kemp-Harper B. K., Drummond G. R. Nitric oxide suppresses NADPH oxidase-dependent superoxide production by S-nitrosylation in human endothelial cells. Cardiovascular Research. 2007;75(2):349–358. doi: 10.1016/j.cardiores.2007.03.030.
    1. Sung J. H., Jo Y. S., Kim S. J., et al. Effect of lutein on L-NAME-induced hypertensive rats. The Korean Journal of Physiology and Pharmacology. 2013;17(4):339–345. doi: 10.4196/kjpp.2013.17.4.339.
    1. Öktem F., Kirbas A., Armagan A., et al. Lisinopril attenuates renal oxidative injury in L-NAME-induced hypertensive rats. Molecular and Cellular Biochemistry. 2011;352(1-2):247–253. doi: 10.1007/s11010-011-0760-2.
    1. Ogaly H. A., Eltablawy N. A., El-Behairy A. M., El-Hindi H., Abd-Elsalam R. M. Hepatocyte growth factor mediates the antifibrogenic action of Ocimum bacilicum essential oil against CCl4-induced liver fibrosis in rats. Molecules. 2015;20(8):13518–13535. doi: 10.3390/molecules200813518.
    1. Čabarkapa A., Živković L., Žukovec D., et al. Protective effect of dry olive leaf extract in adrenaline induced DNA damage evaluated using in vitro comet assay with human peripheral leukocytes. Toxicology In Vitro. 2014;28(3):451–456. doi: 10.1016/j.tiv.2013.12.014.
    1. Fabiani R., Rosignoli P., De Bartolomeo A., et al. Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other olive phenolic compounds in human blood mononuclear cells and HL60 cells. The Journal of Nutrition. 2008;138(8):1411–1416.
    1. Ferroni P., Basili S., Paoletti V., Davi G. Endothelial dysfunction and oxidative stress in arterial hypertension. Nutrition, Metabolism and Cardiovascular Diseases. 2006;16:222–233. doi: 10.1016/j.numecd.2005.11.012.
    1. Nakmareong S., Kukongviriyapan U., Pakdeechote P., et al. Tetrahydrocurcumin alleviates hypertension, aortic stiffening and oxidative stress in rats with nitric oxide deficiency. Hypertension Research. 2012;35:418–425. doi: 10.1038/hr.2011.180.
    1. Zhao Y., Vanhoutte P. M., Leung S. W. Endothelial nitric oxide synthase-independent release of nitric oxide in the aorta of the spontaneously hypertensive rat. Journal of Pharmacology and Experimental Therapeutics. 2013;344:15–22. doi: 10.1124/jpet.112.198721.
    1. Giani J. F., Janjulia T., Taylor B., et al. Renal generation of angiotensin II and the pathogenesis of hypertension. Current Hypertension Reports. 2014;16(9):p. 477. doi: 10.1007/s11906-014-0477-1.
    1. Pushpakumar S. B., Kundu S., Metreveli N., Sen U. Folic acid mitigates angiotensin-II-induced blood pressure and renal remodeling. PLoS One. 2013;8(12, article e83813) doi: 10.1371/journal.pone.0083813.
    1. Monhart V. Hypertension and chronic kidney diseases. Cor et Vasa. 2013;55(4):e397–e402. doi: 10.1016/j.crvasa.2013.07.006.
    1. Biwer L. A., D'souza K. M., Abidali A., et al. Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition. Hypertension Research. 2016;39:8–18. doi: 10.1038/hr.2015.107.
    1. Yu Q., Horak K., Larson D. F. Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodeling. Hypertension. 2006;48(1):98–104. doi: 10.1161/01.hyp.0000227247.27111.b2.
    1. Hale T. M., Robertson S. J., Burns K. D., deBlois D. Short-term ACE inhibition confers long-term protection against target organ damage. Hypertension Research. 2012;35(6):604–610. doi: 10.1038/hr.2012.2.
    1. Chou T. C., Yen M. H., Li C. Y., Ding Y. A. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension. 1998;31(2):643–648. doi: 10.1161/01.hyp.31.2.643.
    1. Francis S. H., Busch J. L., Corbin J. D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacological Reviews. 2010;62(3):525–563. doi: 10.1124/pr.110.002907.
    1. Fadel P. J. Nitric oxide and cardiovascular regulation. Hypertension. 2017;69(5):778–779. doi: 10.1161/HYPERTENSIONAHA.117.08999.
    1. Melikian N., Seddon M. D., Casadei B., Chowienczyk P. J., Shah A. M. Neuronal nitric oxide synthase and human vascular regulation. Trends in Cardiovascular Medicine. 2009;19(8):256–262. doi: 10.1016/j.tcm.2010.02.007.
    1. Rodriguez-Rodriguez R., Herrera M. D., De Sotomayor M. A., Ruiz-Gutierrez V. Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression. American Journal of Hypertension. 2007;20(7):728–734. doi: 10.1016/j.amjhyper.2007.01.012.
    1. Ajay M., Chai H. J., Mustafa A. M., Gilani A. H., Mustafa M. R. Mechanisms of the anti-hypertensive effect of Hibiscus sabdariffa L. calyces. Journal of Ethnopharmacology. 2007;109(3):388–393. doi: 10.1016/j.jep.2006.08.005.
    1. Lim Y. C., Budin S. B., Othman F., Latip J., Zainalabidin S. Roselle polyphenols exert potent negative inotropic effects via modulation of intracellular calcium regulatory channels in isolated rat heart. Cardiovascular Toxicology. 2017;17(3):251–259. doi: 10.1007/s12012-016-9379-6.
    1. Pechánová O., Dobešová Z., Cejka J., Kuneš J., Zicha J. Vasoactive systems in L-NAME hypertension: the role of inducible nitric oxide synthase. Journal of Hypertension. 2004;22(1):167–173. doi: 10.1097/00004872-200401000-00026.
    1. Santhanam L., Lim H. K., Lim H. K., et al. Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. Circulation Research. 2007;101(7):692–702. doi: 10.1161/circresaha.107.157727.
    1. Oliveira-Paula G. H., Lacchini R., Tanus-Santos J. E. Inducible nitric oxide synthase as a possible target in hypertension. Current Drug Targets. 2014;15(2):164–174. doi: 10.2174/13894501113146660227.
    1. Meira L. B., Bugni J. M., Green S. L., et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. The Journal of Clinical Investigation. 2008;118(7):2516–2525. doi: 10.1172/jci35073.
    1. Ghosh I., Poddar S., Mukherjee A. Evaluation of the protective effect of Hibiscus sabdariffa L. calyx (Malvaceae) extract on arsenic induced genotoxicity in mice and analysis of its antioxidant properties. Biology and Medicine. 2015;7(1):p. 218. doi: 10.4172/0974-8369.1000218.
    1. Abdul Hamid Z., Lin Lin W. H., Abdalla B. J., et al. The role of Hibiscus sabdariffa L. (Roselle) in maintenance of ex vivo murine bone marrow-derived hematopoietic stem cells. The Scientific World Journal. 2014;2014:10. doi: 10.1155/2014/258192.258192
    1. Machowetz A., Poulsen H. E., Gruendel S., et al. Effect of olive oils on biomarkers of oxidative DNA stress in northern and southern Europeans. The FASEB Journal. 2007;21(1):45–52. doi: 10.1096/fj.06-6328com.

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