|Ahead of print publication
Long-term administration of Ziziphus jujuba extract attenuates cardiovascular responses in hypertensive rats induced by angiotensinii
Reza Mohebbati1, Maryam Rahimi2, Kosar Bavarsad2, Mohammad Naser Shafei3
1 Department of Physiology, Faculty of Medicine; Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Mohammad Naser Shafei,
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad
Source of Support: None, Conflict of Interest: None
Objective: The fruit of Ziziphus jujuba (ZJ) traditionally has been used for the treatment of hypertension in Iran. The mechanism of this effect of ZJ is unknown but may be mediated via an effect on the renin-angiotensin system (RAS). This study evaluates the effect of hydroalcoholic ZJ extract on acute hypertension induced by angiotensinII (AngII), a main product of RAS. Materials and Methods: Animals were divided into six groups; 1) saline, 2) AngII that received (50 ng/kg) intravenously (i. v.), 3) Losartan (Los, 10 mg/kg) +AngII group that received Los (i.v.) before AngII and 4-6) three groups of ZJ (100, 200 and 400 mg/kg) that were treated four weeks by gavage and on 28th day of experiment received AngII (i. v.). Cardiovascular responses were recorded by cannulation of the femoral artery and drug injection done via the tail vein. Systolic blood pressure (SBP), Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously by power lab system. Maximal changes (Δ) of SBP,MAP and HR were calculated and compared with those of control and AngII groups. Statistical analysis was performed by one-way ANOVA. Results: In AngII group maximal Δ SBP, ΔMAP significantly increased than in control but ΔHR was not significant. Pretreatment of two lower doses (100 and 200 mg/kg) of ZJ significantly attenuate increased ΔSBP and ΔMAP induced by AngII. In contrast pretreatment with a higher dose (400 mg/kg) significantly increased the ΔSBP and ΔMAP compared to AngII group. The ΔHR only in dose 200 mg/kg was significantly lower than AngII group. Conclusion: Consistent with the traditional view, the results indicate that ZJ extract has an antihypertensive effect, and effect of its lower doses partly mediated by an inhibitory effect on RAS.
Keywords: Angiotensin II, heart rate, mean arterial pressure, renin-angiotensin system, Ziziphus jujuba
|How to cite this URL:|
Mohebbati R, Rahimi M, Bavarsad K, Shafei MN. Long-term administration of Ziziphus jujuba extract attenuates cardiovascular responses in hypertensive rats induced by angiotensinii. Ancient Sci Life [Epub ahead of print] [cited 2019 Mar 22]. Available from: http://www.ancientscienceoflife.org/preprintarticle.asp?id=252116
| Introduction|| |
Ziziphus jujuba (ZJ) is a member of the Rhamnaceae family that is distributed in the subtropical and tropical areas of Asia and has well-known therapeutic effects., In China, the fruit of ZJ is commonly used as an antidote for snake venom. In Iranian traditional medicine ZJ is administrated for the treatment of gut problems such as ulcers. The people in the Southeast and East of Iran have used the stem and fruit of ZJ to treat digestive disorders and as a laxative, antitussive and hypotensive agent., In addition, local traditional healers use the stem bark powder and leaves of ZJ to cure wounds., In ancient Chinese works on herbal medicine, ZJ has been described as one of the five most valuable fruits that have effects such as blood nourishing and improving quality of sleep. In the recent years fruit, leaves, bark and seeds of ZJ plant have been used in the treatment of several diseases such as hypoglycemia, cancer, depression, anxiety, and diarrhea. Several effects such as antioxidant, anti-inflammatory, antispastic, antiulcer and diuretic are also attributed to ZJ. The main compounds of ZJ are various vitamins including C and E, flavonoids, triterpene acids, phenols, polysaccharides, saponins and glycosides., The effect of ZJ on cardiovascular system has been reported. In a previous study, it has been shown that ZJ stimulates the release of nitric oxide (NO) from cultured endothelial cells. The ZJ also have several active compounds such as jujuboside A/B and saponin as a flavonoid that plays important role in cardiovascular regulation.,
The renin-angiotensin system (RAS) is a well-known system that has physiological and pathophysiological effects on the cardiovascular system. The main product of RAS is AngiotensinII (AngII) that has various effects on the cardiovascular system such as vasoconstriction and induction of vascular smooth muscle proliferation. It has been thought that the predominant acute effect of AngII on vascular is vasoconstriction that is mediated via angiotensin type-1 receptor (AT1). In addition, the systemic synthesis of AngII which is also synthesized in multiple tissues such as kidney, heart, and brain may be involved in cardiovascular regulation. Activation of RAS induces hypertension and drugs that have an inhibitory effect on RAS are important in the treatment of hypertension. There are studies which show that medicinal plants by their effect on RAS and AngII can produce beneficent effects on hypertension. Although the hypotensive effect of ZJ has been reported but its mechanisms are unknown. In this study, we investigated the effect of hydroalcoholic extract of ZJ on blood pressure and HR in acute AngII hypertensive rats.
| Materials and Methods|| |
ZJ Fruit provided from an herb store in Birjand city, East of Iran, and identified by botanists in Herbarium of the Ferdowsi University of Mashhad, Iran. About 100g of dried fruit without seed was powdered, ground and then macerated in 1 liter of 70% ethanol and shaken for 72 h at 37°C. After that, the mixture was filtered with different sized sieves. The solvent was evaporated using an oven at 40°C.
Animals and surgery
Animals were kept at standard conditions. The animals were anesthetized with urethane (1.5 g/kg, i. p). After that, the left femoral artery was cannulated with a polyethylene catheter (PE-50) filled with heparinized saline, the catheter connected to a blood pressure transducer and blood pressure (BP) and heart rate (HR) were continuously recorded by a power lab system (ID instrument, Australia). The tail vein was also cannulated for drug injection.
Drug and animal groups
The drugs used included urethane, AngII, and Losartan (Los) manufactured by Sigma, USA. All drugs were dissolved in saline.
Animals were divided randomly into six groups as follows (n = 7 in each group):
- Control – received saline (i.v.)
- AngII – received AngII (50 ng/kg, i.v.)
- Los – received Los (10 mg/kg, i.v.) before injection of AngII
- 4, 5 and 6. ZJ 100, 200 and 400 – received 100, 200 and 400 mg/kg of extract orally for four weeks and on the day of the experiment received AngII.
The AngII group received AngII (50 ng/kg) intravenously (i. v.), in Los group Los (10 mg/kg, i. v.) was injected before AngII. In the ZJ groups rats were separately treated with three doses of hydroalcoholic extract of ZJ (100, 200 and 400 mg/kg) by gavage for four weeks. On the day of the experiment (28th day) after cannulation, the AngII was injected. In all the groups, systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were recorded throughout the experiments.
The changes (Δ) of MAP, SBP and HR values were calculated and were expressed as mean ± standard error of means (SEM). Statistical analysis was performed by one-way ANOVA followed the Tukey's post hoc test using SPSS version 11.5. A value of P < 0.05 was used to indicate statistical significance.
| Results|| |
After a stabilizing time of 15 min, saline was injected intravenously and cardiovascular responses were recorded. Injection of saline had no significant effects on SBP (before: 122.5 ± 10 mmHg and after: 123.3 ± 9.9 mmHg), MAP (before: 114.3 ± 9.5 mmHg and after: 115 ± 8.9 mmHg) and HR (before: 332.8 ± 15.5 beats/min and after: 336.1 ± 19.7 beats/min).
In AngII group, AngII (50 ng/kg; i. v.) slowly perfused and cardiovascular parameters were recorded. The changes of SBP and MAP after injection of AngII have been shown in [Figure 1]a and [Figure 1]b. As has been shown, changes of ΔSBP and ΔMAP significantly increased compared to control group (ΔSBP: AngII: 53.4 ± 4.9 vs Control: 1.5 ± 2.3, and ΔMAP: AngII: 43.3 ± 3.7 vs Control: 1.6 ± 1.6; P < 0.001). The HR also decreased compared to control group but it was not significant [ΔHR; AngII:-21.8 ± 13.6 vs Control: 4.1 ± 3.4 beats/min, [Figure 1]c.
|Figure 1: Effects of AngII (50 ng/kg; intervenes) and AngII + Los (10 mg/kg) on SBP (a), MAP (b) and HR (c) in anesthetized rats. The data were compared with Control group and expressed as mean ± standard error of the mean. One-way ANOVA used for Statistical analysis. ***: P <0.001 compared to control, #: P <0.05, ##: P <0.01 compared to AngII. SBP: Systolic blood pressure, MAP: mean arterial pressure, HR: heart rate|
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In Los group, Los was injected (10 mg/kg, i. v.) before AngII. The Los ameliorated increased cardiovascular responses induced by AngII. [Figure 1]a and [Figure 1]b shows the effect of Los on increased SBP and MAP induced by AngII. As has been shown, pre-treatment with Los could significantly attenuate the effect of AngII on cardiovascular parameters.(ΔSBP, Los + AngII: 23.7 ± 1.6 vs AngII: 53.4 ± 4.9; P < 0.01 and ΔMAP; Los + AngII: 19 ± 0.8 vs AngII: 43.3±0.7; P < 0.05). The changes of HR in Los + AngII group also were lower compared to AngII group but not significant [ΔHR: Los + AngII:-14.7 ± 3.8, AngII:-21.8 ± 13.6, [Figure 1]c. The HR changes in Los + AngII group also was not significant than the control group.
In ZJ 100 mg/kg + AngII group, ΔSBP and ΔMAP significantly decreased compared to the AngII group [ΔSBP: 18.4 ± 5.3 vs AngII: 53.4 ± 4.9 and ΔMAP; 17.1 ± 4.9 vs AngII: 43.3 ± 3.7; P < 0.001 to P < 0.01; [Figure 2]a and [Figure 2]b. The changes of HR in this dose were not significant than the AngII alone [ΔHR: 11.7 ± 10 vs AngII:-21.8 ± 13.6, [Figure 3]c.
|Figure 2: Effects of the hydroalcoholic extract of ZJ on cardiovascular parameters in AngII hypertensive rats. Rats treated with three doses of ZJ (100, 200, 400 mg/kg) for four weeks then AngII injected and cardiovascular responses determined. The data were compared with AngII group and expressed as mean ± SEM. One-way ANOVA used for Statistical analysis. #: P <0.05, ##: P <0.01, ###: P <0.001compared to AngII. SBP: Systolic blood pressure, MAP: mean arterial pressure, HR: heart rate|
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|Figure 3: Effects of the hydroalcoholic extract of ZJ on body weight of rats after four-week treatment. One-way ANOVA used for Statistical analysis. **: P <0.01, ***: P <0.001 compared to control group|
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In ZJ 200 mg/kg + AngII group, ΔSBP and ΔMAP significantly decreased compared to AngII group [ΔSBP: 27.1 ± 7.1 vs AngII: 53.4 ± 4.9 and ΔMAP; 23.7 ± 6.1 vs AngII: 43.3 ± 3.7; P < 0.05; [Figure 2]a and [Figure 2]b. The changes of HR in this dose were significant than AngII alone [ΔHR: 22.9 ± 9.3 vs AngII:-21.8 ± 13.6 ; P<0.05, [Figure 3]c.
In ZJ 400 mg/kg AngII group, ΔSBP and ΔMAP significantly increased compared to AngII group [ΔSBP: 101.2 ± 11.2 vs AngII: 53.4 ± 4.9 and ΔMAP; 80.3 ± 10.3 vs AngII: 43.3 ± 3.7; P < 0.001; [Figure 2]a and b] the changes of HR in this dose were not significant than AngII alone [ΔHR: 18.3 ± 15.3 vs AngII:-21.8 ± 13.6, [Figure 3]c.
The body weight in all treated animals with extract increased. However, change in rats receiving doses of 200 and 400 mg/kg were significant compared to the control group [P < 0.01 to P < 0.001; [Figure 3].
| Discussion|| |
This study shows that intravenous injection of AngII increased SBP and MAP and decreased HR. Two lower doses of hydroalcoholic extract of ZJ (100 and 200 mg/kg) significantly attenuated cardiovascular responses of AngII but higher dose (400 mg/kg) significantly potentiate these effects of AngII.
RAS is one of the important systems that play a critical role in cardiovascular regulation. Important product of RAS is AngII and most properties of RAS is attributed to AngII action. The effects of AngII on the cardiovascular system is complicated and mediated by both peripheral and central mechanisms. The peripheral effect of AngII is vasoconstriction that is mostly mediated by AT1 receptor. AT1 via cellular signaling pathways stimulates phospholipase C and phosphatidylinositol that result in enhancement of intracellular free calcium concentration and after that activate protein kinase C (PKC). PKC action increases the intracellular free concentrations of Ca2+ and activates several enzymes that have a tyrosine kinase action. The above pathways of AT1 increase smooth muscle contraction. Concomitant with this result, our finding also shows that Los, an antagonist of AT1, significantly ameliorates the effect of AngII on the cardiovascular system.
Treatment of animals for 4 weeks with two lower doses (100 and 200 mg/kg) of ZJ significantly attenuate the effect of AngII on MAP and SBP that is comparable with Losartan. Therefore, his effect of ZJ may be mediated by the direct inhibitory effect of the extract on AT1 receptors on smooth muscle of vessels. In addition, the presence of AT1 receptor in endothelium and its involvement in production agents such as NO, prostaglandins and endothelin has been indicated. We suggest that ZJ extract by inhibition of AT1 in endothelium, reduces production of prostaglandins and endothelin agents and causes vasodilator effect. However, future studies are needed to evaluate this opinion.
Inhibitory effect of ZJ on cardiovascular is attributed to compounds such as flavonoids, jujubosides, and saponins. Jujubosides have a relaxant effect on vessels and significantly reduce arterial blood pressure in the spontaneous hypertensive rat. The study shows that jujuboside B reduces vascular tension by increasing Ca2+ influx and activating endothelial NO synthase. Flavonoids have an inhibitory effect on angiotensin-converting enzyme (ACE) that has a critical role in the production of AngII and regulation of BP. The function of this enzyme is converting angiotensinI (AngI) to AngII. Therefore, one of the therapeutic lines for hypertension treatment is the usage of ACE inhibitors. Flavonoids as main compounds of ZJ also may have a hypotensive effect via inhibition of ACE and decrease the production of AngII.
Saponins are another active biological compounds of ZJ. These have a lowering effect on blood pressure that is supported by phytomedicine studies., The possible suppressing mechanism of saponins on vascular system is mainly via increasing of NO production in vascular bed.
AngII is a potent mediator of oxidative stress that results in endothelial dysfunction by NO scavenging. Hypertension induced by AngII is related with the increase of reactive oxygen species (ROS) such as superoxide and hydroxyl radicals' production in endothelium that impairs the vasorelaxation response of vessels to acetylcholine. It is possible that ZJ extract via its antioxidant effect, ameliorates the inhibitory effect of Ang II on NO production and has a beneficial effect on cardiovascular system.
AngII also has an excitatory effect on the sympathetic nervous system and aldosterone secretion that elicit cardiovascular responses. There are pieces of evidence that AngII enhances release of norepinephrine. AngII also are said to stimulate adrenal medulla increasing catecholamine secretion. It is reported that AngII also has a central effect on the sympathetic system. The possible area is area postrema, a circumventricular organ located in the medulla. It is possible that extract of ZJ centrally decreases AngII activity and reduces sympathetic activity.
AngII in dose 50 ng/kg decreased the HR but this effect was not more significant than saline. Bradycardia effect of AngII is mostly related to baroreflex activity. In this reflex, the HR diminishes as blood pressure increases. In addition, HR decreases via an AT2 receptor that has a negative chronotropic effect. The ZJ extract increases HR and this effect in a dose of 200 mg/kg was significant. This effect of ZJ is unknown and need future studies. However, we suggest that the extract may act by an inhibitory effect on the parasympathetic system or inhibition effect of AT2 increases HR. In a previous study, we used a dose of 300 ng/kg that increased HR. However, dose 300 ng is high therefore in this study we used a lower dose (50 ng/kg) that is near to physiologic dose.
In this study, higher dose of extract 400mg/kg significantly increased cardiovascular parameters. The mechanism of this effect is not determined. However, AT1 receptors activation results in vasodilator agent's production include NO and prostacyclin (PGI2), which counteract the direct vasoconstrictor effects of AngII on the adjacent smooth muscle cells. Hence, high dose of ZJ can impair the balance between vasoconstriction and vasorelaxation with high tendency to affect vasoconstriction effect of AngII.
Our previous study (unpublished data) also showed that in the normotensive rats, the cardiovascular effect of higher dose (400 mg/kg) of ZJ is lessened than that of a lower dose (100 mg/kg) that confirm our result in this study.
According to changes in weight in ZJ treated rats dose dependency was observed. Increased appetite in rats suggested that treatment with ZJ extract may be the cause of weight gain.
| Conclusion|| |
The results confirm the traditional view of the hypotensive effect of ZJ. Because lower doses (100 and 200 mg/kg) of ZJ suppress cardiovascular responses induced by AngII, we suggest that cardiovascular effect of ZJ at least partially is mediated by its inhibitory effect on RAS.
We would like to thank the Research Council of Mashhad University of Medical Sciences for their financial support. Also, we would like to thank the Dr. Rakhshandeh and Miss Aghaei for their help in plant extraction.
Financial support and sponsorship
Conflicts of interest
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