Scholarly article on topic 'Antihypertensive effect of allicin in dexamethasone induced hypertension in rats'

Antihypertensive effect of allicin in dexamethasone induced hypertension in rats Academic research paper on "Veterinary science"

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{Allicin / Glucocorticoid / Dexamethasone / Hypertension / Nicorandil}

Abstract of research paper on Veterinary science, author of scientific article — Harikesh Dubey, Anamika Singh, Angad M. Patole, Chandrashekhar R. Tenpe

Abstract Background Glucocorticoid is among the most commonly prescribed medicine. Unfortunately, Excess glucocorticoid level leads hypertension in 80–90% patients. Garlic (Allium sativum) has been used since ancient times and even nowadays as a part of popular medicine for various ailments and physiological disorders. Hence this study was undertaken to investigate the antihypertensive activity of allicin in dexamethasone induced hypertension in wistar rats. Methods The animals were randomly divided into four groups comprising of six rats per group. Hypertension was induced by subcutaneous injection of dexamethasone (10μg/rat/day) in hypertensive rats. Two hypertensive group animals were treated with nicorandil (6mg/kg/day, po) and allicin (8mg/kg/day, po) respectively for 8 weeks. While systolic blood pressure (SBP) was measured by the tail-cuff method weekly up to 8 weeks. Results Dexamethasone treatment resulted in significant increase in SBP while allicin treatment significantly decreases the SBP. Thus, this study confirmed that allicin treatment for 8 weeks partially reverse dexamethasone induced hypertension in rats. Allicin treatment also attenuated dexamethasone-induced anorexia and loss of total body weight. Conclusion This result suggests antihypertensive effects of allicin in dexamethasone induced hypertension. However, further studies are needed to explore the detailed mechanism of antihypertensive effect of allicin.

Academic research paper on topic "Antihypertensive effect of allicin in dexamethasone induced hypertension in rats"

Accepted Manuscript

Title: Antihypertensive effect of allicin in dexamethasone induced hypertension in rats

Author: Harikesh Dubey Anamika Singh Angad M. Patole Chandrashekhar R. Tenpe

PII: S2213-4220(16)30087-7

DOI: http://dx.doi.org/doi:10.1016/j.imr.2016.12.002

Reference: IMR231

To appear in:

Received date: 4-8-2016

Revised date: 7-10-2016

Accepted date: 1-12-2016

Please cite this article as: Harikesh Dubey, Anamika Singh, Angad M.Patole, Chandrashekhar R.Tenpe, Antihypertensive effect of allicin in dexamethasone induced hypertension in rats, http://dx.doi.org/10.1016/jimr.2016.12.002

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Antihypertensive effect of allicin in dexamethasone induced hypertension in rats

Harikesh Dubey*1, 2, Anamika Singh1 , Angad M. Patole2, Chandrashekhar R. Tenpe2,

1. Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India.

2. Department of Pharmacology, Institute of Pharmaceutical Education and Research, Wardha 442 001, Maharashtra State, India.

* Corresponding author. Fax no: +91 7152241684

E-mail address: dubey.harikesh@gmail.com (H. Dubey).

1. Introduction

Glucocorticoid is among the most commonly prescribed medicine for asthma, rheumatological syndrome, eye disorder, skin disorder, organ transplant, glomerulopathies, malignancies, pain syndrome and other conditions1'2. Glucocorticoids have potent anti-inflammatory and immunosuppressant activities. Unfortunately, long term glucocorticoid therapy leads to hypertension and diabetic condition. 80-90% of glucocorticoid treated patients having Cushing syndrome, causes hypertension and abnormal glucose metabolism2'3. In current scenario we are looking for herbal drugs to avoid such adverse effects. The usage of herbal and nutritional supplements is widespread in all over the world. Now huge population of patients are using herbals drugs for cardiovascular diseases. Certain herbal drugs such as St. john's wort, yohimbine, licorice, ephedra, garlic etc have been in used for many decades for the treatment of hypertension4. However the underlying mechanism of action of herbal drugs is not clearly understood. Most prominent among these herbs commonly used Indian traditional spice is garlic, Allium sativum L. is a member of the Alliaceae family, has been used since ancient times and even nowadays is part of popular medicine for various ailments and physiological disorders5,6,7. Fresh garlic extract containing organosulfur compound (allicin), considered to be responsible for various pharmacological activities, including, antithrombotic, antidiabetic, antitumorigenetic antioxidant, anticarcinogenic, antiatherosclerotic and antihypertensive activities5'8'9'10'11'12. Therefore the aim of the present study was to explore the effects of allicin in treatment on dexamethasone induced hypertension in rats. Dexamethasone is most potent synthetic glucocorticoid which has virtually pure glucocorticoid activity1.

2. Material and methods

2.1 Animals

The Wistar rats (150-200 g) of either sex were used and each experimental group was comprised of 6 animals. Animals bred in the animal house of Institute of Pharmaceutical Education and Research (Reg. No.535/02/a/CPCSEA/Jan2002), Wardha (MS), India. They were housed under standard laboratory conditions. The rats were housed under standard laboratory conditions (22 ± 2 °C, 12 hours light/dark cycle) with free access to food (normal pellet diet) and water. The animals were treated in accordance with the CPCSEA guidelines. The experimental protocol was approved by the institutional animal ethics committee (IAEC) with the approval number 10/200910.

2.2 Chemicals

Dexamethasone and Nicorandil were procured from Zydus Cadila Healthcare Ltd. (Bangalore), Medreich Saimirra Ltd. (Chennai) respectively. All the other chemicals used for experimental purpose were of analytical grade.

2.3 Induction of hypertension

In the experimental rats, hypertension was induced by subcutaneous injection of Dexamethasone (10^g/kg/day) in the evening13,14.

2.4 Preparation of garlic aqueous extract

The garlic (Allium sativum L.) grown in Wardha, obtained from market. The garlic bulb was identified and authenticated by Dr. Alka Chaturvedi, "Post graduate Teaching Department of Botany, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, with a voucher specimen

(No.9803). The garlic bulbs were stored at 4 °C, and used for analysis within 30 day. Allicin containing garlic extract was prepared from 10 g of garlic cloves. The cloves were crushed with an electric vegetable crusher and the juice was poured in to a sterile centrifuge tube and centrifuged at 5000 rpm (3000g) for 10 min in order to separate the majority of the pulp from the supernatants liquid. The supernatants garlic extract (allicin) were either used immediately for activity or stored at 4°C, it was relatively stable during the weeks of the experiment. Accordingly animals were administered with 8mg/kg body wt of allicin15'16.

2.5 Analysis of allicin from fresh garlic extract

Allicin in the garlic extract (10, 20, 30 and 40pl of extract were used) was reacted with cysteine via the thiol-disulphide exchange reaction and the remaining cysteine was subsequently determined by reaction with Ellman's reagent 5, 5'-dithiobis-(2-nitrobenzoic acid) (DTNB) to produce the 2-nitro-5-thiobenzoate anion. Absorbance was taken at wavelength 412 nm. One mol of thiosulphinite reacts with 2 mol cysteine and since allicin makes up 60-80% of the thiosulphinates produced in garlic, multiplying the total thiosulphinate content by a factor of 0.7 gives the approximate allicin content15.

2.6 Experimental Design

Animals were randomly divided into four groups consisting 6 in each and assigned as follows. Animals in Group I (normal control rats) received 1 ml (po/day) 1% acacia gum suspension, Group II (hypertensive control rats) received 1 ml (po/day) 1% acacia gum suspension, animals in Group III (hypertensive rats), received nicorandil 1ml (6mg/kg/po/day) in 1% acacia gum suspension17, 18 and Group IV (hypertensive rats) animals received allicin 1 ml (8mg/kg/po/day) in 1% acacia gum suspension16 during the course of the entire study of 8 weeks.

2.7 Estimation of systolic blood pressure (SBP)

SBP measurements were recorded weekly by the same investigator, between 10 am and 12 noon, using the integrated BIOPAC and NIBP 200A system. The animal is placed in the restrainer (animal holder) leaving the tail outside and adjusted to the position where the animal has limited movements. The restrainer is placed in heating chamber and heated up to 32oC. BSL PRO software is used for recording of SBP. The basic software setup is done and IRSENSORS are calibrated prior to starting the measurement. IRSENSOR is then connected to the tail of the animal inside the restrainer. After the required setup and calibration of IRSENSORS, SBP was recorded.

2.8 Estimation of body weight, food and water intake

Body weight, food and water intake of each group animals were measured weekly up to 8 weeks.

2.9 Statistical Analysis

Statistical analysis was carried out by Two-way ANOVA followed by Bonferroni posttests. All values were expressed as mean ± SEM. All groups were compared with hypertensive control animals. P<0.05 was considered to be statistically significant.

3. Results

3.1 Quantification of allicin from fresh garlic aqueous extract Garlic extracts contained approximately 12.8mg allicin/ml.

3.2 Effect of allicin on SBP in hypertensive rats

Table 1, shows that SBP significantly (#P<0.05) increased in hypertensive control animals when compared with normal control group. Allicin treated animals were found to be significantly (*P<0.05) decreased when compared with hypertensive control group.

3.3 Effect of allicin on body weight

There were significant decrease in the body weight was recorded in all groups of dexamethasone treated animals. Hence all treated animals have not shown any significant changes when compared with group II (hypertensive control) animals. While group I (normal) animals significantly increases in body weight in 7th (*p < 0.05) and 8th (***p < 0.001) week (Table 2) as compared with group II (hypertensive control) animals.

3.4 Effect of allicin on food intake

There were no significant changes in the food intake were found in any group of animals till 7th week while in 8th week there were significant increase (*p < 0.05) in food intake recorded in group I (normal) and group IV (allicin treated) animals when compared with hypertensive control animals (Table 3).

4. Discussion

In the present study, we found that dexamethasone increased SBP in rats, and this hypertension was attenuated by the allicin, this result showed the antihypertensive effect of allicin. There have been various studies suggest that dexamethasone causes overproduction of reactive oxygen species (ROS) such as superoxide, interact with nitric oxide (NO) produced by the vascular endothelium, a vasodilator, causes nitric oxide-redox imbalance and reduce its bioavailability which may leads to hypertension 13, 14 19, 20, 21. Further dexamethasone can also block nitric oxide synthase gene expression at the transcriptional level 22. Thus,

dexamethasone can act by several pathways to deplete the supply of nitric oxide and consequently leads to vasoconstriction 23. Other possible explanations include dexamethasone increases the levels of enzymes such as angiotensin converting enzyme which is might be responsible for significant elevation of blood pressure24,25. The hypertensive effect of dexamethasone can be reduced by elimination of above risk factors via increases NO level and ACE inhibitor activity, free radical scavenges activities. It has been already established that antioxidants are effective in the treatment of dexamethasone induced hypertension. In the present study, the experimental animals of hypertensive groups such as group I (normal) and group IV (allicin treated) animals shows lower SBP (*P<0.05) when compared group II (Hypertensive Control) rats (Table 1).

Various mechanisms for antihypertensive effect of garlic has been reported including, reduction in vascular resistance and a subsequent fall in total peripheral resistance contributing substantially to the antihypertensive action by activating nitric oxide synthase, the enzyme which produces NO26,27. Further Park et al., (2016) reported that fermented garlic contain nitrite which is converted to NO in the body and increases protein kinase (PKG) and eNOS protein expressions in aortic tissues. This further leads to antihypertensive effects via sGC-cGMP-PKG pathway28. Also garlic (allicin) has antioxidant property, might be responsible for antihypertensive effect of allicin by lowering the level of oxidative stress in hypertensive rats consequently restoring nitric oxide-redox imbalance and increasing NO bioavailability26,27. Recently Hiramatsu et. al., (2016), reported that aged garlic extract (AGE) increases expression of nuclear factor erythroid 2-related factor 2 (Nrf2) which is responsible for antioxidant activity. They confirmed that AGE decreases oxidative stress and maintains cellular redox balance via Nrf2-antioxidant response element signaling pathway29. Further garlic has potent vasorelaxant activity and K+ channels opener activities which leads to vasodilation, thus exerting an antihypertensive effect5,6,11,30,31. This report was further

supported that allicin selectively open SUR2, type of K+ channel receptor, present in blood vessel, leads to dilation of blood vessels that may be a possible mechanism for antihypertensive activity of allicin32. Other studies also have revealed that fresh garlic extract (allicin) has inhibitory activity of angiotensin 1 converting enzyme and diuretic activity which may be involved in the antihypertensive action of garlic10,11,12,28,33,34. Previous evidence supports the theory that corticosteroids induce an imbalance between vasoconstriction and vasodilation, favouring vasoconstriction, resulting in hypertension34 Corticosteroids seem to negatively affect the production of other vasodilatory substances as well, such as prostaglandin I2 (PGI2), prostaglandin E2 (PGE2) and positive effect on vasoconstrictor PGs such as thromboxane-B2 in vascular endothelium35,36,37. Garlic causes more reduction in the synthesis of thromboxane B2 thereby reducing hypertension. Garlic also inhibited endothelin-1 induced contraction37,38. Recently a randomized database search clinical trial reports suggested that garlic is an effective and safe therapeutic approach for hypertension treatment39.

Also dexamethasone causes decrease in body weight and food intake. The possible mechanism could be dexamethasone increases leptin mRNA expression in the adipose tissue and induces long lasting hyperleptinemia in rats plasma leptin may play a role in dexamethasone-induced anorexia. Additionally, increased expression of monoamine oxidase A and 5-HT reuptake transporter genes by repeated dexamethasone appears to be implicated in decreases of the brain 5-HT level in hypothalamus40,41, synergistically low level of 5-HT and high plasma leptin level suppresses feeding and increases energy expenditure resulting loss of both fat and lean mass, may this mechanism involved in leading to reduction in total body weight and food intake in dexamethasone treated animals.

This study indicates that long term treatment with allicin containing garlic extract shows significant effect in reversing dexamethasone induced SBP as well as improves body weight

and food intake in dexamethasone induced hypertensive rats. However this study has some limitations and needs to explore the molecular mechanism involved in antihypertensive effects. Also it is already established that allicin is the major compound of garlic and all sulfoxides except cyloalliin are converted into allicin by enzymatic reactions42. Hence we need to evaluate the cyloalliin related activities. Further it is well documented that allicin has very short half life and it is difficult to maintain its long term therapeutic activities. There are some other compounds such as stable active metabolite of allicin may be is responsible for antihypertensive activity. Hence further study needs to explore the molecular mechanism and active molecule responsible for antihypertensive action.

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Table 1: Effect of allicin on Systolic blood pressure in hypertensive rats

Systolic blood pressure (mmHg)

Group(s) 0 Week 1st week 2nd Week 3rd Week 4th week 5th week 6th Week 7th week 8th week

I 109.5 ± 2.52 108.66 ± 1.56 105.00 ± 2.09 103.00 ± 1.21 99.83 ± 1.66 102.83 ± 2.57 100.16 ± 2.68 100.83 ± 3.17 101.16 ± 2.90

II 107.8 ± 2.34 119.0 ± 0.89 125.5 ± 1.11 130.5 ± 1.31 133.5 ± 0.84# 134.6 ± 0.49# 132.6 ± 1.33# 132.0 ± 0.85# 133.6 ± 0.80#

III 118.5 ± 1.25 113.0 ± 1.41 107.5 ± 1.23 110.5 ± 1.47 113.0 ± 1.36 109.3 ± 0.92 105.6 ± 0.66 110.8 ± 0.91 108.6 ± 0.98

IV 118.3 ± 2.18 112.3 ± 2.23 108.8 ± 2.41 108.1 ± 3.70 105.6 ± 4.06 104.5 ± 3.28* 102.0 ± 2.04* 100.1 ± 2.31* 103.8 ± 1.90*

Table: 1. Effect of allicin on Systolic blood pressure in hypertensive rats. Data expressed as Mean ± SEM. (n=6), Significance was determined by Two-way ANOVA followed by Bonferroni posttests. P< 0.05 was #

considered significant. p < 0.05 (group I vs group II), *p < 0.05 (group II vs group IV), All treated groups were compared with group II- Hypertensive Control animals. Group (I - Normal Control, II-Hypertensive Control, III- Nicorandil treated, IV-Allicin treated).

Table 2: Effect of allicin on body weight in hypertensive rats

Body weight (gm.)

Group(s) 0 1st 2nd 3rd 4th 5th 6th th 8th

Week week Week Week week week Week week week

I 160.33±10.50 163.33±12.80 165.83±11.30 168.00±9.70 170.17±9.58 179.00±8.70 193.50±10.65 205.17±13.80* 220.67± 12.60***

II 165.83±12.40 162.50±10.50 159.00±13.43 155.83±11.75 152.16±9.80 153.33±10.60 151.66±10.37 149.83±11.45 147.33± 8.32

III 164.67±18.90 160.16±16.55 156.66±13.34 153.66±15.87 151.83±10.84 149.16±9.60 150.83±12.53 148.66±11.55 148.16± 9.89

IV 165.83±17.70 163.16±15.66 160.83±12.74 158.66±11.95 155.50±14.75 153.00±10.55 150.50±9.50 147.33±11.43 144.83± 9.30

Table: 2. Effect of allicin on body weight in hypertensive rats. Data expressed as Mean ± SEM. (n=6), Significance was determined by Two-way ANOVA followed by Bonferroni posttests. P< 0.05 was considered significant. All groups were compared with group II- Hypertensive Control animals. Group (I - Normal Control, II- Hypertensive Control, III- Nicorandil treated, IV-Allicin treated).

Table 3: Effect of allicin on food intake in hypertensive rats

Food Intake (gm/day)

Group(s) 0 1st 2nd 3rd 4th 5th 6th th 8th

Week week Week Week week week Week week week

I 14.00± 3.91 13.00± 1.79 11.50± 1.64 9.00± 2.60 12.00± 2.39 10.60± 2.06 13.80± 1.62 15.60± 1.60 17.30± 1.17*

II 12.30± 2.67 8.50± 1.48 9.00± 2.12 10.00± 2.77 6.50± 1.71 8.30± 1.83 11.40± 1.92 9.20± 1.51 7.80± 1.84

III 15.30± 1.98 9.33± 1.57 9.00±1.74 8.33± 2.09 10.50± 2.48 8.50± 3.43 11.20± 3.22 15.00± 4.37 13.66± 3.11

IV 18.30±17.70 12.60± 1.96 7.90± 1.55 8.00± 2.34 7.66± 1.68 11.33± 2.05 13.40± 1.47 15.70± 1.31 17.66± 2.80*

Table: 3, Data expressed as Mean ± SEM. (n=6), Significance was determined by Two-way ANOVA followed by Bonferroni posttests. P< 0.05 was considered significant. All groups were compared with group II- Hypertensive Control animals. Group (I - Normal Control, II- Hypertensive Control, III- Nicorandil treated, IV-Allicin treated).