1 INTRODUCTION
Hypertension is mainly responsible for 45% of deaths in ischemic heart disease and 51% of deaths in stroke. Based on WHO data collected in 2008, it was found that about 40% of adults older than 25 years old had been diagnosed with hypertension.
The highest prevalence of hypertension, 37%, was found in southeast Asia region. Based on the measurement of blood pressure in patients older than 18 years old, the prevalence of hypertension in Indonesia is 25.8%. However, based on the diagnosis of health workers or medication record, the prevalence is only 9.5% (Health of Ministry, 2014).
Traditional medicine or herbal medicine is vastly used as an alternative medicine for the treatment of hypertension. Most People consider herbal remedies could reduce the side effects of the medicines and increase the efficacy of the treatment (Inamdar et al, 2008). The use of herbal medicines is generally not supervised by the physician or pharmacist. Herbal remedies derived from plants have many secondary metabolites that are likely to cause interaction when used together with synthetic drugs. The interaction may involve the components contained in plants that
can cause an increase or decrease in the effect of conventional drugs (Staines, 2011). The recent study reported an interaction of Ginkgo plant with thiazide diuretics which causes an increase in blood pressure.
Co-administration of liquorice and antihypertensive drugs cause hypokalemia (Izzo, 2012).
Interactions between herbal and synthetic drugs can be classified as pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions implicate the absorption, distribution, metabolism, and excretion of a drug that can be seen from the changes in the pharmacokinetic profile of the drug. The pharmacodynamic interaction includes additive and antagonistic interactions. Additive interaction leads to the enhancement of the main effect of the drug when herbal medicine and conventional drug are taken together. On the other hand, antagonistic interaction is when the main effect is reduced due to consumption of other drug or herbal medicine (Staines, 2011).
Captopril, the first drug from the class of angiotensin-converting enzyme (ACE) inhibitors, works by preventing the changes of angiotensin I to angiotensin II, a potential vasoconstrictor and an aldosterone secretion stimulant. ACE inhibitors prevent the degradation of bradykinin and stimulate
Interaction between Apium graveolens L. and captopril in hypertension therapy
Siska
Faculty of Pharmacy, University of Indonesia
Faculty of Pharmacy and Science, University of Muhammadiyah Prof.Dr.Hamka
F. D. Suyatna
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Indonesia
A. Mun`im
Faculty of Pharmacy, University of Indonesia
A. Bahtiar
Faculty of Pharmacy, University of Indonesia
ABSTRACT: Use of herbal medicines among patients who are undergoing treatment of hypertension occurs without consultation with physician or pharmacist. This study aimed to determine the interaction of herbal medicine (celery extract) with antihypertensive drugs (captopril, propranolol, and hydrochlorothiazide). This study used white male rats (n = 25) divided into 5 groups. Group I (normal control), group II (negative control), Group III (captopril dose of 0.25 mg/kg), Group IV (celery extract dose of 10 mg/kg), group V (combination of extracts celery and captopril). Induction of hypertension was performed by giving 4% NaCl for 2 weeks and continued throughout the study. The extract and antihypertensive drug were given for 2 weeks. Systolic blood pressure compared between normal, after induction, and after treatment with the extract and/or antihypertensive drug. Results, analyzed using one-way ANOVA (ρ<0.05), showed significant differences. Captopril, celery extract, and combination groups lowered systolic blood pressure by 22.22%, 15.88%, and 27.00%, respectively. Celery extract combined with antihypertensive medicine captopril lowered systolic blood pressure greater than the single treatment of each.
Keywords: drug interaction, captopril, Apium graveolens L., herbal medicine
the synthesis of other vasodilators including prostaglandin E2 and prostacyclin, stimulates vasodilation, and decrease secretion of aldosterone, which in turn causes sodium and water excretion, and potassium retention. As a result, a decline in blood pressure in patients with hypertension (Brunton, 2011). This class of drug is recommended in the National Formulary for patients with mild to moderate hypertension (Health of Ministry, 2015).
Similar to captopril, Apium graveolens Linn or celery is believed to lower blood pressure in patients with hypertension. The previous study reported that the celery plant contains terpenoids and flavonoids compounds (Yao et al, 2010 and Zhou et al, 2009).
Flavonoid compounds reported having an activity as anti-atherosclerosis, anti-inflammatory, antioxidant and antihypertensive (Groos, 2004). The previous research reported that apigenin isolated from Apium graveolens relaxes the aorta in mice in vitro (Feng et al, 1991 and Jin et al, 2009). Ethyl acetate extract of Apium graveolens has vasorelaxation effect on isolated rat aorta (Jorge et al, 2013). Apigenin lowers blood pressure of anesthetized dogs and rats from 120 mmHg to 70 mmHg when given at dose 10 mg/kg (Hapsari, 2006). It is reported that the ethanol fraction root Apium graveolens lowers blood pressure of hypertension-induced rats and is comparable to captopril dose of 2.5 mg/kg (Siska et al, 2011).
Based on the argumentations above, it is possible that taking herbal medicine together with captopril may lead to interaction. However, information on the interactions between herbal remedies with synthetic drugs is still limited (Gohil and Patel, 2007). Thus, the research to examine the effect of celery extract treatment on antihypertensive effect of captopril is needed.
2. MATERIALS AND METHODS 2.1 Materials
Celery herb (Apium graveolens L.) was collected from Research Centers Spices and Medicinal Plants. The plant was identified at The Research Center For Biology, Indonesian Institute of Sciences. Male rats strain Sprague-Dawley from Bogor Agriculture Institute were used. Ethanol 50%
and NaCl technical level were purchased from PT Brataco, Jakarta. Captopril, propranolol, and hydrochlorothiazide were purchased from PT Kimia Farma, Bandung. Blood pressure apparatus used in this research were Coda non-invasive blood pressure from Kent Scientific.
2.2 Methods
2.2.1 Extract Preparation
Preparation of celery extract was started with collecting the fresh celery herb (15 kgs).
Determination of plants was conducted to determine the classification of the plants (Sarker et al, 2006).
After washing to remove dirt, a small cut of Simplicia was dried at room temperature, or in the oven, to prevent microbial fermentation and degradation of metabolites, and to minimize chemical reactions that are induced by ultraviolet rays from direct sunlight. The dried celery powder was then macerated repeatedly (3 × 5 L) using 50%
ethanol for 2 days at room temperature. Once extraction is complete, extract separated by filtration using filter paper and the filtrate was evaporated with vacuum rotary evaporator. The viscous extract obtained is collected and stored at 4 °C before use (Johnson et al, 2014).
2.2.2 Phytochemical Screening
Extract of Apium graveolens Linn was qualitatively analyzed for flavonoids, alkaloids, triterpenoids, tannins, and saponins by following the standard phytochemical procedures (Health of Ministry, 1995).
2.2.3 Test activities of antihypertensive
This research used albino male rats (n = 25) divided into 5 groups. Group I (normal control), group II (negative control), Group III (captopril dose of 0.25 mg/kg), Group IV (celery extract dose of 10 mg/kg), Group V (combination of extract and captopril). Induction of hypertension was conducted using treatment with 4% NaCl for 2 weeks and continued throughout the study. The extract and antihypertensive drugs were given for 2 weeks.
Measurement of systolic blood pressure was performed using Coda non-invasive blood pressure (Kent Scientific) for 3 times, the baseline blood pressure before treatment, after induction with NaCl 4% for 2 weeks, and after the treatment with the extract and/or captopril.
The use of animal experiments in this study was approved by the Health Research Ethics Committee of the Faculty of Medicine, University of Indonesia No. 666 / UN2.F1 / ETHICS / 2016.
2.2.4 Data analysis
The average systolic blood pressure was statistically analyzed using one-way ANOVA test to measure the significant differences between treatment groups. Subsequently, statistical analysis was performed using LSD to examine the difference between each treatment group.
1.28 2.58
22.22
20.48 27
0 5 10 15 20 25 30
I II III IV V
% of SBP decrease
Treatment groups
3. RESULTS AND DISCUSSION
The results of the identification of secondary metabolites showed that celery extract contains flavonoids, alkaloids, tannins, triterpenoids and saponins (Table 1). Induction of hypertension by using NaCl 4% w/v orally for 2 weeks increased systolic blood pressure by 42.25% as compared to the baseline systolic blood pressure. NaCl consumption increases the concentration of sodium in the body. Excess salt in the fluid extracellular increases fluid osmolality and this situation may stimulate thirst centers in the brain causes the craving to drink more water to restore normal extracellular salt concentrations (Dipiro et al, 2006).
Increased osmolality caused by excess salt in the extracellular fluid also stimulate the hypothalamic- pituitary gland to secrete more posterior antidiuretic hormone. Antidiuretic hormone then causes the kidneys to reabsorb water in bulk from the renal tubular fluid, thereby reducing the volume of urine excreted but increase in extracellular fluid volume (Dipiro et al, 2006).
Table 1: Results of phytochemical screening of ethanol 50%
celery extracts
Statistical analysis of systolic blood pressure showed a decrease in blood pressure of hypertensive rats treated with captopril, extract celery and combination of celery with captopril (p <0.005;
Table 2; Figure 1). Captopril dose of 2.5 mg/kg, celery extract dose of 10 mg/kg, and the combination of captopril with celery extract decreased systolic blood pressure by 22.22 %, 20.48
%, and 27.00 %, respectively. Celery extract lowered systolic blood pressure better than the captopril-treated group. The group treated with a combination of captopril and celery extract showed a decrease in systolic blood pressure greater than that of captopril and celery extract alone. This suggests the possibility of an increased efficacy when captopril combined with celery extract.
Captopril is an antihypertensive drug that works by blocking the angiotensin-converting enzyme (ACE). Inhibition of this enzyme would reduce levels of angiotensin II and inhibits the inactivation of bradykinin, a potent vasodilator that works by stimulating the release of nitric oxide, prostaglandin
E2 and prostacyclin (Carey and Siragy, 2003).
Angiotensin II is a potent vasoconstrictor that also stimulates the release of aldosterone. Inhibition of angiotensin II lowers blood pressure mainly by reducing peripheral vascular arrest (Mackraj et al, 2008).
Table 2: Average percentage decrease in systolic blood pressure in hypertensive rats after treatment with extract celery and captopril.
Group % Average decrease in
blood pressure
I (Normal control) 1.28 %
II (Negative control) 2.58 %
III (Captopril) 22.22 %
IV (Celery extract) 20.48 %
V (Captopril & Celery extract) 27.00 %
Figure 1. Percentages of the average decrease in systolic blood pressure (SBP) of (I) normal, (II) negative control, (III) captopril, (IV) celery extract, (V) combination.
Celery ethanol fraction which contains flavonoids that were reported as potential cardioprotective antioxidants (Mackraj et al, 2008). Flavonoids improve endothelial function of hypertensive rats, which is caused by its antioxidant and vasodilation activity (Machha and Mustafa, 2005). Other researchers have reported that the water and ethanol extracts of Apium graveolens dose of 0.5 to 15 mg/kg administered intravenously lower blood pressure in the rabbit with ethanol extract exhibits the largest decline in blood pressure (Al-Snafi, 2014). Ethyl acetate fraction of Apium graveolens has been reported to exhibit the vasorelaxant effect on isolated rat aorta (Jorge et al, 2013). Apigenin, one of flavonoid isolated from Apium graveolens, has been reported to relax the aorta of mice in vitro (Feng et al, 1991 and Jin et al, 2009).
The interaction performed by co-administration of celery extract and captopril simultaneously can increase systolic blood pressure lowering effects.
This is probably due celery extract contains chemical compounds having antihypertensive
Phytochemical Celery extracts
Alkaloids +
Flavonoids +
Saponins +
Tannins +
Triterpenoids +
activity and work synergistically with captopril in reducing blood pressure through different mechanisms. It has been reported that celery juice inhibits the cytochrome P450 (Jakovljevic et al, 2002), which possibly causes interaction with the drugs metabolized by the enzyme, including antihypertensive drugs (Winitthana et al, 2009).
Enzyme P450 plays a role in the process of drug
metabolism, the enzyme inhibition leads to the reduction in drug metabolism (Burnett et al, 2011).
It is possible that the metabolism of captopril decreases when captopril and celery extract are taken together, which may lead to the increase in captopril level in blood and in turn increase the systolic blood pressure lowering effect.
4. CONCLUSION
The results of the present study provide valuable information and supporting data to the toxicity study and pharmacokinetic interaction study in the future.
ACKNOWLEDGMENT
We have greatly appreciated the financial support from Ministry of Higher Education Republic of Indonesia.
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