Background and Objectives: Herbal medicines are recommended as remedy for different cardiac diseases. Acacia possessing significant pharmacological activities, widely found in KSA. The effect of Acacia tortilis leaves decoction (ATLD) on cardiac hemodynamics was evaluated in rats. Methods: Different hemodynamic parameters (systolic, diastolic, mean arterial blood pressure and heart rate) were recorded in normotensive rats before and after the intravenous administration of ATLD. Results: The different doses showed a dose dependent significant hypotensive effect. However the highest dose (30 mg kg1) showed maximum activity and lowered the systolic pressure (17.4±2.95%), diastolic blood pressure (15.2±1.8%) and mean arterial blood pressure (17.1±2.4%). Intravenous administration of ATLD also showed a dose-dependent reduction in heart rate (p<0.001). Conclusion:The hypotensive and bradycardia might had been due to presence of N,N Dimethyltryptamine in extract that reduced the blood pressure and heart rate. Thus, the authors conclude that the ATLD possesses potent hypotensive activity and sought to be useful for anti hypertensive drug development and worth much merit to be investigated.
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Blood pressure is the normal force produced by heart, exerted by blood against the walls of the arteries. Blood pressure varies normally throughout the day1, but continuous blood pressure elevation can cause health problems. Pathophysiology of hypertension in perspective to pharmacological studies have been carried out in recent years2-5. The British Hypertension Society guidelines proposed that changes in lifestyle can be helpful for the primary prevention of hypertension6. However, hypertensive patients need proper treatment if systolic/diastolic blood pressure is greater than 160/90 mmHg7. Hypertension is one of the most common chronic medical problem that requires adequate management. Hospital appointments, diagnostic laboratory tests and treatment charge about $420 per year8. During 2010, the mean expenditure per person for treatment for hypertension was somewhat higher (for women: $751 and men: $713) as reported9. Hypertension is continually increasing in Kingdom of Saudi Arabia (KSA)10. The Global Burden of Disease estimates that hypertension was the leading risk factor for death in KSA11. In KSA, 81% of the population is under the age of 4010. The burden of hypertension in future will become major health problem to the health system. Thus searching for new low cost hypertensive drug is necessary12. Herbal medicines are recommended for the treatment of different diseases especially in Europe, Middle East and Asia. Scientists agree with some aspects of traditional use of herbal drugs and plants as remedy for different cardiac diseases (hypertension). Few of these are Hibiscus sabdariffa L.13, Tribulus terrestris14, Persea Americana15, Tropaeolum majus L.16. Search for new anti hypertensive drugs continue that can counter the currently available high cost medicines and other drugs with little efficacy. Acacia possessing significant pharmacological activities is one of the 86 different medicinal species reported more than a decade ago in KSA17. The literature reveals anti diarrhoeal and antimicrobial activity of Acacia nilocita18,19, antioxidant activity of Acacia confusa, Acacia seyal and Acacia laeta20,21, antidiabetic activity of Acacia ataxacantha 22. Fortunately, the species of acacia (Acacia tortilis) are widely found in Saudi Arabia especially in Makkah region. However, acacia plant in KSA is only contributing to form a good habitat for the honey bee that produces good quality honey: marketably known as acacia honey. Acacias widely spread in KSA have numerous uses and values. Now a days home remedies and use of plants to cure different diseases are becoming more popular in people beside pharmaceutical market. Hypoglycemic and hypocholesterolemic activity23, diazepam like activity24, neuroprotective and anticonvulsant activity25 of Acacia tortilis has recently been investigated in KSA. It is quite interesting to mention that Acacia tortilis have not yet been scientifically screened for hypotensive and anti hypertensive activity and mechanism of action and safety. Hence, it is quite fascinating to search thoroughly the influences and efficacy of this plant especially in cardiology/cardiovascular system disorders. The present part of this project using relevant methods, procedures and instruments mentioned in the project comprised mainly the collection and authentication of Acacia species, preparation of standard rat model for studying the pharmacodynamic cardiovascular efficacy of plants extracts available in Makkah, KSA.
MATERIALS AND METHODS
Collection and authentication of plant: Acacia tortilis plant was plucked from Al-Abdiyah region, Makkah, KSA, in December, 2016 and verified by Dr. Ibrahim Abd-Elhady, Associate Professor, Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University. A voucher specimen number PHG128 was deposited. Acacia tortilis leaves were separated and washed by using tap water.
Preparation of Acacia tortilis leave decoction (ATLD): For the preparation of ATLD, leaves (100 g) were grinded and macerated in distilled water for 1 h after that boiled in same distilled water as reported by Chinese medicinal herbs26. At the end a bright green color extract was obtained and filtered. This filtrate was used for intravenous administration in rats.
Oral toxicity test (acute): Acute oral toxicity test was performed in healthy rats and mice, following OECD (Organization of Economic Cooperation and Development) Guideline 423. In rats and mice (3 each), 2000 mg kg1 (maximum dose) of ATLD was administered orally. Animals were monitored for the next 48 h27 for any sign of toxicity and mortality.
Experimental animals: In the current study ten albino Sprague-dawley rats (200-250 g: either sex) were used for the recording of data. The rats were fed on a standard pellet diet and tap water ad libitum. The experimental protocol followed was permitted by the Animal Ethics Committee, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia (Ethical approval number HAPO-02-K-012-2015-11-125).
Measurement of normal blood pressure of rats (In vivo activity): Sprague-Dawley rats (normotensive: 200-250 g) were anaesthetized with thiopental sodium (40 mg kg1, i.p)28. Once animal was anaesthetized, it was positioned on dissection bench (dorsal decubitus), under an overhead lamp to maintain body temperature. Afterward the trachea of a rat was intubated with polyethylene cannula to promote extempore respiration. A mid trachea longitudinal incision (20 mm) exposed the right jugular vein and both common carotid arteries. The right jugular vein was catheterized with a scalp vein set (BROMED) filled with a saline solution to administer drugs. The left carotid artery was catheterized and reusable blood pressure transducer (Millar Micro tip Pressure volume catheter SPR 838, Powerlab, AD Instruments) was inserted. Transducer was used for monitoring the systolic and diastolic pressure (mm Hg), as well as heart rate (beats min1, bpm) continuously during the experiment and calculated internally in the Powerlab using the Chart software (labChart Pro v8.1.5, Powerlab AD instrument). After surgery, rat and all parameters were equilibrated for at least 30 min before starting the tests. For control reading saline was administered (0.20-0.25 mL) through a scalp vein set introduced into the external jugular vein. After normal Data (Control), Ach (10‾6 M) and extract were administered one by one and their activity was recorded. These records were used for the calculation of arterial blood pressure (Systole and Diastole: mmHg), cardiac cycles (s) and Heart rate (BPM).
Statistical analysis: A software Minitab 17 was used for statistical analysis. A power analysis suggested that the sample size be set at N = 3 to achieve a power of 0.8 at an alpha of 0.05 calculated by G*Power29. However, in the present study number of animals per group were N = 10. All hypotheses were tested using one way analysis of variance (ANOVA) tests. Alpha was set at (0.05). Significant effects were subjected to Tukey's multiple-range tests for comparison of treatment means with a control.
The blood pressure recording and parameters before (normal) and after the administration of ATLD are presented in Table 1. ATLD doses (10, 30 mg kg1) lowered the systolic, diastolic and the mean arterial pressure of normotensive rats significantly (p<0.05) and the effect of ATLD was more pronounced as compared to Ach in normotensive rats. Fall in Blood pressure was dose dependent. Greater effect was observed at 30 mg kg1 with reductions of 17.4±2.9 and 15.2±1.8% in systolic and diastolic blood pressures respectively. Decreases in various blood pressure parameters were statistically significant (p<0.005).
Effect of Acacia on heart rate and cardiac cycle: There was a significant decrease in the heart rate in rats following the administration of the Acacia extract. Dose of 10 mg kg1 caused significant reduction in heart rate (p<0.01), initially 361.72±26.13 beats/min, to 238.91±65.5 (Table 1). Intravenous administration of ATLD at 10 and 30 mg kg1 dose led to decrease in heart rate at (34 and 42%, respectively, p = 0.0001) and increase in the duration of cardiac cycle significantly (p<0.001) as shown in Table 1.
|Table 1:||Effect of Acacia tortilis on various blood pressure parameters|
|n = 10, Each value represents the Mean±STDEV|
|Fig. 1:||Tracing from a typical experiment showing the ATLD for its effects on blood pressure (BP) in the anesthetized rats|
Toxicological studies in mice and rats: Toxicological studies of ATLD were carried out in mice and rats. Administration of ATLD (P.O. 2000 mg kg1) did not show any significant change in physical behavior of mice and rats. None of the groups showed any significant change.
This present study is related to in vivo pharmacodynamics cardiovascular efficacy of KSA Acacia tortilis using rat model. Acacia tortilis have scientifically been screened for hypotensive activity. The results obtained from the acute oral toxicity study showed that ATLD demonstrated high safety margin when the animals tolerated ATLD up to 2000 mg kg1 b.wt., orally. Previously Mukhtar et al.30 has also reported that the margin of ethanolic extract of Acacia tortilis leaves safety up to 2000 mg kg1.
In the present study the i.v. administration of ATLD caused a transient fall in blood pressure parameters (Systolic, Diastolic, MABP) and heart rate significantly as shown in Fig. 1. These hypotensive effects were brief returning to normal within 5 min. The significant hypotensive effect after ATLD administration depends on the Acacia tortilis components ratios. Previously another species (Acacia catechu) was reported to produce a dose dependent decrease in blood pressure in both anaesthetized dogs and rats31. Acacia Nilotica32 and Acacia Phenol33 were also considered to exhibit anti-hypertensive effects.
It was suggested that serum sodium was dropped after the administration with gum arabic33. This might be the cause of hypotensive activity and drop of blood pressure. The presence of N, NDimethyltryptamine (DMT) has been confirmed previously in Acacia leaves water extract34 belong to tryptamine family (psychedelic compound), tend to reduced systolic blood pressure and heart rate35. DMT (inhaled or injected), the effects last a short period of time (about 5-15 min), our results are in accordance with this study that after the i.v. administration of ATLD effect persist for only 5 min36.
Crowch and Okello37 demonstrated acetylcholinesterase antagonist activity of Acacia nilotica and Acacia auriculiformis in experimental models37,38. Inhibition of acetylcholinesterase amplifies and prolongs the cholinergic response. Acetylcholine binds and stimulates the M2 receptor in heart cause bradycardia (negative chronotropic effect)39. However the stimulation of M3 receptors causes vasodilation and decreased peripheral resistance which lowers blood pressure40.
CONCLUSION ANS FUTURE RECOMMENDATION
Conclusively, ATLD exhibits profound hypotensive and heart rate lowering (Bradycardia) activities. It is proposed that ATLD might causes vasodilation and decreased peripheral resistance which lowers blood pressure. However, further studies are needed to be carried out for understanding the mechanism of action of ATLD.
In present study oral administration of ATLD (2000 mg kg1) was safe and did not cause any mortality or side effect in rats.
In this research work, an intravenous administration of different doses of ATLD produced hypotensive activity significantly comparable to Ach.
ATLD not only produced profound hypotensive effect in experimental rats, but also appeared to have a heart rate lowering (Bradycardia) activities.
It was a preliminary study, due to increase in the rate of hypertension in Saudi Arabia. This study will open the doors for further research and will provide an alternative low cost therapy for hypertensive patients.
For future it is recommended to carry out further studies on understanding the mechanism of action of ATLD.
The authors are thankful to the institute Deanship of Scientific Research for providing financial support through grant no.15-MED-3-1-0064, Umm Al Qura University, Makkah, KSA.
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