1Department of Pharmacology, Faculty of Pharmacy, Hamdard University, Karachi, PAKISTAN
2Faculty of Pharmaceutical Sciences, Dow College of Pharmacy, Dow University of Health Sciences, Karachi, PAKISTAN
3Department of Pharmacology, Hamdard College of Medicine and Dentistry, Hamdard University, Karachi, PAKISTAN
Corresponding author.
Author Notes
Contents
ABSTRACT
Background
High Blood Pressure (BP) is a dreadful condition worldwide. Available scientific data confirms the antihypertensive potential of traditional plants. Present study was aimed to assess the blood pressure lowering effect of hexane (MURK-HEX), ethyl acetate (MURK-EA) and methanol (MURK-MeOH) extracts of Murraya koenigii leaves in L-NAME induced hypertensive rats with possible mechanism of action.
Materials and Methods
Air dried leaves of “ Murraya koenigii” were extracted with different organic solvents namely methanol (MURK-MeOH), Hexane (MURK-HEX) and ethyl acetate (MURK-EA). Wistar rats of either sex were used in the study. Hypertension was developed by L-NAME and then data was collected after jugular vein cannulation using Oscillograph and powerlab data acquisition system. For possible mode of action muscarinic pathway was chosen. Data was analysed using SPSS-20 by applying independent sample t-test.
Results and Discussion
The invasive method revealed that “MURK-HEX”, “MURK- EA” and “MURK- MeOH” extracts exhibited significant dose dependent (18.8-50.1) % fall in MABP at the log doses (1,3, 5, 10 and 30 mg/kg) in normotensive rats. Except, “MURK-HEX”, the “MURK-EA” and “MURK-MeOH” altered the BP lowering effect, when these extracts followed by “Atropine” (Atr 10-4M) via intravenous route. Results demonstrate that MURK- EA and MURK-MeOH showed the involvement of muscarinic receptors while hypotensive effect of MURK-HEX may mediate via another pathway. In L-NAME induced hypertensive rats, MURK-HEX, MURK- EA and MURK- MeOH exhibited an immediate (18.37-51.93% falls) in MABP but it did not persist for longer time.
Conclusion
Murraya koenigii caused a significant decrease in MABP by the stimulation of muscarinic receptor in activation of EDRF which release nitric oxide to produce vasorelaxation.
INTRODUCTION
Cardiac diseases are one of the principal reasons of mortality all over the world and are continuously increasing day by day.1 Amongst them hypertension has a complex incidence as all kind of heart diseases. The major factors contributing in occurrence of High BP are smoking; metabolic syndrome marked by (obesity and diabetes mellitus) and altered endothelial function.
“Nitric oxide” is a very potent cardio-protective agent which is an integral component of “Endothelium Dependant Relaxing Factor (EDRF)” whose release is facilitated by various vasorelaxants. These vasorelaxants (like acetylcholine, serotonin and bradykinin etc) mainly produce “eNOS (enothelium Nitric Oxide Synthase)” by Ca2+ pump mechanism.2
To confirm that a drug is improving blood pressure using Nitric oxide pathway a nitric oxide deficient model is required. To produce Nitric oxide deficient experimental model “L-NAME (NG- nitro-L- arginine methyl- ester)” is most appropriate3 as it blocks nitric oxide release and cause hypertension. Plant “polyphenolic compounds” tend to improve such hypertension by reverting endothelial abnormality and thereby increasing NO release.4
Commonly used antihypertensive agents like diuretic etc are treatment of choice but are associated with adverse reactions.5 The Intention of the current study is to find agents with fewer harmful effects.
“Murraya koenigii” (Rutaceae) is cultivated in “Pakistan”, “Sri Lanka” and “East India” to “China” and “Hainan”.6 Locally, it is name as Karipatta and curry tree. Phytochemical analysis shows mahanine, mahanimbine, rheiin, girimimbine and mangiferin along with essential oils as main component of the plant. It is used traditionally in many diseases. In the sub-continent it is widely used in common household cooking. It is supposed to purify blood, relief stomach pain and flatus7 relieve diarrhoea and vomiting.8 Leaf oil is used to treat skin problems9 Leaves and roots are said to relief pain, inflammation and rash.10 The powder of leaves has antioxidant11 and anti-amnesic12 effects. It water based extract has been revealed anti-nociceptive13 anti-diabetic14 and anti-microbial15 activities.
Hepato-protective effect is shown by carbazole alkaloids and tannins isolated from hydro-alcoholic extract.16 Murraya leaves exhibit anti-cancer effect with their methanolic extract17 and improved obesity and serum lipid levels by ethanolic, ethyl acetate and dichloromethane extracts.18 The alkaloid fraction of the leaves has shown anti-inflammatory, anti-ulcerogenic19 and neuroprotective20 activities.
Aim of the current study is to explore hypotensive and anti-hypertensive activity and to determine mode of action of hexane, ethylacetate and methanolic extracts of Murrayya koenigii leaves in normotensive and L-NAME induced hypertensive rats.
MATERIALS AND METHODS
Plant
Leaves were collected in March 2013 from Azizabad No. 2. The plant was authenticated by Prof. Dr. Anjum Perveen at “Centre for plant conservation”, from Botany Department at University of Karachi with receipt sample number “(GH No. 86543-4 KUH)”.
Extraction of Plant Murraya koenigii
Murraya koenigii leaves in the form of fresh air-dried and uncrushed form were taken for sequential extraction. The procedure was carried out with different organic solvents e.g., “hexane”, “dichloromethane”, “ethyl acetate”, “methanol” and “acetone” at room temperature in increasing polarity order. The process of each extraction was executed thrice.
A rotary evaporator was used for evaporation of extracts separately21 to obtain their respective dry extracts like “hexane, MURK- HEX” (25.798 g, 1.289%), “dichloromethane, MURK-DC” (60.487, 3.024%), “ethyl acetate, MURK-EA” (51.98, 2.59%), “methanol, MURK-MeOH” (116.43 g, 5.82%) and “acetone, MURK-AC” (5.68 g, 0.284%) residues.
For the blood pressure regulation evaluation “MURK- HEX”, “MURK- EA” and “MURK- MeOH” were used as other extracts were not soluble in available vehicles. Extracts were kept in refrigerator at 4°C until further used.
Drugs
“NG-nitro-L-arginine methyl ester hydrochloride (L-Name)” was purchased from (“Sigma Aldrich”). “Acetylcholine” from “E. Merck”, “Atropine sulphate” from “C. H. Beohringer Sohn Ingelheim Rhein,” Germany. “Urethane and heparin” were obtained from “Unichem” and “Leo Pharma” respectively.
Animals
“Normotensive Wistar rats” (200-240 g) of either sex were used in the study. Animals were “procured” from animal house of “Dr HMI Institute of Pharmacology and Herbal Sciences” and placed under standard condition. Rats were nourished with standard diet with free access to water ad libitum. Handling of laboratory animals and the procedure of cannulation were approved by “Hamdard University Ethical Review Board, HU-ERB” (Ref No. AEC-17-01). The protocols were followed according to international standard guidelines for animal use.
Blood pressure lowering effect
1.2-1.5 g/kg intraperitoneal “Urethane” was used to anesthetize the rats and procedure was performed on animals in supine position. Plastic canula was used for tracheal cannulation which cleans to facilitate respiration throughout the whole procedure. Juglar vein and carotid artery were cannulated using polyethylene canula by making small incisions with the help of scissor, probe and forceps. A saline flush followed all the drug administration’s via jugular vein (0.2 mL) and the “carotid artery” was heparinized. Cannulated carotid artery with PE-50 polyethylene tubing was used to measure “blood pressure”. The “blood pressure transducer” (model ML 4856) was connected with “N12128 bridge amplifier” and “power lab data acquisition system”.
To maintain the body temperature of animal the overhead lamp was used. After 15-20 min of stabilization period, the extracts of Murraya koenigii leaves “MURK-HEX, MURK EA and MURK MeOH” were given in log doses of 1 mg/kg, 3 mg/kg, 5 mg/kg and their 10 folds higher doses i.e., “10 mg/kg, 30 mg/kg and 50 mg/kg respectively”. Blood pressure was permitted to return to normal basal value between each drug administration. Alterations in mean arterial blood pressure were determined as percentage difference from normal basal values, which were obtained immediately before the drug administration. “Mean Arterial Blood Pressure (MABP)” was calculated by adding 1/3rd of pulse pressure to “diastolic blood pressure”.22 Acetylcholine (10-6 M) was used as a positive control which produced 43.47±0.18% fall (mean±S.E.M, n=3) in MABP. The “blood pressure” was recorded on oscillograph at a chart speed of 10 mm/sec.5
Mode of action of blood pressure lowering effect
By Muscarinic pathway
Urethane (1.2-1.5g/kg, i.p.) was administered to anesthetize Wistar rats (200-250 g). Rats then cannulated to determine arterial blood pressure as described previously. After 15-20 min of stabilization period, Atropine (Atr 10-4 M), the cholinergic antagonist was administered, Acetylcholine (Ach 10-6 M), then cholinergic agonist was given for confirmation of muscarinic receptor blockade, thereafter from Murraya koenigii leaves extracts of “hexane (MURK-HEX)”, “ethyl acetate (MURK-EA)” and “methanol (MURK-MeOH)” at the dose of 30 mg/kg was administered and the subsequent variations in mean arterial blood pressure were then noted.22
Acute anti-hypertensive activity
The procedure was performed on normotensive rats by measuring mean arterial blood pressure. The invasive method of hypotension activity is same as described earlier. Intravenous administration of “L-NAME”, a “nitric oxide synthase” inhibitor (20 mg/kg) induced hypertension.23 When “L-NAME” induced maximum rise mean “arterial blood pressure (MABP)”, the “hexane (MURK-HEX)”, “ethyl acetate (MURK-EA)” and “methanol (MURK-MeOH)” extracts of leaves of “Murraya koenigii” were then given at 30 mg/kg dose through jugular vein. The variation in mean arterial blood pressure was monitored through BP transducer.
Statistical analysis
The results were analysed via the Software of “SPSS-20”. Data was considered significant when p was found <0.05. The results are displayed as “mean±Standard Error Mean (SEM)” by dependent sample t-test.
RESULTS
Blood pressure lowering effect of “MURK-HEX”, “MURK-EA” and “MURK-MeOH”
Results of extracts “MURK-HEX”, “MURK-EA” and “MURK-MeOH” at the doses of 1 mg/kg, 3 mg/kg, 5 mg/kg and 10 mg/kg caused a dose dependent decrease in systolic and diastolic blood pressure in Table 1. The doses 10 and 30 mg/kg in MURK- HEX and doses 30 and 50 mg/kg in MURK-EA and MURK-MeOH displayed significant and comparable hypotensive effect. However, in all three extracts, the dose 30 mg/kg was exhibited the optimum % drop in blood pressure.
| Extract | Dose | % fall in MABP±SEM | Duration of action (sec)±SEM |
|---|---|---|---|
| MURK- HEX | 1 | 22.4±0.9a | 77.9±20.8 |
| 3 | 34.9±4.2b | 58.0±40.8 | |
| 5 | 40.8±1.4a | 56.2±25.0 | |
| 10 | 50.1±1.4a | 190.0±29.4 | |
| 30 | 61.1±3.3b | 155.3±35.0 | |
| 50 | 51.6±1.4a | 149.7±23.9 | |
| MURK-EA | 1 | 18.9±3.8# | 20.5±4.5 |
| 3 | 20.5±2.5$ | 56.3±0.9 | |
| 5 | 41.6±3.1b | 69.3±1.5 | |
| 10 | 48.4±1.5b | 85.3±34.7 | |
| 30 | 54.9±5.2b | 28.0±2.5 | |
| 50 | 51.8±3.7a | 47.8±4.0 | |
| MURK- MeOH | 1 | 18.9±1.4b | 12.7±1.9 |
| 3 | 29.3±2.7c | 51.7±11.7 | |
| 5 | 33.9±5.5# | 34.7±2.85 | |
| 10 | 49.8±1.4a | 71.0±42.0 | |
| 30 | 55.0±3.7$ | 57.3±9.5 | |
| 50 | 54.3±1.8a | 61.3±18.7 |
Mode of action of blood pressure lowering effect
By muscarinic pathway
Rats pretreated with Atropine (Atr, 10-4M) abolished the hypotensive effect of “MURK- MeOH” and “MURK- EA” at the dose of 30mg/kg, whereas when Atropine was given prior to “MURK- HEX”, the blood pressure lowering effect of “MURKHEX” did not change as shown in Figure 1.
Figure 1:
Effect of methanol, ethyl acetate and hexane extract of Murraya koenigii leaves on Muscarinic receptors.
Results are expressed as mean±S.E.M. ap<0.0005, bp<0.005, cp<0.01, $p<0.025, #p<0.05 Anti-hypertensive effect of “MURK- HEX”, “MURK- EA” and “MURK- MeOH”
Antihypertensive effect of “MURK- HEX”, “MURK- EA” and “MURK- MeOH”
The results demonstrated that “MURK-HEX”, “MURK-EA” and “MURK-MeOH” from Murraya koenigii leaves ameliorates the blood pressure related with nitric oxide deficient L- NAME induced hypertensive rats. The L-NAME (20 mg/kg) via intravenous administration, induced hypertension which produced significant rise in MABP of 165.4±9.04 from 111.1±7.58 mmHg± that persist for about half an hour.
Following the L-NAME injection, MURK-HEX and MURK-MeOH exhibited correspondingly decrease (18.3% and 31.1%) in elevated MABP by 162.7 mmHg±3.8 to 132.7 mmHg±11.1 and 145.8 mmHg±3.2 to 101.2 mmHg±5.31 respectively. MURK-EA produced the maximum fall (51.9%) at 0.15 min in MABP from 152.4 mmHg±4.3 to 73.1 mmHg±3.8 just after 0.15 min of drug administration. Apart from MURK-HEX, which showing little antihypertensive effect, MURK-EA and MURK-MeOH returned to their initial values in 15 min as shown in Figure 2.
Figure 2:
Effect of the hexane, ethyl acetate and methanol extracts from Murraya koenigii leaves on the mean arterial blood pressure in L-NAME induced hypertensive rats. Each point represents the mean±SEM (n=3); ap<0.0005, bp<0.005, #p<0.025 and ##p<0.01 significantly different when compared to the initial value (0 min).
DISCUSSION
Blood pressure is a serious health condition which affects various organs of the body and deteriorates their function. Therefore, the use of medicinal plants gains popularity due to safe therapeutic agent, low toxicity and curative remedy for numerous diseases. Several studies showed that Murraya koenigii leaves possess cardioprotective potential24,25 in various experimental models. Data obtained in this study (Table 1) indicates that leaves of Murraya koenigii of hexane, “MURK-HEX”, ethyl acetate, “MURK-EA” and methanol, “MURK-MeOH” extracts at the doses of 1 mg/kg, 3 mg/kg, 5 mg/kg and 10 mg/kg displayed the dose dependent decrease in systolic and diastolic blood pressure. The doses 10 and 30 mg/kg in MURK- HEX and doses 30 and 50 mg/kg in MURK-EA and MURK-MeOH showed significant and comparable hypotensive effect. However, MURK-HEX when compared with “MURK-EA” and “MURK-MeOH” exhibited maximum % decrease (61.09±3.21) at the dose of 30 mg/kg in MABP which persists for more than 2 min (Table 1).
In addition to this, the duration of action in lowering blood pressure was increased in rats treated with MUR-HEX at the doses of 10, 30 and 50 mg/kg, which persisted for about 2.5-3 min. However, the longevity in lowering blood pressure at the dose of 10 mg/kg produced a more pronounced effect in comparison to 30 and 50 mg/kg doses. At the dose of 30 mg/ kg, the maximum % reduction in MABP was found in all three extracts of “MURK-HEX”, “MURK-EA” and “MURK-MeOH.”
The cholinergic pathway plays a vital role in regulating the vascular tone, by stimulating the production of endothelial nitric oxide.26 Therefore, there is a possibility of compromising vascular relaxation when muscarinic receptors are blocked by given Atropine 10-4 M prior to extracts.
Intravenous injection of MURK-MeOH and MURK-EA when pretreated with Atropine 10-4 M abolished hypotensive effect of both extracts (Figure 1). However, MURK- HEX failed to alter its hypotensive effect when the extract, followed by Atropine. Results demonstrate that the mode of hypotensive effect of “MURK-EA” and “MURK- MeOH” might comprise the muscarinic receptors, whereas “MURK-HEX” is not depending on cholinergic path.
Liu et al.27 is reported that L-NAME-induced hypertensive rats has been widely used in research purposes to antagonize the effect of Nitric Oxide Synthase (NOS).27
The results demonstrated that “MURK-HEX”, “MURK-EA” and “MURK-MeOH” from Murraya koenigii leaves ameliorates the blood pressure related with nitric oxide deficient L- NAME induced hypertensive rats. The L-NAME (20 mg/kg) via intravenous administration, induced hypertension which produced significant rise in MABP of 165.4±9.04 from 111.1±7.58 mmHg± that persist for about half an hour.
Following the L-NAME injection, MURK-HEX and MURK-MeOH exhibited correspondingly decrease (18.3% and 31.1%) in elevated MABP by 162.7 mmHg±3.8 to 132.7 mmHg±11.1 and 145.8 mmHg±3.2 to 101.2 mmHg±5.31 respectively. MURK-EA produced the maximum fall (51.9%) at 0.15 min in MABP from 152.4 mmHg±4.3 to 73.1 mmHg±3.8 just after 0.15 min of drug administration. Apart from MURK-HEX, which showing little antihypertensive effect, MURK-EA and MURK-MeOH returned to their initial values in 15 min as shown in Figure 2.
Vasodilation is the primary response of the muscarinic pathway caused by the contribution of endothelial muscarinic receptor subtypes.28 MURK-EA and MURK-MeOH exhibited the vasodilating and relaxant effect when atropine blocked the muscarinic receptors. This emphasized that both MURK-EA and MURK-MeOH possess the same mechanism as acetylcholine to produce endothelium-dependent relaxation leading hypotensive action. The involvement of the muscarinic pathway also supports the results of L-NAME-induced acute anti-hypertension. However, these findings determined that both “MURK-EA” and “MURK-MeOH” may ameliorate the nitric oxide release from the endothelium but might not re-establish the vasorelaxation for a longer duration. Nitric Oxide Synthase (NOS) is responsible for releasing Nitric Oxide (NO) using L-arginine substrate found in endothelium. Nitric oxide is the major endogenous vasodilator. Its production activates the guanyl cyclase by increasing cGMP, which leads to the stimulation PKG. This PKG potentiates the NO-cGMP pathway and produces relaxation by inhibiting Ca+2 influxes.29
CONCLUSION
Extracts of “hexane” (“MURK-HEX”), “ethyl acetate” (“MURK-EA”) and “methanol” (“MURK-MeOH”) isolated from Murraya koenigii leaves appear to exhibit favourable effect for the treatment and deterrence of hypertension. The mechanism of L-Name-induced hypertension comprises the inhibition of NO production with a subsequent decline of vasorelaxant activity. However, the L-Name-induced acute antihypertensive effect of Murraya koenigii leaves may maintain their endothelium- derived vasodilation to some extent. Thus, additional work is required to improve vascular endothelial cells relaxation for prolonged intervals of time by increasing the potency of these extracts and to determine the chronic L-Name induced anti-hypertensive study. We could not isolate the marker compounds liable for these activities. However, this study will have a significant impression on further research on this distinct natural herb.
Cite this article
Sadaf F, Shamim S, Ishaq H, Rehman A, Younus I, Siddiqui F. Evaluation of Hypotensive and Vasodilatory Effects of Murraya koenigii Leaves Extract in L-NAME Induced Hypertensive Rats in Relation with Muscarinic Receptors. Int. J. Pharm. Investigation. 2024;14(2):359-64.
ACKNOWLEDGEMENT
The authors are thankful to Dow University of Health Sciences to provide facilities in the project.
ABBREVIATIONS
| L-NAME-N(G) | Nitro-L-arginine methyl ester |
|---|---|
| NO | Nitric Oxide |
| eNOS | Endothelium Nitric oxide synthase |
| MABP | Mean arterial blood pressure |
| BP | Blood Pressure |
| MURK-HEX | Murrayya koenigii Hexane extract |
| MURK-MeOH | Murrayya koenigii methanolic extract |
| MURK-EA | Murrayya koenigii ethyl acetate extract |
| EDRF | Endothelium dependent relaxing factor |
| HU-ERB | Hamdard university-Ethical review board |
References
- WHO. Cardiovascular diseases (CVDs). 2020 [Array]. Available fromhttps://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases(CVDs)
- Zhao Y, Vanhoutte PM, Leung SW. Vascular nitric oxide: beyond eNOS. J Pharmacol Sci. 2015;129(2):83-94. [PubMed] | [CrossRef] | [Google Scholar]
- Nguelefack-Mbuyo PE, Nguelefack TB, Dongmo AB, Afkir S, Azebaze AG, Dimo T, et al. Anti-hypertensive effects of the methanol/methylene chloride stem bark extract of Mammea africana in L-NAME-induced hypertensive rats. J Ethnopharmacol. 2008;117(3):446-50. [PubMed] | [CrossRef] | [Google Scholar]
- Tang F, Yan HL, Wang LX, Xu JF, Peng C, Ao H, et al. Review of natural resources with vasodilation: traditional medicinal plants, natural products, and their mechanism and clinical efficacy. Front Pharmacol. 2021;12:627458 [PubMed] | [CrossRef] | [Google Scholar]
- Nwokocha CR, Owu DU, Nwokocha MI, Ufearo CS, Iwuala MO. Comparative study on the efficacy of Allium sativum (garlic) in reducing some heavy metal accumulation in liver of Wistar rats. Food Chem Toxicol. 2012;50(2):222-6. [PubMed] | [CrossRef] | [Google Scholar]
- Schmelzer GHG-FA. Plant resources of tropical Africa. Med Plants. 2013;2(11(2)) [PubMed] | [CrossRef] | [Google Scholar]
- Mandal S, Nayak A, Kar M, Banerjee SK, Das A, Upadhyay SN, et al. Antidiarrhoeal activity of carbazole alkaloids from Murraya koenigii Spreng (Rutaceae) seeds. Fitoterapia. 2010;81(1):72-4. [PubMed] | [CrossRef] | [Google Scholar]
- Sastri. The wealth of India. A dictionary of Indian raw materials and industrial products. New Delhi: Council of scientific and industrial research: NISCIR. 2007;6:446-7. [PubMed] | [CrossRef] | [Google Scholar]
- Sim KM, Teh HM. A new carbazole alkaloid from the leaves of Malayan Murraya koenigii. J Asian Nat Prod Res. 2011;13(10):972-5. [PubMed] | [CrossRef] | [Google Scholar]
- Mhaskar KS, Blatter E, India C. Shri satguru publication, Indian Medical Science Delhi. JF., Kirtikar and Basu’s Illustrated Indian Medicinal Plants their usage in Ayurveda and Unani Medicine. 3rd ed. 2000;1(11):86-96. [PubMed] | [CrossRef] | [Google Scholar]
- Zahin M, Aqil F, Husain FM, Ahmad I. Antioxidant capacity and antimutagenic potential of Murraya koenigii. BioMed Res Int. 2013;2013:263509 [PubMed] | [CrossRef] | [Google Scholar]
- Vasudevan M, Parle M. Antiamnesic potential of Murraya koenigii leaves. Phytother Res. 2009;23(3):308-16. [PubMed] | [CrossRef] | [Google Scholar]
- Gupta R, Gupta LK, Bhattacharya SK. Naloxone blocks the beneficial effects of aqueous extract of Murraya koenigii (L.) Spreng leaves in models of pain. Eur Rev Med Pharmacol Sci. 2013;17(13):1748-51. [PubMed] | [Google Scholar]
- El-Amin M, Virk P, Elobeid MA, Almarhoon ZM, Hassan ZK, Omer SA, et al. Anti-diabetic effect of Murraya koenigii (L) and Olea europaea (L) leaf extracts on streptozotocin induced diabetic rats. Pak J Pharm Sci. 2013;26(2):359-65. [PubMed] | [Google Scholar]
- Imran S. Studies on the antibacterial peptide isolated from Murrya Konigii leaves. Res J Biotechnol. 2013;8(12):49-53. [PubMed] | [Google Scholar]
- Sathaye S, Bagul Y, Gupta S, Kaur H, Redkar R. Hepatoprotective effects of aqueous leaf extract and crude isolates of Murraya koenigii against in vitro ethanol-induced hepatotoxicity model. Exp Toxicol Pathol. 2011;63(6):587-91. [PubMed] | [CrossRef] | [Google Scholar]
- Ghasemzadeh A, Jaafar HZ, Rahmat A, Devarajan T. Evaluation of bioactive compounds, pharmaceutical quality, and anticancer activity of curry leaf (Murraya koenigii L.). Evid Based Complement Alternat Med. 2014;2014:873803 [PubMed] | [CrossRef] | [Google Scholar]
- Tembhurne SV, Sakarkar DM. Antiobesity and hypoglycemic effect of ethanolic extract of Murraya koenigii (L). Asian Pac J Trop Dis. 2012;2:S166-8. [CrossRef] | [Google Scholar]
- Mani V, Ramasamy K, Abdul Majeed ABA. Anti-inflammatory, analgesic and anti-ulcerogenic effect of total alkaloidal extract from Murraya koenigii leaves in animal models. Food Funct. 2013;4(4):557-67. [PubMed] | [CrossRef] | [Google Scholar]
- Mani V, Ramasamy K, Ahmad A, Wahab SN, Jaafar SM, Kek TL, et al. Effects of the total alkaloidal extract of Murraya koenigii leaf on oxidative stress and cholinergic transmission in aged mice. Phytother Res. 2013;27(1):46-53. [PubMed] | [CrossRef] | [Google Scholar]
- Sadaf F, Saleem R, Ahmed M, Ahmad SI, Navaid-ul-Zafar. Healing potential of cream containing extract of Sphaeranthus indicus on dermal wounds in Guinea pigs. J Ethnopharmacol. 2006;107(2):161-3. [PubMed] | [CrossRef] | [Google Scholar]
- Saleem R, Sana A, Faizi S, Sadaf F. New esters of aromatic hydroxyl acids from Moringa oleifera Roots. Chem Nat Compd. 2016;52(2):208-12. [CrossRef] | [Google Scholar]
- Nyadjeu P, Nguelefack-Mbuyo EP, Atsamo AD, Nguelefack TB, Dongmo AB, Kamanyi A, et al. Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats. BMC Complement Altern Med. 2013;13(1):27 [PubMed] | [CrossRef] | [Google Scholar]
- Sandamali JAN, Hewawasam RP, Jayatilaka KAPW, Mudduwa LKB. Cardioprotective potential of Murraya koenigii (L.) Spreng. Leaf extract against doxorubicin-induced cardiotoxicity in rats. Evid Based Complement Alternat Med. 2020;2020:6023737 [PubMed] | [CrossRef] | [Google Scholar]
- Ambreen G, Siddiq A, Hussain K, Hussain AS, Naz Z. Repeatedly heated mix vegetable oils-induced atherosclerosis and effects of Murraya koenigii. BMC Complement Med Ther. 2020;20(1):222 [PubMed] | [CrossRef] | [Google Scholar]
- Alves-Lopes R, Neves KB, Touyz RM. Muscarinic receptor type-3 in hypertension and cholinergic-adrenergic crosstalk: genetic insights and potential for new antihypertensive targets. Can J Cardiol. 2019;35(5):555-7. [PubMed] | [CrossRef] | [Google Scholar]
- Liu T, Zhang M, Mukosera GT, Borchardt D, Li Q, Tipple TE, et al. L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation. Redox Biol. 2019;26:101238 [PubMed] | [CrossRef] | [Google Scholar]
- Saternos HC, Almarghalani DA, Gibson HM, Meqdad MA, Antypas RB, Lingireddy A, et al. Distribution and function of the muscarinic receptor subtypes in the cardiovascular system. Physiol Genomics. 2018;50(1):1-9. [PubMed] | [CrossRef] | [Google Scholar]
- Díaz-Juárez JA, Tenorio-López FA, Zarco-Olvera G, Valle-Mondragón LD, Torres-Narváez JC, Pastelín-Hernández G, et al. Effect of Citrus paradisi extract and juice on arterial pressure both in vitro and in vivo. Phytother Res. 2009;23(7):948-54. [PubMed] | [CrossRef] | [Google Scholar]