Journal of Cardiovascular Pharmacology:
Ginger Lowers Blood Pressure Through Blockade of Voltage-Dependent Calcium Channels
Ghayur, Muhammad Nabeel MPhil; Gilani, Anwarul Hassan PhD
From the Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi, Pakistan.
Received for publication June 18, 2004; accepted October 27, 2004.
Reprints: Dr. Anwarul Hassan Gilani, Professor of Pharmacology, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi 74800, Pakistan (e-mail: firstname.lastname@example.org).
Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in a wide variety of ailments including hypertension. We report here the cardiovascular effects of ginger under controlled experimental conditions. The crude extract of ginger (Zo.Cr) induced a dose-dependent (0.3-3 mg/kg) fall in the arterial blood pressure of anesthetized rats. In guinea pig paired atria, Zo.Cr exhibited a cardiodepressant activity on the rate and force of spontaneous contractions. In rabbit thoracic aorta preparation, Zo.Cr relaxed the phenylephrine-induced vascular contraction at a dose 10 times higher than that required against K+ (80 mM)-induced contraction. Ca2+ channel-blocking (CCB) activity was confirmed when Zo.Cr shifted the Ca2+ dose-response curves to the right similar to the effect of verapamil. It also inhibited the phenylephrine (1 μM) control peaks in normal-Ca2+ and Ca2+-free solution, indicating that it acts at both the membrane-bound and the intracellular Ca2+ channels. When tested in endothelium-intact rat aorta, it again relaxed the K+-induced contraction at a dose 14 times less than that required for relaxing the PE-induced contraction. The vasodilator effect of Zo.Cr was endothelium-independent because it was not blocked by L-NAME (0.1 mM) or atropine (1 μM) and also was reproduced in the endothelium-denuded preparations at the same dose range. These data indicate that the blood pressure-lowering effect of ginger is mediated through blockade of voltage-dependent calcium channels.
Ginger (rhizome of the perennial herb Zingiber officinale Roscoe) is a popular spice and is considered as an essential component of the kitchen pharmacy. It grows abundantly in the Indo-Pak subcontinent, and this region is the biggest exporter of ginger in the world.1 Ginger has been used since the ancient times as a food additive to impart its taste and smell and also for its therapeutic value in a wide variety of diseases, especially in the gastrointestinal disorders such as constipation, diarrhea, anorexia, colic, dyspepsia, nausea, vomiting, and also in motion sickness.2,3 The rhizome is known to have gingerol, shogaol, zingerone, and paradol as the pungent principles.4 The main aroma-defining component is zingiberol.5 Ginger is reported to possess anti-inflammatory, analgesic, antipyretic, antimicrobial, hypoglycemic, antimigraine, molluscicidal, antischistosomal, anti-motion sickness, antioxidant, hepatoprotective, hypocholesterolemic, and antithrombic activities.6 Because of the antithrombic potential of ginger, it may interact with blood-thinning drugs such as warfarin and must be used carefully in patients with blood-clotting disorders.
The use of ginger in cardiovascular diseases has long been known. Ginger is known to have a diuretic7 and blood pressure (BP)-lowering effect.3,8 In the traditional medicine practice of Pakistan, herbalists prescribe ginger to hypertensive patients to be taken after dinner. Interestingly a few studies have been carried out to explore the BP-lowering potential of ginger extract and its active constituents but produced conflicting results,9-11 and the precise mode of action remains to be elucidated. In this investigation, we report the BP-lowering effect of the crude extract of fresh ginger in anesthetized rats and the possible mode of action was explored using isolated cardiovascular preparations.
Drugs and Standards
The following reference chemicals were obtained from the sources specified: acetylcholine chloride, atropine sulfate, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), norepinephrine hydrochloride, phenylephrine hydrochloride, and verapamil hydrochloride (Sigma Chemical Company, St Louis, MO). The following chemicals were used to make the physiological salt solutions: potassium chloride (Sigma Chemical Company, St. Louis, MO), calcium chloride, glucose, magnesium chloride, magnesium sulfate, potassium dihydrogen phosphate, sodium bicarbonate, sodium chloride, sodium dihydrogen phosphate (E.Merck, Darmstadt, Germany); and ethylenediaminetetra-acetic acid (EDTA) from BDH Laboratory Supplies (Poole, UK). All chemicals used were of the highest purity grade. Stock solutions of all the chemicals were made in saline, and the dilutions were made fresh on the day of the experiment.
Experiments performed complied with the rulings of the Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council.12 Sprague-Dawley rats (170-200 g), local rabbits (around 1 kg), and guinea pigs (500-700 g) of either sex used in the study were bred and housed in the animal house of The Aga Khan University under a controlled environment (23-25°C). Animals were given tap water ad libitum and a standard diet consisting of (g/kg): flour 380, chokar 380, molasses 12, sodium chloride 5.8, nutrivet L 2.5, potassium metabisulfate 1.2, vegetable oil 38, fish meal 170, and powdered milk 150.
A total of 1 kg of fresh ginger was purchased from the main vegetable market in Karachi. A sample of the rhizome was deposited at the Herbarium of Natural Products Research Unit, the Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi with the voucher ZO-RH-06-02-46.
The ginger rhizomes were washed to remove any contaminants, and then they were crushed in a mortar and pestle to expose the inner part. The plant material was then soaked in 2 L of 70% aqueous methanol and kept for a total of 3 days. After 3 days, it was filtered through a porous cloth, the filtrate was collected, and the plant material was again soaked in 2 L of water for 3 days, twice. At the end, all of the filtrate was combined, filtered through Whatman qualitative Grade 1 filter paper, and then concentrated in a rotary evaporator to obtain a thick, light brown colored crude extract (Zo.Cr) weighing 39.4 g (yield of 4.2%).
Preliminary Phytochemical Analysis
Ginger crude extract was screened for the presence of saponins, flavonoids, flavanols, flavones, chalcones, tannins, phenols, coumarins, sterols, terpenes, alkaloids, and anthraquinones by using methods described previously.13
Blood Pressure in Anesthetized Rats
These experiments were performed as described earlier.14 Adult rats (180-200 g) of either sex were used. The animals were anesthetized with an intraperitoneal injection of sodium thiopental (Pentothal, 70-90 mg/kg body weight), and the arterial BP was recorded through carotid artery cannulation via a pressure transducer (P23 XL) coupled with a Grass Model 7 Polygraph. Drugs were injected through a cannula inserted into the jugular vein. After a 20-minute period of equilibrium, the rats were injected intravenously with 0.1 mL saline (NaCl 0.9%) or with the same volume of test substance. Arterial BP was allowed to return to the resting level between injections. Control responses of standards such as acetylcholine (ACh, 1 μg/kg) and norepinephrine (NE, 1 μg/kg) were obtained before the testing of the extracts. Changes in BP were recognized as the difference between the steady-state value before and the lowest reading after injection. Mean BP was calculated as the diastolic BP plus one-third pulse width.
Guinea Pig Atria
The isolated tissue experiments were carried out as previously described.15 Paired atria from guinea pigs, killed by cervical dislocation, were mounted in 20-mL tissue baths containing Krebs solution maintained at 32°C (unsteady recording at >32°C) and aerated with carbogen gas (5% carbon dioxide in oxygen). The composition of Krebs solution was (mM): NaCl 118.2, NaHCO3 25.0, CaCl2 2.5, KCl 4.7, KH2PO4 1.3, MgSO4 1.2, and glucose 11.7 (pH 7.4). The tissues were allowed to beat spontaneously under the resting tension of 1 g. An equilibrium period of 30 minutes was given before the application of any drug. Control responses to verapamil (0.3-10 nM) and norepinephrine (1 μM) were obtained at least in duplicate. Tension changes in the tissue were recorded via a Grass force-displacement transducer (model FT-03) using Grass Model 7 Polygraph.
Rabbits were killed by cervical dislocation. The descending thoracic aorta was removed and cut into 2- to 3-mmwide rings that were individually mounted in 20-mL tissue baths containing Krebs solution at 37°C and aerated with carbogen gas. A resting tension of 2 g was applied to each tissue, and an equilibrium period of 1 hour was allowed before any experimentation. The changes in isometric tensions of the rings were measured via a force-displacement transducer (FT-03) using a Grass Model 7 Polygraph. Following an equilibrium period of 1 hour, the tissues were stabilized with a fixed dose of phenylephrine (PE) 1 μM. The tissues were considered stable only when similar responses were obtained from repeated doses of PE (1 μM), which usually took 60-90 minutes. Effect of the extract was first determined on the resting baseline of the tissue to see if it had any vasoconstrictor effect. The extract was later tested for its ability to relax the contractions induced with PE (1 μM) and high K+ (80 mM). The ability of the extract to relax K+ (80 mM)-induced contraction would indicate an L-type voltage-dependent calcium channel-blocking (CCB) mode of vasodilation, whereas inhibition of the PE-induced contraction would signify the blockade of the calcium influx through receptor-operated calcium channels.16 To confirm the CCB activity, Ca2+ dose-response curves were constructed in a Ca2+-free medium. Then the effect of the increasing doses of the extract was determined on the Ca2+ dose-response curves. A shift in the Ca2+ curves to the right would confirm CCB activity. To determine if the extract was inhibiting the Ca2+ release from intracellular stores or blocking calcium influx across the cell membrane (through the voltage-dependent or receptor-operated channels), the effect of increasing doses of the extract was observed on PE (1 μM) peaks in normal-Ca2+ and in Ca2+-free Krebs solution, with Ca2+ omitted and EDTA (0.1 mM) added to ensure total elimination of extracellular Ca2+ without harmful effects on Ca2+ inside the cell.17 In Ca2+-free Krebs solution, PE acts through stimulation of α1-adrenergic receptors, and then the consequent conversion of phosphatidylinositol to inositol-1,4,5-trisphosphate, which in turn releases Ca2+ from the intracellular stores, brings about the contraction.18,19 In a normal-Ca2+ Krebs solution, the PE-stimulated contractions come about possibly through the influx of Ca2+ from the L-type voltage-dependent Ca2+ channels and the receptor-operated nonselective cation channels.20
Endothelium-Intact Rat Aorta
The procedure of Furchgott and Zawadski21 was followed with some modifications. Thoracic aorta was isolated from male rats. Care was observed in isolating the tissue to avoid any damaging of endothelium. Rings 3 mm wide were mounted in 5-mL tissue baths with Krebs solution maintained at 37°C and aerated with carbogen gas. A preload of 1 g was applied to the preparation and allowed to incubate for 30 minutes before exposing the tissue to any drug. Changes in tension were recorded via a World Precision Instrument (WPI) isometric force transducers (Fort 100) connected to Transbridge 4M and displayed on a personal computer via a CVMS Data Acquisition System. Following the equilibrium period of 30 minutes, the tissue was stabilized with repeated doses of PE (1 μM). After stabilization, an induced contraction was obtained with PE (1 μM), and ACh (0.1 μM) was then administered on this PE-induced contraction to confirm an endothelium-dependent relaxation. The endothelium lining of the tissues was removed by gentle rubbing, which resulted in the disappearance of this relaxation. To study whether or not the vasodilator effect of the test substance is endothelium-dependent, the PE (1 μM)-induced contraction was preincubated with L-NAME (0.1 mM) or atropine (1 μM) for 20 and 60 minutes, respectively, to explore the possible mode of endothelium-dependent vasodilator action.22,23
All the data expressed are mean ± SE of mean (SEM). The statistical parameter applied is the Student t test with P < 0.05 noted as significantly different.
Preliminary Phytochemical Analysis
The crude extract of ginger showed the presence of saponins, flavonoids, and alkaloids while other classes of compounds did not test positive.
Effect on BP in Anesthetized Rats
The crude extract induced a dose-dependent (0.3-3 mg/kg) fall in BP of rats under anesthesia (Figs. 1 and 2A) with an EC50 value of 0.9 ± 0.1 mg/kg (mean ± SEM, n = 3).
Effect on Guinea Pig Atria
In guinea pig paired atria, the extract caused an inhibitory effect on the spontaneous force and beating rate of atrial contractions (Fig. 2B and 3). The inhibitory effect was dose-dependent, mediated at the dose range of 0.1 to 3.0 mg/mL (Fig. 2B and 3) with an EC50 value of 0.57 ± 0.03 (n = 7) and 0.88 ± 0.07 (n = 3) mg/mL (mean ± SEM) for the force and rate of contraction, respectively. Verapamil, in a concentration-dependent manner (0.3-10 nM), also caused an inhibitory response in the tissue preparations.
Effect on Rabbit Aorta
When tested on the resting baseline of the rabbit aorta, Zo.Cr was devoid of any effect up to the dose of 10 mg/mL. The extract was then tested on high-K+ (80 mM) and PE (1 μM)-induced contractions, which produced dose-dependent vasodilation (Fig. 4A) with an EC50 value of 0.11 ± 0.01 mg/mL and 0.92 ± 0.04 mg/mL (mean ± SEM, n = 4), respectively. The ginger extract in increasing doses (0.01-0.03 mg/mL, n = 8) also shifted to the right the Ca2+ dose-response curves that were constructed in a Ca2+-free medium (Fig. 5A). This shift of Ca2+ curves was similar to the one obtained under the influence of verapamil (0.1-0.3 μM, n = 3, Fig. 5B). When Zo.Cr was tested in increasing doses against PE (1 μM) peak responses, it dose-dependently (0.03-0.3 mg/mL, n = 3) relaxed the agonist peaks in normal-Ca2+ and Ca2+-free Krebs solution (Fig. 6A). Similarly, verapamil (0.03-0.3 μM) also inhibited the PE peaks in both the normal-Ca2+ and Ca2+-free Krebs solution (Fig. 6B; n = 3).
Effect on Endothelium-Intact and Denuded Rat Aorta
Zo.Cr was first tested on the resting baseline of the rat aorta. It showed no activity up to 10 mg/mL. Zo.Cr was then tested on the endothelium-intact rat aorta precontracted with high K+ (80 mM) and PE (1 μM). The extract inhibited both of these induced contractions from 0.01 to 1 mg/mL (Fig. 4B) with an EC50 value of 0.091 ± 0.002 mg/mL (mean ± SEM, n = 4) and from 0.03 to 3 mg/mL (Fig. 4B) with an EC50 value of 1.26 ± 0.08 mg/mL (mean ± SEM, n = 6), respectively. The vasodilator effect of the extract on PE (1 μM)-induced contraction was resistant to blockade by atropine (1 μM) and/or L-NAME (0.1 mM) pretreatment (Fig. 4B). In the endothelium-denuded aorta, the extract dose-dependently (Fig. 4B) relaxed the PE (1 μM)-induced contraction with an EC50 value of 1.2 ± 0.1 mg/mL (mean ± SEM, n = 3).
Fresh ginger crude extract, when injected intravenously in rats under anesthesia, evoked a dose-dependent fall in arterial BP, which is in line with its traditional use in hypertension.24 The possible mode of action was studied in isolated cardiovascular tissue preparations. In the isolated guinea pig paired atria, the extract depressed the force and rate of spontaneous atrial contractions in a dose-dependent manner, similar to verapamil, a standard calcium antagonist.25 Previously, Weidner and Sigwart9 have observed that the standardized "ethanol extract of dried ginger" was devoid of any activity on the systolic BP or heart rate in conscious rats when given orally. On the contrary, the ginger pungent principles, gingerol and shogaol, have been studied for their cardiovascular effects in laboratory animals,10,11 and both were found to produce depressant responses when injected intravenously at low dose, whereas a triphasic response, consisting of an initial hypotensive followed by a sharp hypertensive and then a delayed hypotensive effect, at high doses in rats under anesthesia was recorded. In our study, we observed that the aqueous-methanol extract of fresh ginger lowered BP in rats under anesthesia, which confirms the presence of BP-lowering constituent(s) in ginger. Gingerols and shogaols, though considered the main active principles of ginger, may not truly represent the crude extract in all aspects because a single plant is known to contain as many as over 100 chemicals,26 and it is possible that the aqueous-methanol extract of fresh ginger contains a dominant hypotensive component, thus masking the vasoconstrictor component reported earlier.11 As far as the inability of the dried ginger extract to lower BP reported in earlier study9 is concerned, there are several differences when compared with our study. Weidner and Sigwart9 used the crude extract of "dried ginger," whereas we used fresh ginger, and it is possible that BP-lowering component(s) was/were lost during the process of drying. Secondly, these authors used pure ethanol extract, whereas we used aqueous-methanol extract, which is known to extract a wider variety of chemicals than pure ethanol alone.27 This speculation gets further strength when this study by Weidner and Sigwart failed to reproduce the hypoglycemic effect earlier obtained by Mascolo et al28 with the aqueous-ethanol extract of ginger. Another explanation could be that these authors tested the extract orally in the conscious rats, whereas we tested it intravenously in rats under anesthesia. It is possible that the active component responsible for the BP-lowering effect is unable to get absorbed into the circulation when given orally. Alternatively, the model used in the study of Weidner and Sigwart (systolic BP monitoring in conscious rats) is not considered as reliable as the one with anesthetized rats because the latter allows studying the effect of drugs directly without any interference of emotional disturbances. The positive control minoxidil (an unusual antihypertensive agent) used in their study produced a hypotensive effect at a dose (10 mg/kg) that is considered very high for a pure compound. We feel that the use of aqueous-methanol extract of fresh ginger is more meaningful, though further studies are required to resolve this discrepancy in different studies.
To see the effect of Zo.Cr on vascular resistance, 2 different vascular tissues were selected. The rabbit aorta was selected (1) to evaluate the effect of the extract on K+- and PE-induced contractions and thus to distinguish between activity at the voltage-operated and receptor-operated channels and (2) to distinguish the inhibitory effect of the crude extract between membrane-bound calcium channels with those inside the cells. Rabbit aorta is routinely used for the screening of CCBs.15,29 The other vascular preparation used was rat aorta, which is a prototype tissue used for evaluating the endothelium-dependent or -independent vasodilatation.30,31 Rat aorta was selected (1) to evaluate the effect of the extract on K+- and PE-induced contractions and (2) to determine if the vasodilator effect of the extract is endothelium dependent or independent.
First, Zo.Cr was found to be devoid of any activity on the resting baseline of the vascular preparations, indicating that it has no vasoconstrictor action. But when tested on the K+-induced contractions, Zo.Cr exhibited a vasodilator action at a dose around 10 times less than that required to relax the PE-induced contractions, thus indicating that the extract was acting through CCB and further that it was specific in inhibiting the voltage-dependent Ca2+ channels.20 The CCB activity of the extract was confirmed when it shifted the Ca2+ dose-response curves, constructed in a Ca2+-free medium, in the rabbit aorta, to the right. Verapamil, a standard CCB,25 also shifted the Ca2+ curves in a concentration-dependent manner.
The CCB effect mediated by the extract in the vascular tissues was more potent than the effect exhibited in cardiac tissue (P < 0.05). There is sufficient evidence of heterogeneity of calcium channels, and different CCBs exhibit selectivity for different organ systems.32 The vasodilator effect of ginger seen here is in accordance with the traditional use of ginger as a vasodilator and an antihypertensive agent.33,34 Recently, Sengupta et al35 have shown modulatory actions of the active principles of the much popular Chinese herb Panax ginseng, or ginseng, as it is commonly known, on angiogenesis via opposing pathways. Likewise, more such studies are needed for the scientific evaluation and rationalization of commonly known botanicals, ginger and ginseng to name a few, that are now gaining mass popularity worldwide.
Smooth muscle contraction is brought about by the activation of the (1) membrane bound Ca2+ channels, which are the voltage-operated and receptor-operated Ca2+ channels,36,37 but this is not the only mechanism for contractility. Ca2+ influx into the cell can also be guided through the (2) Ca2+ release from the internal stores of inositol-1, 4, 5-trisphosphate (IP3)-sensitive sarcoplasmic reticulum.38
When PE control responses were taken in the absence and presence of Zo.Cr, the crude extract in increasing doses inhibited the agonist responses irrespective of the presence or absence of Ca2+ in the bathing solution, indicating that the extract is acting via inhibiting both the receptor-operated channels and the intracellular Ca2+ channels. The results were similar to the ones obtained with verapamil.
The endothelium-intact rat aorta helped to determine that the vasodilator effect of the crude extract was independent of the endothelium, as was evident from the fact that the vasodilator effect of Zo.Cr in the endothelium-intact rat aorta was not blocked by either L-NAME, a standard nitric oxide (NO) synthase inhibitor,39 or atropine, a standard cholinergic antagonist that also brings about its effect by the release of NO.21 The vascular endothelium plays a pivotal role in modulating the contractility of the vascular tone through the release of vasodilator and constrictor factors.23 The claim that the vasodilator effect was endothelium independent was further strengthened when the rat aorta was denuded of the endothelium, and even then the extract mediated the relaxation of the PE-induced contraction at the same concentration as in the intact preparation.
In summary, the results of this study show that the intravenous administration of fresh ginger extract exhibits blood pressure lowering effect in anaesthetized rats. In the isolated tissue preparations, ginger extract exhibited a negative inotropic and chronotropic effect while also showing a vasodilator effect through specific blockade of the voltage-dependent Ca2+ channels. The vasodilator effect was found to be independent of endothelium. This study may be a step forward toward evidence-based phytomedicine.
This study was supported by the Pakistan Science Foundation through research project # R & D/S-AKU/BIO (178).
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Zingiber officinale; ginger; calcium channel blocker; hypotensive; vasodilator
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