- Open Access
- Open Peer Review
Effect of garlic on cardiovascular disorders: a review
Nutrition Journalvolume 1, Article number: 4 (2002)
Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic.
Dietary factors play a key role in the development of various human diseases, including cardiovascular disease. Epidemiological studies have shown that diets rich in fruits, herbs and spices are associated with a low risk of cardiovascular disease. Garlic acquired a reputation in the folklore of many cultures over centuries as a formidable prophylactic and therapeutic medicinal agent. Garlic has attracted particular attention of modern medicine because of its widespread health use around the world, and the cherished belief that it helps in maintaining good health warding off illnesses and providing more vigor. To date, many favorable experimental and clinical effects of garlic preparations, including garlic extract, have been reported. These biological responses have been largely attributed to i) reduction of risk factors for cardiovascular diseases and cancer, ii) stimulation of immune function, iii) enhanced detoxification of foreign compound, iv) hepatoprotection, v) antimicrobial effect and vi) antioxidant effect. This review has been made indicating an overall view of the efficacy of garlic in cardiovascular disease conditions both in human and animals.
Historical perspective of garlic
It is fascinating to observe how cultures that never came into contact with one another came to the same conclusions about the role of garlic in health and disease. If folk wisdom is not ignored, it may teach us valuable lessons. Some of the earliest references to this medicinal and culinary plant are found on Sumerian clay tablets dating from 2600–2100 BC. Garlic was an important medicine to the ancient Egyptians listed in the medical text Codex Ebers (ca. 1550 BC) specially for the working class involved in heavy labor [1, 2]. There is evidence that during the earliest Olympics in Greece, garlic was fed to the athletes for increasing stamina . In ancient Chinese medicine, garlic was prescribed to aid respiration and digestion, most importantly diarrhea and worm infestation . Three ancient medical traditions in India i.e., Tibbi, Unani and Auryveda, made extensive use of garlic as a central part of the healing efficacy of plants . The leading Indian ancient medical text, Charaka-Samhita recommends garlic for the treatment of heart disease and arthritis for over many centuries. In another ancient Indian medical textbook, Bower Manuscript (~300 AD), garlic was used for fatigue, parasitic disease, digestive disorder and leprosy . With the onset of Renaissance, increasing attention was paid in Europe to the medical use of garlic. A leading physician of the 16th century, Pietro Mattiali of Siena, prescribed garlic for digestive disorders, infestation with worms and renal disorders, as well as to help mother during difficult childbirth . In England, garlic was used for toothache, constipation, dropsy and plague . In modern era scientists have been trying to validate many of these properties of garlic, specially in terms of the identity of the active components, their mechanisms of action and exploring the potential benefits as food supplements.
Garlic preparations and their chemical compounds
Raw garlic homogenate has been the major preparation of garlic subjected to intensive scientific study, as because it is the commonest way of garlic consumption. Raw garlic homogenate is essentially same as aqueous extract of garlic, which has been used in various scientific studies. Allicin (allyl 2-propenethiosulfinate or diallyl thiosulfinate) is thought to be the principal bioactive compound present in aqueous garlic extract or raw garlic homogenate. When garlic is chopped or crushed, allinase enzyme, present in garlic, is activated and acts on alliin (present in intact garlic) to produce allicin. Other important sulfur containing compounds presents in garlic homogenate are allyl methyl thiosulfonate, 1-propenyl allyl thiosulfonate and γ-L-glutamyl-S-alkyl-L-cysteine. The adenosine concentration increases several-fold as the homogenate is incubated at room temperature. The enzyme allinase responsible for converting alliin (S-allyl cysteine sulphoxide) to allicin is inactivated by heat. Thus the water extract of heat-treated garlic contains mainly alliin. Since garlic powder is a simply dehydrated, pulverized garlic clove, the composition, especially allinase activity of garlic powder is identical to those of fresh garlic. However, dehydration temperature should not exceed 60°C, above which allinase is inactivated .
Another widely studied garlic preparation is aged garlic extract (AGE). Sliced raw garlic stored in 15–20% ethanol for 20 months is refereed to as AGE. This whole process is supposed to cause considerable loss of allicin and increased activity of certain newer compounds, like S-allylcysteine (SAC), S-allylmercaptocysteine, allixin and selenium which are stable, highly bioavailable and significantly antioxidant . Another recently identified antioxidant compound of AGE is N-alpha-(1-deoxy-D-fructos-1-yl)-L-arginine (Fru-Arg) which is not present in raw or heat treated garlic .
Medicinally used garlic oil is mostly prepared by steam-distillation process. Steam-distilled garlic oil consists of the diallyl (57%), allyl methyl (37%) and dimethyl (6%) mono to hexa sulfides. A typical commercial preparation of garlic oil contains diallyl disulfide (DADS, 26%), diallyl trisulfide (DATS, 19%), allyl methyl trisulfide (15%), allyl methyl disulfide (13%), diallyl tetrasulfide (8%), allyl methyl tetrasulfide (6%), dimethyl trisulfide (3%), penta sulfide (4%) and hexa sulfide (1%). Oil-macerated garlic oil contains the vinyl-dithiins and ajoenes. Ether extracted garlic oil (essential oil) contains nine times as much of the vinyl-dithiins (5.7 mg/gm) and allyl sulfides (1.4 mg/g) and four times as much of the ajoenes (0.4 mg/g) .
Atherosclerosis and lipid metabolism
Atherosclerosis is a complex disease, characterized by an excessive inflammatory, fibro-fatty, proliferative response to damage of the artery wall involving several cell types, particularly smooth muscle cells, monocyte-derived macrophages, T-lymphocyte and platelets . Hyperlipidemia constitutes a major etiopathological factor for atherosclerosis. The medicinal value of garlic is best known for its lipid lowering and antiatherogenic effects.
Several groups of investigators [8–14] studied the effects of long term (2–9 months) feeding of garlic and garlic preparations (2% garlic powder in diet) on experimental atherosclerosis induced by a high-cholesterol diet in rabbits. Most of these studies reported a statistically significant reduction in atheromatous lesions, particularly in the aorta, that averaged about 50%.
The chronic effects of garlic on lipid metabolism in rats were also encouraging. The duration of these studies was at least 4 weeks. Garlic (1–4% in diet) and garlic protein administration in hypercholesterolemic rats induced by a high-cholesterol diet, significantly reduced serum cholesterol, triglyceride and LDL cholesterol [11, 15–20] but there was no effect on serum HDL. Total lipid content and cholesterol levels in liver were also decreased in rat after chronic garlic consumption. Abramoviz et al. (1999) investigated the effect of allicin as an active component of garlic on the formation of fatty streaks in aorta and lipid profile in mice . While no significant differences were observed between blood lipid profiles, the microscopic evaluation of formation of fatty streaks in the aortic sinus showed that values for mice in the allicin treated groups were significantly lower by nearly 50%.
Aged garlic extract 'Kyolic' also significantly inhibited the development of thickened, lipid-filled lesions in the pre-formed neointimas produced by balloon-catheter injury of the right carotid artery in cholesterol-fed rabbits [22, 23].
Since 1975 there have been more than 46 (from medline search) human studies on lipid-lowering effects of garlic and garlic preparations. These studies, were mostly randomized, double blind, placebo-controlled using garlic powder rather than raw garlic of 4–16 weeks, in hyperlipidemic patients. Most of these studies showed significant decrease in serum cholesterol and serum triglyceride. Only about one-third of these studies measured lipoproteins, where significant favorable changes in LDL-cholesterol level (11–26% decrease) were consistently observed. A few studies using garlic powder (having low allicin yields) failed to show any lipid lowering effects [24, 25]. During the last one decade (1993–2002), 18 clinical studies have been published regarding the hypolipedemic effect of garlic. Nine studies showed negative results and garlic powder was used in seven of these studies (Table- 1) [26–34]. The different composition and quantity of sulfur components of different garlic preparations used in various studies could account for the inconsistent findings. It highlights the need for standardization of different garlic preparations and to arrive at a valid conclusion. Other factors might include the subject recruitment, duration of study, dietary control, lifestyle and methods of lipid analyses [35, 36].
Four meta-analysis of randomized, placebo-controlled human studies on hypocholesterolemic effects of garlic are available [35–38]. The analyses further detected that the extent of cholesterol-lowering properties of garlic differed markedly from one study to another. Warshafsky and his colleagues deduced from five randomized clinical trials that hypercholesterolemic patients treated with garlic had a mean plasma cholesterol concentration, that was 9% lower than that of patients treated with placebo . Silagy and Neil (1994) analyzed sixteen trials, with data from 952 subjects in the meta-analysis . Garlic, in powder and non-powder form, significantly lowered serum lipid levels over a 1–3 month period. Serum cholesterol fell by 8% with dried powder preparations and 15% with non-powder preparations. Serum triglyceride level also dropped significantly, while HDL-cholesterol was essentially unchanged. Amongst the garlic powder preparations these effects appeared to be similar across the daily dose range of 600–900 mg. Another meta-analysis  revealed that there was no significant difference in the mean concentrations of serum lipids, lipoproteins or apo A1 or B amongst the groups receiving garlic (900 mg/day of dried garlic powder standardized to 1.3% allicin) and placebo. In this meta-analysis, garlic was less effective in reducing total cholesterol than suggested by previous meta-analyses. However, in a more recent meta-analysis of thirteen trials , garlic reduced total cholesterol level from baseline significantly more than placebo, while six diet-controlled trials with the highest scores for methodological quality revealed a nonsignificant difference between garlic and placebo groups. The available data suggests that garlic is superior to placebo in reducing total cholesterol levels. However, the size of the effect is modest, and the robustness of the effect is debatable. Therefore, the hypocholesterolemic effect of garlic remains to be firmly established.
Protective effect of garlic on atherosclerosis has been attributed to its capacity to reduce lipid content in arterial wall. Garlic causes direct antiatherogenic (preventive) and antiatherosclerotic (causing regression) effects at the level of artery wall . Garlic depressed the hepatic activities of lipogenic and cholesterogenic enzymes such as malic enzyme, fatty acid synthase, glucose-6 phosphate dehydrogenase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase . Garlic also increased the excretion of cholesterol, as manifested by enhanced excretion of acidic and neutral steroids after garlic feeding . LDL isolated from human subjects given AGE  and aqueous garlic extract  was found to be significantly more resistant to oxidation. These data indicate that suppressed LDL oxidation may be one of the powerful mechanisms accounted for the benefits of garlic in atherosclerosis . Allicin was identified initially as the active compound responsible for antiatherosclerotic effect. However, recent in vitro studies revealed that water-soluble organosulfur compounds, especially S-allyl cysteine (SAC), present in aged garlic extract and diallyl-di-sulfide (DADS), present in garlic oil are also potent inhibitors of cholesterol synthesis [40, 44].
Inhibition of fibrinolytic activity (FA) or deficiency of the factors involved might upset the hemostatic balance and allow excessive fibrin deposition. In diabetes, hypertension, hypercholesterolemia etc, it is possible that disturbance in the coagulation-fibrinolytic system may be an important factor leading to the development of thrombosis and ischemia. Accordingly, the greater the FA, the more favorable is the antithrombic effect. FA is generally determined by euglobulin lysis time. The patients who died with acute or old myocardial infarction showed the highest values of plasma fibrinogen, euglobulin lysis time and antiplasmin. This suggests that prognosis in myocardial infarction is partly influenced by the degree to which plasma fibrinolysis is impaired .
Marked rise in blood coagulability of rabbits that followed 3 months of cholesterol feeding (0.2 g/kg/day) was significantly reduced by the essential oils of garlic. Fibrinolytic activity was actually increased even above the normal control levels. The essential oils of garlic (equivalent to 1 g/kg/day of raw bulbs) proved effective in mediating fibrinolytic activity [10, 46]. Experimental study also revealed that garlic juice (raw garlic; 250 mg/day) had significant effect in enhancing the fibrinolytic activity in rabbit after receiving a cholesterol rich diet for 13 weeks . The plasma fibrinolytic activity in rabbit, which was decreased on cholesterol feeding, was considerably increased when this diet was supplemented with garlic .
Almost all human studies on fibrinolytic activity of garlic have been found to have positive effect (Table- 2). Acute as well as chronic intake of garlic oil and raw garlic increased fibrinolytic activity (FA). In 1975, Bordia first demonstrated that garlic oil increased FA after 3 hours of administration. Bordia also reported that chronic (3 weeks to 3 months) administration of garlic oil (dose: equivalent to 1 gm/kg of fresh garlic) increased FA significantly ranging from 36% to 130% in healthy as well as acute myocardial infarction patients [49–52]. Some other investigators also found the same results [53–55]. Dried garlic powder has been also tested for its fribinolytic activity. While two studies [24, 25] showed no difference in FA, one study  showed increased FA as well as tissue plasminogen activator activity after acute and chronic garlic powder intake. Chutani and Bordia (1981) designed one study to show that both raw and fried garlic significantly enhance FA . Frying removes the strong acrid smell of garlic, but preserves it useful effects on FA. The rise in FA has been observed within 6 hours of garlic administration, which showed that garlic has a rapid onset of action and the effect is well maintained as long as garlic is being taken. Recently Bordia (1998) found that intake (3 months) of ethyl acetate extract of crushed raw garlic also increased FA .
Platelet aggregation superimposed on an atherosclerosis vessel is an antecedent event causing total blockage of blood flow leading to myocardial infarction and thromboembolic diseases. Platelets adhere to the exposed collagen, laminin and von Willebrand factor in the injured vessel wall. This process is called platelet activation. Activation can also be produced by ADP and thrombin. The activated platelets change shape, put out pseudopodia, discharge their granules, and stick to other platelets, initiating the process of platelet aggregation. Aggregation is also fostered by platelet activating factor (PAF), a cytokine secreted by neutrophil and monocytes as well as platelets . Studies have shown that garlic has great potential in inhibiting platelet aggregation.
Pretreatment of rabbits with an aqueous extract of garlic (500 mg/kg) significantly inhibited thromboxane-B2 (TXB2) synthesis (a potent platelet aggregator) and protected against thrombocytopenia induced by collagen or arachidonate infusion. These observations indicate that garlic may be beneficial in the prevention of thrombosis . Aqueous extract of garlic was found to inhibit platelet aggregation induced by ADP, epinephrine, collagen and arachidonate in a dose-dependent manner in vitro and inhibited biosynthesis of prostacyclin in rat aorta . A dose-dependent inhibition of cyclooxygenase activity and collagen-induced platelet aggregation was observed in rabbit platelets treated with raw garlic in vitro. The concentration required for 50% inhibition of the platelet aggregation for garlic was calculated to be approximately 6.6 mg/ml plasma. But boiled garlic was found to be of little effect. This finding indicates that garlic may be beneficial in the prevention of thrombosis if ingested raw rather in a cooked form [62, 63]. Garlic extract containing diallyl disulfide and diallyl trisulfide, prevented acute platelet thrombus formation in stenosed canine coronary arteries . Fresh garlic extract is effective in reducing thromboxane formation by platelets both in vivo and in vitro animal models of thrombosis. It was observed that garlic inhibits thrombin-induced platelet synthesis of TXB2 in a dose-and time-dependent manner in rabbits. Maximum inhibition of TXB2 occurred between 0.5 h and 6 h at 25 and 100 mg/kg garlic. The rapid recovery of platelet cyclooxygenase activity after infusion of a single dose of garlic suggests that garlic should be taken more frequently in order to achieve beneficial effects in the prevention of thrombosis . Garlic was also capable of delaying hyperthermia-induced platelet aggregation in mouse pial arterioles, in vivo, which was comparable to acetyl salicylic acid [66, 67]. Ajoene, a constituent of essential oil of garlic, has been shown to inhibit in vitro platelet aggregation in different species of animals i.e., cow, dog, guinea-pig, horse, monkey, pig, rabbit and rat . Under in vivo flow conditions and in the presence of physiological calcium levels, ajoene prevented thrombus formation induced by severe vascular damage, mainly in arterial sites with local low shear stress [69, 70]. Makheja and Bailey (1990) identified three main antiplatelet constituents, namely adenosine, allicin and polysulfides in garlic . Adenosine and allicin both inhibited platelet aggregation without affecting cyclooxygenase and lipoxygenase metabolites of arachidonic acid. The polysulfides inhibited platelet aggregation as well as thromboxane synthesis. The observed in vivo antiplatelet effects of ingesting garlic are attributable more to adenosine than to allicin and polysulfide constituents.
In human studies a positive response to garlic has been observed. Like enhancement of fibrinolysis, garlic also has a beneficial effect on platelet adhesion or aggregation in human (Table- 3). Bordia (1978) first showed the dose-dependent inhibition of platelet aggregation by garlic . Raw garlic, garlic oil and other extract of garlic have been shown to inhibit platelet aggregation in in vitro induced by ADP, collagen, arachidonate, epinephrine and calcium ionophore [57, 61, 73–75]. Chronic intake of garlic powder and garlic oil also inhibits platelet aggregation [28, 50, 55, 76–79]. Single dose of garlic has also been shown to inhibit platelet aggregation [54, 56, 80].
The antiplatelet mechanism of garlic is much more established than its any other biological effects. Aqueous extract of garlic inhibited platelet aggregation induced by ADP, collagen, arachidonate, epinephrine and calcium ionophore A23187 in a dose-dependent manner . It was found that garlic reduced the formation of thromboxane, inhibited the phospholipase activity and lipoxygenase products formed in platelets. These effects may explain, in part, inhibition of platelet aggregation. Further, since garlic was also effective in inhibiting aggregation induced by calcium ionophore A23187 it may be suggested that the antiaggregation effect may be related to intraplatelet mobilization of calcium. Inhibition of epinephrine-induced aggregation by garlic extract may suggest that it may be inhibiting uptake of calcium into platelets thereby lowering cytosolic calcium concentrations . In regard to a specific mechanism of ajoene's antiplatelet action, several suggestions have been made. Ajoene strongly inhibits the metabolism of arachidonic acid by both cyclooxygenase and lipoxygenase pathways [81, 82], thus inhibiting the synthesis of thromboxane A2 and 12-HETE. Antiaggregatory effect of ajoene may also be causally related to its direct interaction with the putative fibrinogen receptor (GPIIb/IIa) . The studies of Jamaluddin et al (1988) demonstrated that ajoene interacts with a purified hemoprotein implicated in platelet activation . Ajoene modifies the binding of the hemoprotein with ligands deemed to be physiologically relevant as effectors. Allicin inhibits human platelet aggregation in vitro without affecting cyclooxygenase or thromboxane synthase activity or cyclic adenosine monophosphate (AMP) levels. Allicin also inhibits platelet aggregation but does not alter the activity of vascular prostacyclin synthase. However, it inhibits ionophore A23187-stimulated human neutrophil lysosomal enzyme release. Thus garlic appears to be in possession of components which might exert their effects at various stages involved in the process of platelet aggregation.
Blood pressure lowering effect
A general definition of hypertension is a systolic blood pressure (SBP) of 140 mm Hg or higher or a diastolic blood pressure (DBP) of 90 mm Hg or higher or both. Prevention and proper management of hypertension decreases the incidence of related morbidity and mortality. A downward shift of 3 mm Hg in SBP decreases the mortality from stroke by 8% and from ischemic heart disease by 5% (Joint National Committee, 1993). Life style modification are definitive therapy for some and adjunctive therapy for all persons with hypertension (Joint National Committee, 1997). Diets that are high in fruits, vegetables and low-fat dairy products; have been shown to reduce hypertension. Increased consumption of garlic is associated with lower incidence of hypertension in population. Based on current information, garlic powder preparations are considered for recommendation as adjuncts in the treatment of hypertensive patients .
In experimental animals, intravenous injection of garlic extracts produced slight reductions in both systolic and diastolic pressures [91, 92]. Oral administration of garlic reduced experimentally induced hypertension, bringing blood pressure back to the normal range. For example 2.5 to 25 mg per kg of alcoholic garlic extract reduced blood pressure by 10 to 50 mm Hg . Blood pressure in dogs has been significantly reduced for several hours following intragastric administration of a small dose of garlic powder (as low as 2.5 mg/kg b.wt) . Other animal experiments on rats and dogs also indicate a 'normalizing' effect of garlic on elevated blood pressure [93, 95–98]. The antihypertensive effect of garlic in these studies has been repeatedly confirmed.
Allicin, a major constituent of garlic, was also evaluated for its antihypertensive effects. Chronic oral administration of allicin lowered blood pressure in hypertensive rats [99, 100]. Allicin also caused pulmonary vasodilatation in isolated lung of rat . Single as well as multiple doses of aqueous garlic extract reduced thromboxane B2 and prostaglandin E2 level and thereby reduced hypertension in '2 kidney 1-clip' model of hypertension in rat . Garlic also inhibited endothelin-1 induced contraction in a dose-dependent manner in isolated rat pulmonary arteries .
Garlic (100 mg/kg) administration for 5 days resulted in a complete inhibition of acute hypoxic pulmonary vasoconstriction in rat . There was a marked decrease in systolic blood pressure in spontaneously hypertensive rats after oral administration of single dose of garlic . Prolongation of life span was also found in hypertensive rats by dietary supplementation with garlic .
Blood pressure lowering effect of garlic on human is given in Table- 4. Leoper and DeBray recognized the hypotensive effect of garlic in 1921 . Damrau (1941) has reviewed the earlier literature, including his own investigations on 26 patients . Blood pressure reduction was observed in 85% of the patients, the average decline being 12.3 mm Hg systolic (SBP) and 6.5 mm Hg diastolic (DBP) blood pressure, over one-quarter of the subjects experienced a decline in SBP of 20 mm Hg or more.
Piotrowski (1948) has reviewed some of the early clinical studies in which garlic was administered under controlled conditions to hypertensive patients . Two-fifths of 100 patients exhibited a 20 mm Hg or greater decline in SBP generally within 1 week after initiation of treatment with 0.6 to 1.2 g daily of a dialyzed, alcoholic garlic extract.
Studies with a dried garlic powder (Kwai tablets) showed an average decrease in blood pressure of about 9% with 0.6 g garlic powder per day [77, 109] and in a randomized double blind trial, a beneficial effect of garlic on blood pressure and blood lipids in mildly hypertensive subjects was demonstrated . Those reports point in the same direction, that garlic can be useful in the control of mild hypertension in many if not all cases.
Pektov (1979) has also cited several studies, mostly from the Soviet Union and Bulgaria, which indicate that garlic and its extracts exhibit antihypertensive activity . Besides subjective improvement, the results of these studies indicated a moderate hypotensive effect involving a drop in SBP of 20–30 mm Hg and in DBP of 10–20 mm Hg. Another study in China (1986) on 70 hypertensive patients who were given garlic oil equivalent to 50 gm of raw garlic/day, 47 patients showed moderate to marked reduction in blood pressure .
There is only one meta-analysis done by Silagy and Neil (1994) . Eight trials were identified all using the same dried garlic powder preparation (Kwai). Data from 415 subjects were included in the analysis. Only three trials were specifically conducted in hypertensive subjects. Of the seven trials that compared the effect of garlic with that of placebo, three showed a significant reduction in systolic blood pressure (SBP) and four in diastolic blood pressure (DBP). The overall pooled mean difference in the absolute change (from baseline to final measurement) of SBP was greater in the subjects who were treated with garlic than in those treated with placebo. For DBP the corresponding reduction in the garlic-treated subjects was slightly smaller. This meta-analysis suggest that this "garlic powder preparation may be of some clinical use in subjects with mild hypertension". However, there is still insufficient evidence to recommend it as a routine clinical therapy for the treatment of hypertensive subjects. More rigorously designed and analyzed trials are needed for firm conclusion.
Rashid and Khan (1985) have postulated that mechanism of antihypertensive action of garlic is due to its prostaglandin like effects, which decreases peripheral vascular resistance . The gamma-glutamylcysteines are the compounds in garlic that may lower blood pressure, as indicated by their ability to inhibit angiotensin-converting enzyme in in vitro . Garlic modulates the production and function of both endothelium derived relaxing and constricting factors and this may contribute to its protective effect against hypoxic pulmonary vasoconstriction . Garlic elicits nitric-oxide-dependent relaxation in pulmonary arteries. This hypothesis was explained by the fact that NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor) abolished the vasodilatory effect of garlic [103, 104]. But another study reported that pulmonary vasodilatory effect of allicin are independent of the synthesis of NO, ATP-sensitive (K+) channel, activation of cyclooxygenase enzyme .
Diabetes mellitus is a group of diseases characterized by high blood glucose levels resulting from defects in insulin secretion, insulin action, or both. Abnormalities in the metabolism of carbohydrate, protein, and fat are also present . Nutrition plays a primary role to control blood glucose level and further complication.
Garlic was effective in reducing blood glucose in streptozotocin-induced [123–126] as well as alloxan-induced [127–132] diabetes mellitus in rats and mice. Most of the studies showed that garlic can reduce blood glucose level in diabetic mice [127, 133], rats [124, 129, 130], and rabbit [131, 132]. Augusti & Sheela consistently showed that S-allyl cysteine sulfoxide (alliin), a sulfur containing amino acid in garlic (200 mg/kg b.wt.) has a potential to reduce diabetic condition in rat almost to the same extent as did glibenclamide and insulin [128–130]. Treatment of diabetic rats with garlic oil decreased serum acid and alkaline phosphatase, serum alanine and asparate transferases, as well as serum amylase in diabetic rats . Aged garlic extract is also effective to prevent adrenal hypertrophy, hyperglycemia and elevation of corticosterone in hyperglycemic mice induced by immobilization stress . Garlic intake (6.25% by weight in diet) for 12 days reduced hyperphagia and polydipsia but did not alter hyperglycemia and hypoinsulinaemia in streptozotocin-induced diabetic mice . Ingestion of garlic juice resulted in better utilization of glucose in glucose tolerance test performed in rabbits [132, 134]. The ethyl alcohol, petroleum ether and ethyl ether extracts of garlic produced a significant fall in blood sugar levels in rabbits . Allicin at a dose of 250 mg/kg is 60% as effective as tolbutamide in alloxan-induced diabetic rabbit .
Hypoglycemic effect of garlic in human is not well studied. Chronic feeding of garlic oil and garlic powder [78, 135] showed significant decrease in blood glucose level whereas some other studies [57, 117, 136] showed no change of blood glucose level. All human studies (Table- 5), except one or two, showing effect of garlic on blood glucose level on normal healthy individuals but not in diabetic patients. Thus the role of garlic in diabetic condition is yet to be confirmed.
Though the exact mechanism/s of garlic as antidiabetic agent is still not clear but in-vivo [124, 132] as well as in-vitro  studies showed that garlic acts as an insulin secretagogue in diabetic rats. Augusti & Sheela also proposed that antioxidant effect of S-allyl cysteine sulfoxide (isolated product from garlic) may also contribute for its beneficial effect in diabetes . Another proposed mechanism is due to spare insulin from sulphydryl group. Inactivation of insulin by sulphydryl group is a common phenomenon. Garlic (allicin) can effectively combine with compounds like cysteine and enhance serum insulin . Jain & Vyas proposed that garlic can act as an antidiabetic agent by increasing either the pancreatic secretion of insulin from the beta cells or its release from bound insulin .
Other cardioprotective properties of garlic
Garlic has a significant antiarrhythmic effect in both ventricular and supraventricular arrhythmias. Garlic powder (1% added to a standard chow for an 8 week period) significantly reduced ischemia reperfusion-induced ventricular fibrillation (VF) in isolated perfused rat heart . Garlic dialysate suppressed premature ventricular contractions and ventricular tachycardia in ouabain-intoxicated dogs as well as ectopic rhythms induced by isoprenaline and aconitine on electrically driven left rat atria . Garlic dialysate decreased the positive inotropic and chronotropic effects of isoproterenol in a concentration dependent manner. β-receptor blocking action of garlic was also suggested by Martin et al . The positive inotropism and chronotorpism induced by isoproterenol were partially antagonized by preincubation of the rat atria with the garlic dialysate. The ECG showed a regular sinus bradycardic rhythm in garlic dialysate fed anaesthetized rat . Direct relaxant effect of cardiac muscles was reported by Aqel et al . Garlic juice inhibited norepinephrine-induced contractions of rabbit and guinea pig aortic rings. It also inhibited the force of contraction of isolated rabbit heart in a concentration-dependent manner . Only one study showed that aqueous garlic extract increased the amplitudes of atrial complex 'p' wave and the ventricular complex 'QRS' of the rat ECG. This is suggestive of increase in voltage output of the atria and ventricles probably in accordance with positive inotropism .
Raw garlic homogenate augmented endogenous antioxidants along with reduction of basal lipid peroxidation in rat heart, liver and kidney in a dose dependent manner [143, 144]. Aged garlic extract (AGE) also exerted its antioxidant action by scavenging reactive oxygen species  and enhancing the cellular antioxidants, like reduced glutathione superoxide dismutase, catalase and glutathione peroxidase of vascular endothelial cells [146, 147]. Augmented endogenous antioxidants on heart and endothelial cells have important direct cytoprotective effects, especially in the event of oxidant stress induced injury. Recently, in our laboratory, we found that chronic oral administration of garlic homogenate protected the rat heart from in vitro ischemic reperfusion injury  and oxidative stress induced by single dose of adriamycin . AGE has been shown to offer protection against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy . Feeding of garlic powder in rats for 11 days had a protective effect on isoproterenol-induced myocardial damage . In another study, the size of the ischemic zone was significantly reduced and the onset of arrhythmia after occlusion of the descending branch of the left coronary artery was significantly prolonged in rats fed with a standard chow enriched with 1% garlic powder for 10 weeks . Aqueous garlic extract was also found to be effective in reducing Cu (+)-initiated oxidation of low density lipoprotein (LDL) as measured by photochemiluminescence method . AGE also protected vascular endothelial cells from H2O2-induced oxidant injury .
Aortic stiffening is as much an important risk factor in cardiovascular morbidity and mortality, as it serves as reliable surrogate marker for clinical endpoints like myocardial and cerebrovascular incidents. Elevated aortic stiffness induces high systolic blood pressure, augmented pulse pressure with increased ventricular afterload, reduced subendocardial blood flow and augmented pulsatile stress in the peripheral arteries . In population, consuming garlic for long period, attenuation of age-related increase in aortic stiffness has been observed. This suggests a protective effect on the elastic properties of the aorta related to aging in human . This study also showed that regular long term garlic powder intake protected endothelial cell from oxidative injury . Twelve week therapy with garlic powder (800 mg/day) was effective in patients with peripheral arterial occlusive disease Stage II. There was a significant decrease of plasma viscosity. It is also quite interesting that the garlic-specific increase in walking distance did not appear to occur until the 5th week of treatment . Microcirculation of skin increased by 48% after administration of 800 mg/day garlic powder over a period of four weeks. Plasma viscosity was decreased by 3.2% . Kiesewetter also reported that garlic improved blood fluidity and increased capillary perfusion . Decreased plasma viscosity and increased (55%) capillary skin perfusion were observed even after 5 hours of garlic powder administration . All these studies are summarised in Table- 6.
Considering the fact that garlic has been an integral part of our diet for centuries, it is taken for granted that garlic is safe in a wide range of doses. But a few isolated reports highlight some of the adverse and toxic effects of garlic.
Higher concentrations of garlic extract have been shown to be clastogenic  in mice, which was appreciably reduced at lower concentrations. Prolong feeding of high levels of raw garlic in rats has resulted in anemia, weight loss and failure to grow due to lysis of red blood cells . Raw garlic juice at a dose of 5 ml/kg has resulted in death of rats due to stomach injury . Surviving rats exhibited swelling of the liver, hypertrophy of the spleen and adrenal glands, and the decrease of erythrocyte count with various morphological changes after 3 and 8 days. Aqueous garlic extract (200 gm/l drinking water) for 10 days exhibited significantly higher levels of aspartate aminotransferase (AST) due to liver injury. Histopathological examination of liver showed focal nonspecific injury with inflammatory cell infiltration in hepatocytes . Chen et al., (1999) have reported that treatment of rats with fresh garlic homogenate for 7 days caused a significant decrease in liver catalase activity in doses of 2 and 4 gm/kg . The ultrastructural study carried out in our laboratory revealed significant loss of normal cellular architecture of heart, liver and kidneys after 30 days feeding of raw garlic homogenate at 1000 mg/kg/day dose [143, 144]. Feeding of allicin (100 mg/kg/day) for 15 days in rats increased the activity of liver lipase and alpha glucal phosphorylase and decreased glucose-6-phosphatase activity . The exact mechanism of such garlic induced alteration in cell structure and function is not clear.
There is also some reported toxicity with garlic powder. Chronic administration of garlic powder (50 mg/day) resulted in inhibition of spermatogenesis in rats. Reduced concentration of sialic acid in the testes, epididymis and seminal vesicles together with decreased leydig cell function reflects antiandrogenic effect of garlic . Higher concentration of garlic powder (200 mg/ml) or allicin isolated from garlic caused considerable cell injuries in the porta hepatis zone in isolated perfused rat liver , which was not observed at a lower concentration. Another in vitro study showed that diallyl sulfide (oxidized product of allicin) at 5 mM significantly decreased cell viability in liver .
Garlic oil fed at a dose of 100 mg/kg after 24 hour fasting has also been found to be lethal. The cause of death appears to be acute pulmonary edema with severe congestion . Garlic oil and Diallyl-disulfide (200 mg/kg b.w.) significantly reduced body weight gain of rats . Ajoene, a garlic derived natural compound, present in other types of garlic oil, is an inhibitor as well as a substrate of human glutathione reductase and expected to increase the oxidative stress of the respective cell .
All the above mentioned toxicity reports can not be explained to its fullest extent but the sulphoxides present in the garlic extract can undergo exchange reaction with the tritable SH-groups of enzymes and other proteins in the body spontaneously at physiological pH and temperature, inhibiting their activity. Garlic has been demonstrated to inhibit the alkaline phosphatase , papain, and alcohol dehydrogenase . These enzyme interactions with garlic components may be a reason for its toxicity.
Relatively few side effects were reported in clinical studies using garlic and its preparations. Most of the reported side effects were non-specific. Gastrointestinal discomfort and nausea were the most frequent complaint . A survey by Koch (1995) showed that allergic reactions to garlic were reported in a total of 39 publications between 1938 and 1994 . Most of these cases involved an allergic contact dermatitis, sometimes severe , which has been reported in people with occupational exposure to garlic. There have also been sporadic reports of allergic conjunctivitis, rhinitis, or bronchospasms occurring in response to garlic inhalation or ingestion [173, 174]. Other reported side effects included bloating, headache, dizziness, and profuse sweating . Ingestion of fresh garlic and garlic powder may have additive effects with anticoagulants or platelet aggregation inhibitors, leading in one case to a life-threatening hemorrhage [175–179].
Epidemiological study shows an inverse correlation between garlic consumption and reduced risk of cardiovascular disease progression [180–182]. The wealth of scientific literature supports the proposal that garlic consumption have significant cardioprotective effect, which include both animal and human studies. But certain issues regarding the proper use of garlic, i.e use of different preparations available, dose, duration and interaction with generic drugs should be optimized. Further research should also be carried out to identify specific compounds from garlic or garlic products that are responsible for most of its biological effects.
Lawson LD: Garlic: a review of its medicinal effects and indicated active compounds. In: Phytomedicines of Europe. Chemistry and Biological Activity. Series 691. Edited by: Lawson LD & Bauer R. 1998, American Chemical Society, Washington, DC, 176-209.
Moyers S: Garlic in Health, History and World Cuisine. Suncoast Press, St. Petersburg, FL. 1996, 1-36.
Woodward PW: Garlic and Friends: The History, Growth and Use of Edible Alliums. Hyland House, Melbourne, Australia. 1996, 2-22.
Rivlin RS: Patient with hyperlipidemia who received garlic supplements. Lipid management. Report from the Lipid Education Council. 1998, 3: 6-7.
Borek C: Antioxidant health effect of aged garlic extract. J Nutr. 2001, 131: 1010S-1015S.
Ryu K, Ide N, Matsuura H, Itakura Y: N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine, an antioxidant compound identified in aged garlic extract. J Nutr. 2001, 131: 972S-976S.
Schwartz CJ, Valente AJ, Sprague EA: A modern view of atherogenesis. Am J Cardiol. 1993, 71: 9b-14b.
Jain RC: Onion and garlic an experimental cholesterol atherosclerosis in rabbits. Artery. 1975, 1: 115-125.
Jain RC: Effect of garlic on serum lipids, coagulability and fibrinolytic activity of blood. Am J Clin Nutr. 1977, 30: 1380-1381.
Bordia A, Verma SK, Vyas AK, Khabya BL, Rathore AS, Bhu N, Bedi HK: Effect of essential oil of onion and garlic on experimental atherosclerosis in rabbits. Atherosclerosis. 1977, 26: 379-386.
Chang MLW, Johnson MA: Effect of garlic on carbohydrate metabolism and lipid synthesis in rats. J Nutr. 1980, 110: 931-936.
Kamanna VS, Chandrasekhara N: Hypocholesteromic activity of different fractions of garlic. Ind J Medical Res. 1984, 79: 580-583.
Mand JK, Gupta PP, Soni GL, Singh R: Effect of garlic on experimental atherosclerosis in rabbits. Ind Heart J. 1985, 37: 183-188.
Betz E, Weidler R: Die Wirkung von Knoblauchextrakt auf die atheerogenese bei kaninchen. In: Die anwendung aktueller methoden in der arteriosklerose. Forschung. Edited by: Betz E. 1989, 304-311.
Rajasree CR, Rajmohan T, Agusti KT: Biochemical effects of garlic on lipid metabolism in alcohol fed rats. Ind J Exp Biol. 1999, 37: 243-247.
Mathew BC, Daniel RS: Hypolipidemic effect of garlic protein substituted for caseinin diet of rats compared to those of garlic oil. Ind J Exp Biol. 1996, 34: 337-340.
Qureshi AA, Din ZZ, Abuirameileh N, Burger WC, Ahmed Y, Elson CE: Suppression of avian hepatic lipid metabolism by solvent extracts of garlic: impact on serum lipids. J Nutr. 1983, 113: 1746-1755.
Kamanna VS, Chandrasekhara N: Effect of garlic on serum lipoproteins cholesterol levels in albino rats rendered hypercholesteremic by feeding cholesterol. Lipids. 1982, 17: 483-488.
Chi MS: Effect of garlic products on lipid metabolism in cholesterol-fed rats. Proc Soc Exp Biol Med. 1982, 171: 174-178.
Chi MS, Koh ET, Stewart TJ: Effect of garlic on lipid metabolism in rats fed cholesterol or lard. J Nutr. 1982, 112: 241-248.
Abramovitz D, Gavri S, Harats D, Levkovitz H, Mirelman D, Miron T, Eilat-Adar S, Rabinkov A, Wilchek M, Eldar M, Vered Z: Allicin-induced decrease in formation of fatty streaks (atherosclerosis) in mice fed a cholesterol-rich diet. Coron Artery Dis. 1999, 10: 515-519.
Efendy JL, Simmons DL, Campbell GR, Campbell JH: The effect of the aged garlic extract, 'Kyolic', on the development of experimental atherosclerosis. Atherosclerosis. 1997, 132: 37-42.
Campbell JH, Efendy JL, Smith NJ, Campbell GR: Molecular basis by which garlic suppresses atherosclerosis. J Nutr. 2001, 131: 1006S-1009S.
Lutomski J: Klinische Untersuchungen Zur therapeutischen wirksamkeit von llya Rogiff knoblanchpillen mit Rutin. Z Phytotherapia. 1984, 5: 938-942.
Luley C, Lehmann-Leo W, Moller B, Martin T, Schwartzkopff W: Lack of efficacy of dried garlic in patients with hyperlipoproteinemia. Arzneimittelforschung / Drug Res. 1986, 36: 766-768.
Ziaei S, Hantoshzadeh S, Rezasoltani P, Lamyian M: The effect of garlic tablet on plasma lipids and platelet aggregation in nulliparous pregnants at high risk of preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2001, 99: 201-206.
Gardner CD, Chatterjee LM, Carlson JJ: The effect of a garlic preparation on plasma lipid levels in moderately hypercholesterolemic adults. Atherosclerosis. 2001, 154: 213-220.
Rahman K, Billington D: Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr. 2000, 130: 2662-2665.
Superko HR, Krauss RM: Garlic powder, effect on plasma lipids, postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and lipoprotein(a). J Am Coll Cardiol. 2000, 35: 321-326.
Byrne DJ, Neil HA, Vallance DT, Winder AF: A pilot study of garlic consumption shows no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after allowance for non-compliance and the placebo effect. Clin Chim Acta. 1999, 285: 21-33.
McCrindle BW, Helden E, Conner WT: Garlic extract therapy in children with hypercholesterolemia. Arch Pediatr Adolesc Med. 1998, 152: 1089-1094.
Berthold HK, Sudhop T: Garlic preparations for prevention of atherosclerosis. Curr Opin Lipidol. 1998, 9: 565-569.
Isaacsohn JL, Moser M, Stein EA, Dudley K, Davey JA, Liskov E, Black HR: Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. Arch Intern Med. 1998, 158: 1189-1194.
Simons LA, Balasubramanian S: Von Konigsmark M, Parfitt A, Simons J, Peters W. On the effects of garlic on plasma lipids and lipoproteins in mild hypercholesterolemia. Atherosclerosis. 1995, 113: 219-225.
Silagy C, Neil A: Garlic as a lipid lowering agent-a meta-analysis. J R Coll Physician Lond. 1994, 28: 39-45.
Warshafsky S, Kamer RS, Sivak SL: Effect of garlic on total serum cholesterol, A meta-analysis. Ann Intern Med. 1993, 119: 599-605.
Neil HA, Silagy CA, Lancaster T, Hodgeman J, Vos K, Moore JW, Jones L, Cahill J, Fowler GH: Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis. J R Coll Physicians Lond. 1996, 30: 329-334.
Stevinson C, Pittler MH, Ernst E: Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Ann Intern Med. 2000, 133: 420-429.
Orekhov AN, Grunwald J: Effects of garlic on atherosclerosis. Nutrition. 1997, 13: 656-663.
Yu-Yan Yeh, Liu L: Cholesterol lowering effect of garlic extracts and organosulfur compounds: Human and animal studies. J Nutr. 2001, 131: 989S-993S.
Munday JS, James KA, Fray LM, Kirkwood SW, Thompson KG: Daily supplementation with aged garlic extract, but not raw garlic, protects low density lipoprotein against in vitro oxidation. Atherosclerosis. 1999, 143: 399-404.
Lewin G, Popov I: Antioxidant effects of aqueous garlic extract. 2nd communication: Inhibition of the Cu(2+)-initiated oxidation of low density lipoproteins. Arzneimittelforschung. 1994, 44: 604-607.
Lau Benjamin HS: Suppression of LDL oxidation by garlic. J Nutr. 2001, 131 (3S): 958S-988S.
Gebhardt R, Beck H: Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte culture. Lipids. 1996, 31: 1269-1276.
Rodger B, Roberty B, Edward S: Fibrinolytic activity in acute myocardial infarction. Am J Clin Pathol. 1972, 57: 359-363.
Bordia A, Arora SK, Kothari LK, Jain KC, Rathore BS, Rathore AS, Dube MK, Bhu N: The protective action of essential oils of onion and garlic in cholesterol-fed rabbits. Atherosclerosis. 1975, 22: 103-109.
Sainani GS, Desai DB, Natu MN, Katrodia KM, Valame VP, Sainani PG: Onion, garlic, and experimental atherosclerosis. Jpn Heart J. 1979, 20: 351-357.
Mirhadi SA, Singh S, Gupta PP: Effect of garlic supplementation to cholesterol-rich diet on development of atherosclerosis in rabbits. Ind J Exp Biol. 1991, 29: 162-168.
Bordia AK, Joshi HK, Sandya YK, Bhu N: Effect of essential oil of garlic on serum fibrinalytic activity in patients with coronary artery disease. Atheroselerosis. 1977, 28: 155-
Bordia AK, Sodhya SK, Rathore AS, Bhu N: Essential oil of garlic on blood lipids and fibribolytic activity in patients with coronary artery disease. J Assoc Phys Ind. 1978, 26: 327-33.
Bordia AK, Sharma KD, Parmar VK, Varma SK: Protective effect of garlic oil on the changes produced by 3 weeks of fatty diet on serum cholesterol serum triglycerides, fibrimolytic acativity and platelet adhesiveness in man. Ind Heart J. 1982, 34: 86-
Chutani SK, Bardia A: The effect of fried versus Raw garlic on fibrinolytic activity in man. Atherosclerosis. 1988, 38: 417-421.
Sainani GS, Desai DB, Gorha NH, Natu SM, Pise DV, Sainani PG: Effect of dietary garlic and onion on serum lipid profile in Jain Community. Ind J of Med Res. 1979, 69: 776-780.
Arora RC, Arora S: Comparative effects of clofibrate, garlic and onion on alimentary hyperlipemia. Atherosclerosis. 1981, 39: 447-452.
Arora RC, Arora S, Gupta RK: The long-term use of garlic in ischemic heart disease. Atherosclerosis. 1981, 40: 175-179.
Legnani C, Frascaro M, Guazzaloca G, Ludovici S, Cesarano G, Coccheri S: Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung. 1993, 43: 119-122.
Bordia A, Verma SK, Srivastava KC: Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1998, 58: 257-263.
Bordia AK, Joshi HK: Garlic on fibrinolytic activity in cases of acute myocardial infarction. J Assoc Physiol Ind. 2978, 26: 323-326.
Harfenist WJ, Murry RK, Murry RK, Mayes PA, Grannen DK, Rodwell VW: Plasma proteins, immunoglobulin and clotting factors. In: Harper's Biochemistry. Edited by: Barnes DA. 2000, McGraw-Hill, New York, A Lange Medical Book, 737-762. 25
Ali M, Thomson M, Alnaqeeb MA, al-Hassan JM, Khater SH, Gomes A: Antithrombotic activity of garlic: its inhibition of the synthesis of thromboxane-B2 during infusion of arachidonic acid and collagen in rabbits. Prostaglandins Leukot Essent Fatty Acids. 1990, 41: 95-99.
Srivastava KC: Effects of aqueous extracts of onion, garlic and ginger on platelet aggregation and metabolism of arachidonic acid in the blood vascular system: in vitro study. Prostaglandins Leukot Med. 1984, 13: 227-235.
Ali M: Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase activity. Effect of raw versus boiled garlic extract on the synthesis of prostanoids. Prostaglandins Leukot Essent Fatty Acids. 1995, 53: 397-400.
Ali M, Bordia T, Mustafa T: Effect of raw versus boiled aqueous extract of garlic and onion on platelet aggregation. Prostaglandins Leukot Essent Fatty Acids. 1999, 60: 43-47.
Laurence WVD, John DF: Garlic extract prevents acute platelet thrombus formation in stenosed canine coronary arteries. Am Heart J. 1989, 117: 973-975.
Thomson M, Mustafa M, Ali M: Thromboxane-B(2) levels in serum of rabbits receiving a single intravenous dose of aqueous extract of garlic and onion. Prostaglandins Leukot Essent Fatty Acids. 2000, 63: 217-221.
el-Sabban F, Fahim MA, Radwan GM, Zaghloul SS, Singh S: Garlic preserves patency and delays hyperthermia-induced thrombosis in pial microcirculation. Int J Hyperthermia. 1996, 12: 513-525.
el-Sabban F, Radwan GM: Influence of garlic compared to aspirin on induced photothrombosis in mouse pial microvessels, in vivo. Thromb Res. 1997, 88: 193-203.
Apitz-Castro R, Escalante J, Vargas R, Jain MK: Ajoene, the antiplatelet principle of garlic, synergistically potentiates the antiaggregatory action of prostacyclin, forskolin, indomethacin and dypiridamole on human platelets. Thromb Res. 1986, 42: 303-311.
Apitz-Castro R, Badimon JJ, Badimon L: A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental model. Thromb Res. 1994, 75: 243-249.
Apitz-Castro R, Badimon JJ, Badimon L: Effect of ajoene, the major antiplatelet compound from garlic, on platelet thrombus formation. Thromb Res. 1992, 68: 145-155.
Makheja AN, Bailey JM: Antiplatelet constituents of garlic and onion. Agents Actions. 1990, 29: 360-363.
Bordia A: Effect of garlic on human platelet aggregation in vitro. Atherosclerosis. 1978, 30: 355-360.
Vanderhock JY, Makheja AN, Bailey JM: Inhibition of fatty acid oxygenases by onion and garlic acts. Evidence for the mechanism by which these oils inhibit platelet aggregation. Biochem Pharmacol. 1980, 29: 3169-3173.
Apitz-Castro R, Cabrera S, Cruz MR, Ledezma E, Jain MK: Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release activity and platelet ultrastructure. Thromb Res. 1983, 32: 155-169.
Srivsatava KC: Evidence for the mechanism by which garlic inhibitors platelet aggregation. Prostaglandin Leukot Med. 1986, 22: 313-321.
Samson RR: Effects of dietary garlic and temporal drift on platelet aggregation. Atherosclerosis. 1982, 44: 119-120.
Harenberg J, Giese C, Zimmermann R: Effect of dried garlic on blood coagulation, fibrinolysis, platelet aggregation and serum cholesterol levels in patients with hyperlipoproteinemia. Atherosclerosis. 1988, 74: 247-249.
Kiesewetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E: Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol. 1991, 29: 151-155.
Steiner M, Lin RS: Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract. J Cardiovasc Pharmacol. 1998, 31: 904-908.
Boullin DJ: Garlic as a platelet inhibitor. Lancet. 1981, 1: 776-777.
Wagner H, Wierer M, Fessler B: Effects of garlic constituents on arachidonate metabolism. Planta Med. 1987, 53: 305-306.
Srivastava KC, Tyagi OD: Effects of a garlic-derived principle (ajoene) on aggregation and arachidonic acid metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids. 1993, 49: 587-595.
Apitz-Castro R, Ledezma E, Escalante J, Jain MK: The molecular basis of the antiplatelet action of ajoene: direct interaction with the fibrinogen receptor. Biochem Biophys Res Commun. 1986, 141: 145-150.
Jamaluddin MP, Krishnan LK, Thomas A: Ajoene inhibition of platelet aggregation: possible mediation by a hemoprotein. Biochem Biophys Res Commun. 1988, 153: 479-486.
Ariga T, Oshiba S, Tamada T: Platelet aggregation inhibitor in garlic. Lancet. 1981, 1: 150-151.
Block E, Ahmad S, Jain MK, Crecely RW, Apitz Castro R, Cruz MR: (E,Z) Ajoene: A potent antithrombic agent from garlic. J Amer Chem Soc. 1984, 106: 8295-8296.
Kiesewetter H, Jung F, Jung EM, Mroweitz C, Koscielny J, Wenzel E: Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. Eur J Clin Pharmacol. 1993, 45: 333-336.
Morris J, Burke V, Mori TA, Vandongen R, Beilin LJ: Effects of garlic extract on platelet aggregation: a randomized placebo-controlled double-blind study. Clin Exp Pharmacol Physiol. 1995, 22: 414-417.
Steiner M, Li W: Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr. 2001, 131 (3s): 980S-984S.
Schulz V, Hansel R, Tyler VE: Cardiovascular system. In: Rational Phytotherapy; physicians' guide to herbal medicine. 2001, Springer-verlag, Berlin, 107-168.
Sial AY, Ahmed SJ: Study of the hypotensive action gerlic extract in experimental animals. J Pak Med Assoc. 1982, 32: 237-239.
Rashid A, Khan HH: The mechanism of hypotensive effect of garlic extract. J Pak Med Assoc. 1985, 35: 357-362.
Chanderkar AG, Jain PK: Analysis of hypotensive action of Allium sativum (garlic). Ind J Physiol Pharmacol. 1973, 17: 132-133.
Pantoja CV, Chiang Ch L, Norris BC, Concha JB: Diuretic, natriuretic and hypotensive effects produced by Allium sativum (garlic) in anaesthetized dogs. J Ethnopharmacol. 1991, 31: 325-331.
Banerjee AK: Effect of aqueous extract of garlic on arterial blood pressure of normotensive and hypertensive rats. Artery. 1976, 2: 369-
Ruffin J, Hunter SA: An evaluation of the side effects of garlic as an antihypertensive agent. Cytobias. 1983, 37: 85-89.
Foushee DB, Ruffin J, Banerjee U: Garlic as a natural agent for the treatment of hypertension: A preliminary report. Cytobios. 1982, 34: 145-152.
Malik ZA, Siddiqui S: Hypotensive effect of freeze dried garlic (Allium sativum) sap in dog. J Pak Med Assoc. 1981, 31: 12-13.
Elkayam A, Mirelman D, Peleg E, Wilchek M, Miron T, Rabinkov A, Sadetzki S, Rosenthal T: The effects of allicin and enalapril in fructose-induced hyperinsulinemic hyperlipidemic hypertensive rats. Am J Hypertens. 2001, 14: 377-381.
Ali M, Al-Qattan KK, Al-Enezi F, Khanafer RM, Mustafa T: Effect of allicin from garlic powder on serum lipids and blood pressure in rats fed with a high cholesterol diet. Prostaglandins Leukot Essent Fatty Acids. 2000, 62: 253-259.
Kaye AD, De Witt BJ, Anwar M, Smith DE, Feng CJ, Kadowitz PJ, Nossaman BD: Analysis of responses of garlic derivatives in the pulmonary vascular bed of the rat. J Appl Physiol. 2000, 89: 353-358.
Al-Qattan KK, Khan I, Alnaqeeb MA, Ali M: Thromboxane-B2, prostaglandin-E2 and hypertension in the rat 2-kidney 1-clip model: a possible mechanism of the garlic induced hypotension. Prostaglandins Leukot Essent Fatty Acids. 2001, 64: 5-10.
Kim-Park S, Ku DD: Garlic elicits a nitric oxide-dependent relaxation and inhibits hypoxic pulmonary vasoconstriction in rats. Clin Exp Pharmacol Physiol. 2000, 27: 780-786.
Fallon MB, Abrams GA, Abdel-Razek TT, Dai J, Chen SJ, Chen YF, Luo B, Oparil S, Ku DD: Garlic prevents hypoxic pulmonary hypertension in rats. Am J Physiol. 1998, 275 (2 Pt 1): L283-L287.
Brandle M, al Makdessi S, Weber RK, Dietz K, Jacob R: Prolongation of life span in hypertensive rats by dietary interventions. Effects of garlic and linseed oil. Basic Res Cardiol. 1997, 92: 223-232.
Leoper M, DeBray M: Hypotensive effect of tincture of garlic. Prog Med. 1921, 36: 391-392.
Damru F: The use of garlic concentrate in vascular hypertension. Med Rec. 1941, 153: 249-251.
Piotrowski'ail en GL: therapeutique. Praxis. 1948, 26: 488-492.
Konig FK, Scineider B: Knoblauch bessert Durch-blutungstorungen Arztliche Praxis. 1986, 38: 44-35.
Auer W, Eiber A, Hertkom E, Kohrle U, Lenz A, Mader F, Merx W, Otto G, Schmid-Oto B, benheim H: Hypertonie and Hyperlipidamie: In leichterenauch Knoblauch. Der Allgemeinarzi. 1989, 3: 205-208.
Petkov V: Plants and hypotensive, antiatheromatous and coronarodilatating action:. Am J Chin Med. 1979, 7: 197-236.
Zheziang Institute of Traditional Chinese Medicine: The effect of essential oil of garlic on hyperlipemia and platelet aggregation – an analysis of 308 cases. Cooperative Group for Essential Oil of Garlic. J Tradit Chin Med. 1986, 6: 117-120.
Silagy CA, Neil HA: A meta-analysis of the effect of garlic on blood pressure. J Hyperten. 1994, 12: 463-468.
Sendl A, Elbl G, Steinke B, Redl K, Breu W, Wagner H: Comparative pharmacological investigations of Allium ursinum and Allium sativum. Planta Medica. 1992, 58: 1-7.
Qidwai W, Qureshi R, Hasan SN, Azam SI: Effect of dietary garlic (Allium Sativum) on the blood pressure in humans – a pilot study. J Pak Med Assoc. 2000, 50 (6): 204-207.
Steiner M, Khan AH, Holbert D, Lin RI: A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr. 1996, 64: 866-870.
Jain AK, Vargas R, Gotzkowsky S, McMahon FG: Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med. 1993, 94: 632-635.
McMahon FG, Vargas R: Can garlic lower blood pressure? A pilot study. Pharmacotherapy. 1993, 13: 406-407.
Auer W, Eiber A, Hertkom E, Kohrle U, Lenz A, Mader F, Merx W, Otto G, Schmid-Oto B, benheim H: Hypertonie and Hyperlipidamie: In leichterenauch Knoblauch. Der Allgemeinarzi. 1989, 3: 205-208.
Zimmermann W, Zimmermann B: Reduction in elevated blood lipids in hospitalised patients by a standardised garlic preparation. Br J Clin Prac. 1990, 44 (suppl 69): 20-23.
Vorberg G, Schneider B: Therapy with garlic: results of a placebo-controlled, double-blind study. Br J Clin Prac. 1990, 44 (suppl 69): 7-11.
Granner DK, Murry RK, Mayes PA, Grannen DK, Rodwell VW: Hormones of the pancreas and gastrontestinal tract. In: Harper's Biochemistry. Edited by: Barnes DA. 2000, McGraw-Hill, New York, A Lange Medical Book, 610-626. 25
Ohaeri OC: Effect of garlic oil on the levels of various enzyme in the serum and tissue of streptozotocin diabtic rats. Biosci Rep. 2001, 21: 19-24.
Patumraj S, Tewit S, Amatyakul S, Jariyapongskul A, Maneesri S, Kasantikul V, Shepro D: Comparative effects of garlic and aspirin on diabetic cardiovascular complications. Drug Deliv. 2000, 7: 91-96.
Swanston-Flatt SK, Day C, Bailey CJ, Flatt PR: Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Diabetologia. 1990, 33: 462-464.
Farva D, Goji LA, Joseph PK, Augusti KT: Effects of garlic oil on streptozotocin-diabetic rats maintained on normal and high fat diets. Indian J Biochem Biophys. 1986, 23: 24-27.
Kumar GR, Reddy KP: Reduced nociceptive responses in mice with alloxan induced hyperglycemia after garlic (Allium sastivum) teratment. Indian J Exp Biol. 1999, 37: 662-666.
Augusti KT, Sheela CG: Antiperoxide effect of S-allyl cysteine sulfoxide, a insulin secretagogue, in diabetic rats. Experientia. 1996, 52: 115-120.
Sheela CG, Kumud K, Augusti KT: Anti-diabetic effect of onion and garlic sulfoxide amino acids in rats. Planta Medica. 1995, 61: 356-357.
Sheela CG, Augusti KT: Antidiabetic effects of S-allyl cysteine sulphoxide isolated from garlic Allium sativum Linn. Indian J Exp Biol. 1992, 30: 523-526.
Jain RC, Vyas CR: Garlic in alloxan-induced diabetic rabbits. Am J Clin Nutr. 1975, 28: 684-685.
Mathew PT, Augusti KT: Studies on the effect of allicin (diallyl disulphide-oxide) on alloxan diabetes I. Hypoglycaemic action and enhancement of serum insulin effect and glycogen synthesis. Indian J Biochem Biophys. 1973, 10: 209-212.
Kasuga S, Ushijima M, Morihara N, Itakura Y, Nakata Y: Effect of aged garlic extract (AGE) on hyperglycemia induced by immobilization stress in mice. Nippon Yakurigaku Zassh. 1999, 114: 191-197.
Jain RC, Vyas CR: Hypoglycemic action of onion and garlic. Lancet. 1973, 2: 1491-
Zhang XH, Lowe D, Giles P, Fell S, Connock MJ, Maslin DJ: Gender may affect the action of garlic oil on plasma cholesterol and glucose levels of normal subjects. J Nutr. 2001, 131: 1471-1478.
Ali M, Thomson M: Consumption of garlic clove a day could be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty acids. 1995, 53: 211-212.
Li G, Shi Z, Jia H, Ju J, Wang X, Xia Z, Qin L, Ge C, Xu Y, Cheng L, Chen P, Yuan G: A clinical investigation on garlicin injectio for treatment of unstable angina pectoris and its actions on plasma endothelin and blood sugar levels. J Tradit Chin Med. 2000, 20: 243-246.
Rietz B, Belagyi J, Torok B, Jacob R: The radical scavenging ability of garlic examined in various models. Bolletino Chimico Farmaceutico. 1995, 134: 69-76.
Martin N, Bardisa L, Pantojaa C, Vargas M, Quezaada P, Valenzuela J: Antiarrhythmic profile of a gaarlic dialystate assaay ed in dogs and isolaated atrial preparations. J Ethanophrmacol. 1994, 43: 1-8.
Martin N, Bardisa L, Pantojaa C, Vargas M, Quezaada P, Valenzuela J: Antiarrhythmic profile of a gaarlic dialystate assaay ed in dogs and isolaated atrial preparations. J Ethanophrmacol. 1994, 43: 1-8.
Aqel MB, Gharaibah MN, Salhab AS: Direct relaxant effects of garlic juice on smooth and cardiac muscles. J Ethnopharmacol. 1991, 33: 13-19.
Tongia SK: Effects of intravenous garlic Juice Aallium sativum on rat Electrocardiogram. Ind J Physiol Pharmacol. 1984, 28: 250-252.
Banerjee SK, Maulik M, Mancahanda SC, Dinda AK, Gupta SK, Maulik SK: Dose-dependent induction of endogenous antioxidants in rat heart by chronic administration of garlic. Life Scicences. 2002, 70: 1509-1518.
Banerjee SK, Maulik M, Manchanda SC, Dinda AK, Das TK, Maulik SK: Garlic-induced alteration in rat liver and kidney morphology and associated changes in endogenous antioxidant status. Food Chem Toxicol. 2001, 39: 793-797.
Imai J, Ide N, Nagae S, Moriguchi T, Matsuura H, Itakura Y: Antioxidant and radical scavenging effects of aged garlic extract and its constituents. Planta Med. 1994, 60: 417-420.
Geng Z, Lau B: Aged garlic extract modulates glutathione redox cycle and superoxide dismutase activity in vascular endothelial cells. Phytother Res. 1997, 11: 54-56.
Wei Z, Lau BHA: Garlic inhibits free radical generation and augments antioxidant enzyme activity in vascular endothelial cells. Nutr Res. 1998, 18: 61-70.
Banerjee SK, Maulik M, Gupta SK, Manchanda SC, Dinda AK, Maulik SK: Effect of chronic garlic intake on endogenous antioxidants and ischemic-reperfusion injury in isolated rat heart. Ind J Pharmacol. 2001, 33: 298-
Mukherjee S, Maulik M, Talwar KK, Dinda AK, Maulik SK: Effect of chronic raw garlic administration in adriamycin induced oxidant stress in rat hearts. Ind J Pharmacol. 2001, 33: 297-
Kojima R, Epstein CJ, Mizui T, Carlson E, Chaqn PH: Protective effects of aged garlic extracts on doxorubicin induced cardiotoxicity in the mouse. Nutr Cancer. 1994, 22: 163-173.
Ciplea AG, Richter KD: The protective effect of Allium sativum and crataegus on isoprenaline-induced tissue necrosis in rats. Arzneim-Forsch / Drug Res. 1988, 38 (II): 1583-1592.
Isensee H, Rietz B, Jacob R: Cardioprotective action of garlic (Allium sativum). Arzneim Forsch / Drug Res. 1993, 43: 94-98.
Yamasaki T, Lau BH: Garlic compounds protect vascular endothelial cells from oxidant injury. Nippon Yakurigaku Zasshi. 1997, 110 (Suppl 1): 138P-141P.
Breithaupt-Grogler K, Belz GG: Epidemiology of the arterial stiffness. Pathol Biol (Paris). 1999, 47: 604-613.
Breithaupt-Grogler K, Ling M, Boudoulas H, Belz GG: Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation. 1997, 96: 2649-2655.
Kiesewetter H, Jung F, Mrowietz C, Pindur G, Heiden M, Wenzel E, Gu LD: Effects of garlic on blood fluidity and fibrinolytic activity: a randomised, placebo-controlled, double-blind study. Br J Clin Pract. 1990, 69: 24-29.
Jung EM, Jung F, Mrowietz C, Kiesewetter H, Pindur G, Wenzel E: Influence of garlic powder on cutaneous microcirculation. A randomized placebo-controlled double-blind cross-over study in apparently healthy subjects. Arzneimittelforschung. 1991, 41: 626-630.
Das T, Roychoudhury A, Sharma A, Talukder G: Effects of crude garlic extract on mouse chromosomes in vivo. Food and Chemical Toxicology. 1996, 34: 43-47.
Augusti KT: Therapeutic values of onion (Allium cepa L) and garlic (Allium sativum L). Ind J Exp Biol. 1996, 34: 634-640.
Nakagawa S, Masamoto K, Sumiyoshi H, Kunihiro K, Fuwa T: Effect of raw and extracted aged garlic on growth of young rats and their organ after peroral administration. J Toxicol Sci. 1980, 5: 91-112.
Joseph PK, Rao KR, Sundaresh CS: Toxic effects of garlic extract and garlic oil in rats. Ind J Exp Biol. 1989, 27: 977-979.
Chen L, Hong JY, So E, Hussain AH, Cheng WF: Decrease of hepatic catalase level by treatment with diallyl sulfide and garlic homogenates in rats and mice. J Biochem Mol Toxicol. 1999, 13: 127-133.
Augusti KT, Mathew PT: Effect of allicin on certain enzymes of liver after a short term feeding to normal rats. Experentia. 1975, 31: 148-149.
Dixit VP, Joshi S: Effects of chronic administration of garlic (Allium sativum Linn) on testicular function. Ind J Exp Biol. 1982, 20: 534-536.
Egen-Schwind C, Eckard R, Kemper FH: Metabolism of garlic constituents in the isolated perfused rat liver. Planta Medica. 1992, 58: 301-305.
Sheen LY, Li CK, Sheu SF, Meng RHC, Tsai SJ: Effect of the active principle of garlic-diallyl sulfide- on cell viability, detoxification capability and the antioxidation system on primary rat hepatocytes. Food Chem Toxicol. 1996, 34: 971-978.
Sheen LY, Chen HW, Kung YL, Liu CT, Lii CK: Effects of garlic oil and its organosulfur compounds on the activities of hepatic drug-metabolizing and antioxidant enzymes in rats fed high- and low-fat diets. Nutr Cancer. 1999, 35: 160-166.
Gallwitz H, Bonse S, Martinez-Cruz A, Schlichting I, Schumacher K, Krauth-Siege RL: Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies. J Med Chem. 1999, 42: 364-372.
Rabinkov A, Miron T, Mirelman D, Wilchek M, Glozman S, Yavin E, Weiner L: S-Allylmercaptoglutathione: the reaction product of allicin with glutathione possesses SH-modifying and antioxidant properties. Biochim Biophys Acta. 2000, 1499: 144-153.
Beck E, Grunwald J: Allium sativum in der Stufentherapie der Hyperlipidamie. Med Welt. 1993, 44: 516-520.
Koch HP, Hahn G, Lawson L, Reuter HD, Siegers CP: Garlic-An introduction to the therapeutic application of Allium sativum L. Williams & Wilkins, Baltimore, im Druck. 1995
Eming SA, Piontek JO, Hunzelmann N, Rasokat H, Scharffetter-Kachanek K: Severe toxic contact dematitis caused by garlic. Br J Dermatol. 1999, 141: 391-392.
Falleroni AE, Zeiss CR, Levitz D: Occupational asthma secondary to inhalation of garlic dust. J Allergy Clin Immunol. 1981, 68: 156-160.
Papageogiou D, Corbet JP, Menezes F-Brando, Pecegueiro M, Benezra C: Allergic: contact dermatitis to garlic (Allium sativum I) identification of the allergens: the role of mono-, di- and trisulfides present in garlic. Arch Dermatol Res. 1983, 275: 229-234.
Rose KD, Croissant PD, Parliament CF, Levin MB: Spontaneous Spinal Epidural Hematoma with Associated Platelet Dysfunction from Excessive Garlic Ingestion: A case Report. Neurosurgery. 1990, 26: 880-882.
Sunter WH: Warfarin and garlic. Pharm J. 1991, 246: 722-
Burnham BE: Garlic as a possible risk for postoperative bleeding. Plast Recon Surg. 1995, 95: 213-
Fugh-Berman A: Herb-drug interactions. Lancet. 2000, 355: 134-138.
Petry JJ: Garlic and postoperative bleeding. Plastic Recon Surg. 1995, 96: 483-484.
Kendler BS: Garlic (Allium sativum) and onion (Allium cepa): a review of their relationship to cardiovascular disease. Prev Med. 1987, 16 (5): 670-685.
Keys A: Wine, garlic and CHD in seven countries. Lancet. 1980, 1 (8160): 145-146.
The authors are thankful to Council for Scientific & Industrial Research (CSIR), Government of India, for financial support for this work.
SKB carried out the extensive search and compilation of the review article. SKM participated in its design, coordination and drafting the manuscript.