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Supplement: Recent Advances on the Nutritional Effects Associated with the Use of Garlic as a Supplement

Study of Garlic Extracts and Fractions on Cholesterol Plasma Levels and Vascular Reactivity in Cholesterol-Fed Rats¹

Department of Pharmacology, School of Pharmacy and ^* Department of Pharmacology, School of Medicine, Complutense University, 28040 Madrid, Spain.

²To whom correspondence should be addressed. E-mail: Teje{at}eucmax.sim.ucm.es.

ABSTRACT

Garlic is known for its pharmacologic and nutritional properties. In previous studies, garlic elicited a reduction in plasma levels of lipids by inhibiting hepatic cholesterol synthesis. The aim of this study was to investigate in an in vivo model the effects of garlic extract and some fractions on cholesterol levels and vascular reactivity in cholesterol-fed rats. Rats were fed a cholesterol-enriched diet for 16 wk and were divided into 10 groups as follows: control and hypercholesterolemic diet groups, 4 groups fed frozen garlic fractions and 4 groups fed raw garlic fractions with different doses. Blood samples were obtained to analyze HDL and LDL cholesterol levels. After treatment, rats were killed. The heart, liver and kidneys were weighed; the aorta was isolated, mounted in organ chambers and vascular reactivity was tested. Plasma concentration of cholesterol was 58 mg/dL (100%) at the beginning of the study and increased to 102 mg/dL (153%; hypercholesterolemic group) at the end of the treatment. Plasma total cholesterol decreased in all groups treated with garlic; moreover, this effect was higher in rats fed raw garlic fractions and extracts. LDL decreased significantly with respect to the hypercholesterolemic group in all groups treated with garlic fractions and extracts (P < 0.01); however, an increase in HDL was found in those treated with frozen fractions and extracts. The liver:body weight ratio decreased in all treated groups. The relaxing effect of acetylcholine (ACh) was enhanced in arteries contracted with noradrenaline (NE). These data suggest that garlic fractions could prevent diet-induced hypercholesterolemia and vascular alterations in the endothelium-dependent relaxation associated with atherosclerosis.

KEY WORDS: • Allium sativum fractions • aorta • rat • hypercholesterolemic diet • vascular reactivity

Atherosclerosis is the principal contributor to the pathogenesis of myocardial and cerebral infarction. Elevated plasma concentration of cholesterol, especially in LDL, is recognized as leading to the development of atherosclerosis. On the other hand, there is convincing evidence that relaxation mediated by endothelium-derived nitric oxide (NO) is impaired in arteries from hypercholesterolemic and atherosclerotic animals (Shimokawa and Vanhoutte 1989 , Verdeuren et al. 1986). Impairment has been reported to be reversed in the aorta of hypercholesterolemic rabbits by exposure in vivo to exogenous L-arginine, implying that NO synthesis may be reduced (Cooke et al. 1991 ).

Garlic (Allium sativum L.) has long been used widely not only as a flavoring agent but also as a folk medication. Its reported beneficial actions include antimicrobial (Cellini et al. 1996 ), antithrombotic (Bordia et al. 1996 ), antihypertensive (Foushee et al. 1982 , Mcmahon and Vargas 1993 ) and antihyperlipidemic effects (Eilat et al. 1995 , Yeh and Yeh 1994 ). Garlic also activates NO synthesis in cell-free homogenate (Das et al. 1995a and 1995b ). In this work, the aim was to examine the possible beneficial effects of garlic extract and its fractions on the alteration in vascular responsiveness that occurs in cholesterol-fed rats and whether any correlation exists between the decreasing effect of garlic on plasma cholesterol levels and its effect on vascular responsiveness.

MATERIALS AND METHODS

Diet and treatment.

Ten groups (n = 80) of male wistar rats (ANUC Complutense University, Madrid, Spain) weighing 200.0 ± 20.5 g at the beginning of the study, were used. Rats were housed identically in an air-conditioned room under a 12-h light:dark cycle. The control group was fed a standard diet (normal control). Group 0 was fed a standard diet plus 0.5% cholesterol (U.A.R., Paris, France; hypercholesterolemic controls). The groups receiving high cholesterol and garlic extracts and fractions were distributed according to the scheme shown in Table 1 . The experiment lasted 16 wk. All of the rats were initially fed a standard laboratory diet (Panlab S.L., Barcelona, Spain) for at least 7 d after delivery to our laboratory. Tap water was freely available. Food intake was monitored daily for the two control groups and the drug-treated groups. The different doses of garlic extracts and fractions were given orally every day. All protocols concerning animals were approved by the Complutense University of Madrid (EEC official registration 28079–15ABC).

Blood samples were collected from the jugular vein; the body weight (BW)³ of each rat was determined before the start the treatment and every 15 d. Serum concentrations of cholesterol, LDL and HDL were determined with commercially available enzyme kits (BioMerieux, Marcy, France). At the end of the treatment, the heart, liver and kidneys were weighed and the organ:BW ratio was calculated and expressed as a percentage.

Isolated blood vessel preparations.

The rats were anesthetized with ethyl ether and killed by exsanguination from the common carotid in wk 16 of treatment. The thoracic aorta was rapidly removed and placed in Krebs-Henseleit solution of the following composition (mmol/L): NaCl, 119; KCl, 4.7; NaHCO₃, 25; MgSO₄, 1.0; glucose, 11.1; KH₂PO₄, 1.2; and CaCl₂, 2.5.

Aortic rings.

Adherent fat and surrounding tissue were cleaned off and the arteries were cut into rings 2–3 mm in width. The rings were then suspended between two stainless steel hooks in organ baths containing 10 mL of Krebs-Henseleit solution. The solution was kept at 36 ± 0.5°C and gassed continuously with a 95% O₂-5% CO₂ gas mixture. The rings were mounted under 1 g tension. Each preparation was allowed to equilibrate for 60 min. Contractile responses were measured isometrically by means of force-displacement transducers (Grass FT 03) and were recorded on a Grass polygraph as previously described (Tejerina et al. 1988 ). The isometric force was also digitalized by a MacLab A/D converter (Chart v3.2, A.D Instruments, Castle Hill, Australia) and stored and displayed on a Macintosh computer (Ruiz and Tejerina 1998 ).

Experimental procedure.

After the equilibration period, aortic rings were contracted with noradrenaline (NE; 10^-6 mol/L) and exposed to acetylcholine (ACh; 10^-8 to 10^-5 mol/L) or to sodium nitroprusside (SNP; 10^-8 to10^-5 mol/L) when contraction had reached a plateau to test the endothelium-dependent and independent relaxation. Other aortic rings were contracted with KCl (80 mmol/L).

Drugs.

The following drugs were used: acetylcholine chloride, noradrenaline bitartrate and SNP were all from Sigma Chemical (St. Louis, MO). All garlic extracts and fractions were provided by Dr. Matsuura (The University of Illinois at Chicago, Chicago, IL) and are listed in Figure 1 . Stock solutions were prepared by dissolving the compound in distilled water. Ascorbic acid was added to the noradrenaline solution to avoid noradrenaline oxidation. Working solutions were made in Krebs-Henseleit solution.

View larger version (30K): [in this window] [in a new window]   Figure 1. Method of extraction of garlic extracts and fractions from raw (RG) and frozen garlic (FG).

All values used in analyses represent means ± SEM for 8 rats in each group of experiments. Comparisons among the different groups were performed by two-way ANOVA test or Student’s t test and differences were considered significant when P < 0.05. Concentration-response curves were used to determine the concentration of the drugs producing 50% inhibition of the maximal contractile response (IC₅₀); a linear regression analysis over the response range of 20–80% of the maximal inhibition was carried out.

RESULTS

Effect of the treatment on body and organ weights.

The BW (Fig. 2 , panel A) increased in all groups throughout the treatment without significant differences among them. There were no differences in the heart:BW ratio (Fig. 2 , panel B). However, the liver:BW ratio (Fig. 2 , panel C) decreased in all of the treated groups compared with the hypercholesterolemic group. Also, the kidney:BW ratio (Fig. 2 , panel D) decreased in groups 5 and 7 with respect to the hypercholesterolemic group.

View larger version (42K): [in this window] [in a new window]   Figure 2. Effect of the garlic fractions and extracts on the organ (heart, kidney, liver):body weight ratios at the end of the treatment. Each bar shows the mean ± SEM of 8 experiments. P < 0.05, P < 0.01 with respect to the control group; *P < 0.05, **P < 0.01 with respect to the hypercholesterolemic;6> group.

Plasma total cholesterol concentration was 58 mg/dL (100%) at the beginning of the study, and increased to 102 mg/dL (153% with respect to the control) in the hypercholesterolemic group at the end of the treatment (16 wk). Plasma total cholesterol decreased in all groups treated with garlic fractions and extracts; moreover, this effect was higher in rats fed raw garlic fractions and extracts (groups 4, 5, 6 and 7; Fig. 3 , panel A).

View larger version (29K): [in this window] [in a new window]   Figure 3. Lipid profiles after 16 wk of treatment. Panel A, total cholesterol; panel B, LDL cholesterol; and panel C, HDL cholesterol. The first group of columns show the differences between the control group (100%) and the hypercholesterolemic group; the second group of bars show the differences between the hypercholesterolemic group (100%) and the garlic-treated groups. Each bar shows the mean ± SEM of 8 measurements. P < 0.05, P < 0.01 with respect to the control group; *P < 0.05, **P < 0.01 with respect to the hypercholesterolemic group.

Effect of the treatment on contractions induced by NE (10^-6 mol/L) or KCl (80 mmol/L) in aortae.

In a first group of experiments, the contractions induced either by NE (10^-6 mol/L) or by KCl (80 mmol/L) were measured. The contractions induced by NE increased in arteries obtained from the hypercholesterolemic group (group 0) with respect to the control group (0.96 ± 0.09 vs. 1.28 ± 0.08 g, P < 0.05, n = 8). Moreover, the contractions in the garlic-treated groups were even higher than those in the hypercholesterolemic group, except in group 6 (RG-HP20-w) in which the contractions decreased, although not significantly, with respect to the hypercholesterolemic group (1.28 ± 0.08 vs 1.10 ± 0.10 g). (Fig. 4 , panel A).

View larger version (32K): [in this window] [in a new window]   Figure 4. Contractions induced by the addition of a single concentration of noradrenaline (NE; 10-6 mol/L, panel A) or KCl (80 mmol/L, panel B) in aortic rings obtained from the different groups studied. Each bar shows the mean ± SEM of 8 experiments. *P < 0.05,**P < 0.01 with respect to the hypercholesterolemic group; P < 0.05, P < 0.01 with respect to the control group.

Effect of the treatment on the relaxation induced by ACh or SNP in aortae.

ACh (10^-8 to 10^-5 mol/L) caused an endothelium-dependent relaxation in a concentration-responsive manner in all of the groups studied. The endothelium-dependent relaxation strongly decreased in the hypercholesterolemic group (group 0) with respect to the control group; the maximal relaxation was induced by ACh (10^-5 mol/L), i.e., 83.3 ± 5.2 and 40.6 ± 7.6% (P < 0.01, n = 8) in the control and hypercholesterolemic groups, respectively. In the frozen fraction–treated groups (groups 1, 2, and 3; Fig. 5 , panel A) the relaxing effect of ACh increased with respect to the hypercholesterolemic group (the IC₅₀ was 6.32 ± 2.5 x 10^-7, 2.3 ± 1.1 x 10^-6 and 6.38 ± 2.1 x 10^-7 mol/L in groups 1, 2 and 3, respectively) as did the maximum effect (maximum relaxation: 40.6 ± 7.6, 57.5 ± 5.4, 55.2 ± 2.6 and 61.4 ± 6.0%, P < 0.05, n = 8 in groups 0, 1, 2 and 3, respectively).

View larger version (18K): [in this window] [in a new window]   Figure 5. Effect of the treatment on the endothelium-dependent relaxation induced by acetycholine (ACh; 10-8 to 10-5mol/L) in aortic rings. Panel A, frozen fraction–treated groups; panel B, raw fraction–treated groups; and panel C, extract-treated groups. Each point represents the mean ± SEM of 8 experiments. P < 0.05, P < 0.01 with respect to the control group; *P < 0.05, **P < 0.01 with respect to the hypercholesterolemic group.

In the extract-treated groups (groups 7 and 8; Fig. 5 , panel C) we found that only the raw extract tended to increase the relaxation induced by ACh, although not significantly.

In addition, we also studied the possible changes in the endothelium-independent relaxation induced by SNP. Contrary to our report in the case of endothelium-dependent relaxation, we did not find any differences between the control and hypercholesterolemic groups in the endothelium-independent relaxation. In the frozen fraction–treated groups (groups 1, 2 and 3; Fig. 6 , panel A), the relaxation was similar to that reached in the hypercholesterolemic group. However, in all of the raw fraction– (Fig. 6 , panel B) and extract-treated (Fig. 6 , panel C) groups, except in group 6 (RG-HP₂₀-w), which presented relaxation similar to the control group, the sensitivity was progressively decreasing, especially in the extract-treated groups (groups 7 and 8).

View larger version (17K): [in this window] [in a new window]   Figure 6. Effect of the treatment on the endothelium-independent relaxation induced by sodium nitroprusside (SNP; 10-8 to 10-5 mol/L) in aortic rings. Panel A, frozen fraction–treated groups; panel B, raw fraction–treated groups; and panel C, extract-treated groups. Each point represents the mean ± SEM of 8 experiments. *P < 0.05, **P < 0.01 with respect to the hypercholesterolemic group.

DISCUSSION

The medical properties of garlic have been known since the ancient Egyptian era. Among its effects is a beneficial action on the development of experimental atherosclerosis. In this work, we investigated the possible beneficial effects of some garlic extracts and fractions on the changes in vascular responsiveness produced by high cholesterol plasma levels induced by a hypercholesterolemic diet in rats. We found an increase in the contractile responses evoked by the nonspecific adrenergic agonist noradrenaline in the arteries isolated from hypercholesterolemic rats with respect to control (normal) rats. This increase in the contraction was counteracted in the arteries isolated from rats given a hypercholesterolemic diet plus the fraction RG-HP₂₀-w at 300 mg/(kg · d) (group 6). Some atherosclerotic arteries in humans and in various hypercholesterolemic animal models of atherosclerosis exhibit increased vasoconstriction (Ginsburg et al. 1984 , Vrints et al. 1990 ). The pathophysiologic basis for the increased vasoconstrictor responses of atherosclerotic blood vessels to certain agonists could be due to an increase in the number of serotonergic and -adrenergic receptors (Nanda and Henry 1982 ) or an increased cholesterol content of smooth muscle cell membranes augmenting the responses to noradrenaline (Yokoyama and Henry 1979 ).

On the other hand, endothelium-dependent relaxation is impaired in vessels from atherosclerotic patients (Bossaller et al. 1987 , Forstemann et al. 1988) and in hypercholesterolemic animal models (Chappell et al. 1987 , Shimokawa and Vanhoutte 1989 ), suggesting modification of an endothelium-derived relaxing factor, which is assumed to be NO, in hyperlipidemia. In this paper, we reported that indeed the endothelium-dependent relaxation induced by ACh was impaired in aortic rings from hypercholesterolemic rats and in some garlic-treated groups, such as group 3 (FG-HP₂₀-w) and especially group 6 (RG-HP₂₀-w), in which the endothelium-dependent relaxation was almost similar to that in control rats.

Numerous mechanisms have been suggested for the effect on vascular relaxation in atherosclerotic and hypercholesterolemic animal models. They include an increased diffusional barrier for NO due to the intima thickening (Lopez et al. 1989 ), L-arginine depletion (Cooke et al.1991 , Schini and Vanhoutte 1991 , Shimokawa and Vanhoutte 1989 ), altered endothelial cell receptor coupling mechanism (Cohen et al. 1988 ) and inactivation of NO by oxygen free radicals (Gryglewski et al. 1986 , Rubanyi and Vanhoutte 1986 ).

It has been reported (Das et al. 1995a and 1995b ) that garlic activates the NO synthase both in vitro (in cell-free homogenate) and in vivo because the hypertension induced by L-NAME (a NO synthase inhibitor) and the decrease in the urinary levels of NO₂^-/NO₃^- induced by L-NAME in rats were prevented by treatment with garlic, which strongly suggests that garlic increases NO synthase in vivo. There is a link between garlic and the L-Arg-NO pathway. Amino acid analysis of garlic powder demonstrated that it is a rich source of arginine, the precursor of NO. However, neither arginine nor alliin-derived products were found to be responsible for the activation of NO synthase by garlic in cell-free homogenate (Das et al. 1996 ). In addition, antioxidant properties of garlic were also suggested by showing that organosulfur compounds inhibited the peroxidation of lipids and Cu²⁺-induced oxidative modification of LDL (Ide et al. 1997 , Prasad et al. 1996 , Török et al. 1994 ). These properties could also explain the effect of garlic treatment on endothelium-dependent relaxation found in this work, together with the direct effect of garlic on NO synthesis found by other authors.

In contrast to endothelium-dependent relaxation, endothelium-independent relaxation is not altered during the atherosclerotic state. Thus, we did not find any significant differences between the relaxation induced by SNP in normal and hypercholesterolemic rats. However, in some garlic-treated groups (groups 4, 5, 7 and 8), this relaxation was decreased.

In other groups of experiments, we found that the treatment with garlic fractions or extracts decreased the total cholesterol in all of the groups treated. These data, together with 1) the decrease in LDL cholesterol that occurred in all of the groups treated, 2) the data that HDL cholesterol increased in some of the groups (1, 3 and 8), all involving frozen fractions, and 3) the impairment of the liver:BW ratio, allowed us to conclude that the treatment with garlic extracts and fraction improves vascular reactivity and the lipid profile in hypercholesterolemic animals, and that this protection is higher in those treated with frozen extracts.

FOOTNOTES

¹ Presented at the conference "Recent Advances on the Nutritional Benefits Accompanying the Use of Garlic as a Supplement" held November 15–17, 1998 in Newport Beach, CA. The conference was supported by educational grants from Pennsylvania State University, Wakunaga of America, Ltd. and the National Cancer Institute. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors: John Milner, The Pennsylvania State University, University Park, PA and Richard Rivlin, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY.

³ Abbreviations: ACh, acetycholine; BW, body weight; IC₅₀, 50% inhibition of the maximal contractile response; NE, noradrenaline; SNP, sodium nitroprusside.

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