Garlic prevents hypoxic pulmonary hypertension in rats
Michael B.
Fallon1,
Gary A.
Abrams1,
Tarek T.
Abdel-Razek2,
Jun
Dai3,
Shi-Juan
Chen3,
Yiu-Fai
Chen3,
Bao
Luo1,
Suzanne
Oparil3, and
David D.
Ku2
1 Liver Center and
3 Vascular Biology and
Hypertension Program, Department of Internal Medicine, and
2 Department of Pharmacology,
University of Alabama at Birmingham, Birmingham, Alabama 35294-0007
 |
ABSTRACT |
Hypoxic pulmonary vasoconstriction underlies the
development of high-altitude pulmonary edema. Anecdotal observations
suggest a beneficial effect of garlic in preventing high-altitude
symptoms. To determine whether garlic influences pulmonary
vasoconstriction, we assessed the effect of garlic on pulmonary
pressures in rats subjected to alveolar hypoxia and on vasoconstriction
in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt)
for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean
arterial pressure or heart rate response to hypoxia was seen between
the groups. Garlic solution resulted in a significant dose-dependent
vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of
NG-nitro-L-arginine
methyl ester (a nitric oxide synthase inhibitor) inhibited the
vasodilatory effect of garlic by 80%. These studies document that
garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a
combination of endothelium-dependent and -independent mechanisms for
the effect in pulmonary arterial rings.
nitric oxide synthase; Allium
sativum; vascular rings
 |
INTRODUCTION |
allium sativum (garlic) has been
employed as an herbal medicinal agent for thousands of years (11).
Among the beneficial effects attributed to garlic is the ability to
relax vascular smooth muscle (16). In the early 19th century during
Argentina's fight for independence, San Martin observed that
administration of garlic to his soldiers while they crossed the Andes
countered the effects of high altitude (11). One explanation for a
beneficial effect of garlic ingestion in these soldiers might have been
amelioration of hypoxic pulmonary vasoconstriction. Recent experimental
studies have demonstrated several effects of garlic, including
activiation of endothelial nitric oxide synthase (6) and smooth muscle cell membrane hyperpolarization (18), which could decrease pulmonary vascular tone. Together, these observations suggest that garlic administration might block the development of hypoxic pulmonary vasoconstriction by inhibiting pulmonary vascular smooth muscle contraction.
The aim of the present study was to evaluate whether garlic
administration alters the development of hypoxic pulmonary
vasoconstriction and to assess the potential mechanisms for the effect
on pulmonary vascular tone. Here, we determine the effects of enteral
garlic administration on the development of pulmonary vasoconstriction in a rat model of hypoxic pulmonary hypertension and investigate the
mechanisms through which garlic influences the pulmonary arterial system in isolated pulmonary arterial segments.
 |
METHODS |
Animals. Male Sprague-Dawley rats
weighing 280-320 g were obtained from Charles River Breeding
Laboratories (Wilmington, MA). For acute hypoxic studies, five
garlic-treated and nine control animals were used. For pulmonary
arterial ring studies, a minimum of 10 rings obtained from 5 separate
animals were studied for each experimental group. The study was
approved by the Institutional Animal Care and Use Committee of the
University of Alabama at Birmingham and conforms to National Institutes
of Health guidelines on the care and use of laboratory animals.
Garlic administration. Dehydrated
garlic powder was obtained from Pure-Gar (Tacoma, WA). For gavage
administration, a garlic solution was prepared daily by mixing
dehydrated garlic powder with 5% gum arabic in double-distilled water.
The mixture was vortexed for 5 min and administered by gavage (100 mg
garlic powder/kg body wt) daily for 5 days. Control animals were given
5% gum arabic solution alone for 5 days. For pulmonary arterial ring
studies, dehydrated garlic powder was mixed 1:9, wt/vol, with
double-distilled water, followed by vortexing for 5 min and
centrifugation at 8,000 g for 5 min.
The supernatant was then diluted to appropriate concentrations for
vessel reactivity testing.
Vascular catheterization. On the
fourth gavage day, femoral arterial and venous cannulas and pulmonary
arterial cannulas were inserted under pentobarbital sodium anesthesia
in the rats through the right jugular vein with a closed-chest
technique as previously described (5, 15). A small incision was made in
the proximal right external jugular vein through which an introducer
and a Silastic catheter (PE-10) were passed. The catheter was filled with a heparin-saline solution, attached by a 25-gauge blunted needle
to a pressure transducer (model CP-01, Century Technology, Inglewood,
CA) coupled to a polygraph (model 7, Grass Instruments, Quincy, MA),
and advanced through the introducer into the pulmonary artery. Catheter
position was identified by the pressure tracing, and the introducer was
removed after the proper position was confirmed. The catheter was
secured and then connected to polyethylene tubing (PE-10 fused to
PE-20), which was exteriorized at the back of the neck.
Acute hypoxic studies. Acute hypoxic
studies were accomplished as previously described (5). Thirty-six hours
after catheterization, mean systemic arterial pressure (MSAP), mean
pulmonary arterial pressure (MPAP), and heart rate (HR) were recorded
through the femoral and pulmonary arterial catheters. After stable MSAP
and MPAP recordings were obtained, the conscious unrestrained rats were
exposed to hypoxia (10% O2) for
90 min in a 330-liter Plexiglas glove box (Manostat, Brooklyn, NY) that
was gassed by adding N2 (Southern
Welding, Birmingham, AL) to the chamber intermittently from a liquid
N2 reservoir. The gas outflow of
N2 was controlled by a solenoid
valve activated by the recorder output of an S3-A O2 analyzer (Applied
Electrochemistry, Sunnyvale, CA) through a control circuit (model
371-K, LFE, Clinton, MA), which ensures uniform and reproducible
lowering of O2 concentrations
within the chamber. A baralyme (Allied Health Care Products, St. Louis, MO) CO2 scrubber kept the
CO2 concentration at <0.2%.
Relative humidity within the chamber was kept at <70% with anhydrous
CaSO4. Boric acid was used to keep
NH3 levels within the chamber at a minimum. A double-doored entry port allowed the animals to be placed
into the chamber without opening it to room air and without producing
measurable alterations in the O2
concentration of the internal atmosphere.
Pulmonary arterial ring studies. On
the day of the experiment, the rats were anesthetized with
pentobarbital sodium (60 mg/kg ip), the thoracic cavity was opened, and
both the left and right main lobes of lung were quickly excised. The
intralobar pulmonary arteries, ~1.5 cm in length, were carefully
dissected from the surrounding connecting tissues under a
stereomicroscope. The arteries were cut into rings (2-3 mm long),
with the outside diameter ranging from 0.5 to 1.2 mm. Each ring was
then mounted, as previously described (8), with two triangular-shaped
30-gauge stainless steel needles in jacketed tissue chambers containing
Krebs-Henseleit solution (in mM: 118 NaCl, 4.6 KCl, 27.2 NaHCO3, 1.2 MgSO4, 1.2 KH2PO4,
1.75 CaCl2, 0.03 Na2EDTA, and 11.1 glucose) at 37°C gassed with 95%
O2-5%
CO2. The upper needle of each
arterial ring was attached with a silk suture to a force-displacement
transducer (Grass FT 0.03C), and changes in isometric force were
recorded on a Grass polygraph (model 7C).
To assess the role of the endothelium in the arterial ring response to
garlic, the endothelium was denuded from a subset of isolated pulmonary
arterial segments by mechanical disruption with a wooden applicator
before vascular reactivity studies. Effectiveness of the endothelial
disruption was assessed in each vessel by documenting a complete loss
of relaxation in response to acetylcholine (1 µM) challenge.
All vessels were passively stretched to generate a resting tension of
2.0 g for isometric contraction recording. After 40 min of
equilibration, the rings were exposed to maximum depolarizing 70 mM
KCl. When contractile responses plateaued, ranging from 0.4 to 0.7 g of
active tension, the rings were rinsed with Krebs-Henseleit solution and
allowed to equilibrate for an additional 40 min in the presence of 5 µM indomethacin before the start of the experiment. At appropriate
times, submaximal tone was elicited with 0.1-1 µM phenylephrine,
and various pharmacological agents were added to the bath. In all
cases, the effects of only one dose-response curve of acetylcholine or
aqueous garlic extract solution was determined in each pulmonary
segment, except for the cases when repeat studies of acetylcholine or
garlic solution were indicated after pretreatment with the nitric oxide
synthase inhibitor
NG-nitro-L-arginine
methyl ester (L-NAME). Data are
expressed as a percentage of relaxation or a percentage of decrease in
phenylephrine-induced constrictive tone.
Reagents. Acetylcholine chloride,
phenylephrine, and
L-NAME were purchased
from Sigma (St. Louis, MO), and all other reagents were purchased from
Fisher Scientific (Norcross, GA). Acetylcholine was prepared in sodium
acetate buffer (pH 4.0) and stored at 4°C to ensure stability. All
other solutions were prepared immediately before use.
Statistics. Data were analyzed with
Student's t-test, ANOVA, and multiple
comparisons between groups with Bonferroni correction as appropriate.
All measurements are expressed as means ± SE. Statistical
significance was designated as P < 0.05.
 |
RESULTS |
Effects of garlic gavage on the vascular response to
acute normobaric hypoxia. To determine whether chronic
garlic ingestion alters the pulmonary vascular responsiveness to
normobaric hypoxia, we subjected control and garlic-gavage animals to a
90-min exposure of 10% O2 after 5 days of garlic gavage. Figure
1 summarizes the responses of
MPAP, MSAP, and HR to acute hypoxic exposure in control and
garlic-gavage animals. In control rats, acute hypoxic exposure was
associated with a significant increase in MPAP of 8-10 mmHg from
baseline, beginning within 2 min of exposure and persisting for the
entire 90-min study (Fig. 1A). In
contrast, animals treated with garlic gavage for 5 days before the
hypoxic challenge had no significant increase in MPAP during acute
hypoxic exposure and were significantly different from control animals.
MSAP fell similarly by ~10 mmHg over 90 min in both the control and
garlic-treated animals (Fig. 1B). HR increased transiently in the
control animals after hypoxic exposure, but no significant differences
in HR were observed between the control and garlic-treated animals
(Fig. 1C). These findings
demonstrate a protective effect of garlic gavage against the
development of pulmonary hypertension in response to acute normobaric
hypoxia.

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Fig. 1.
Effects of garlic (100 mg · kg 1 · day 1,
1 gavage/day for 5 days) on mean pulmonary arterial pressure (MPAP;
A), mean systemic arterial pressure
(MSAP; B) and heart rate
(C) in rats during short-term
exposure to hypoxic conditions (10%
O2 for 90 min;
left arrows).
Right arrows, return to 21%
O2. bpm, Beats/min. Values are
means ± SE; n, no. of rats.
* P < 0.05.
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Effects of garlic exposure on isolated pulmonary
arterial segments. To determine whether garlic exerts a
direct effect on the pulmonary vasculature, intralobar pulmonary
arterial segments were isolated from untreated animals, and their
responses to the garlic solution were assessed in vitro. Figure
2 depicts typical tracings of
endothelium-intact pulmonary arterial ring responses to both
acetylcholine and garlic solution. Figure
2A shows the rapid dose-dependent
relaxation response to acetylcholine. Figure 2B shows the relaxant response to
garlic solution (1-300 µg/ml). Exposure to garlic resulted in a
significant dose-dependent vasorelaxation similar to acetylcholine.
However, in contrast to acetylcholine, relaxation induced by garlic
developed more slowly, with the average time for the maximum
garlic-induced relaxant response being ~2-3 min compared with
25-45 s for acetylcholine-induced relaxation. In addition, the
effects of garlic were reversible with washout and reproducible with a
second exposure to the garlic solution (data not shown), indicating a
lack of direct toxicity on the vascular endothelium. These results
document a direct effect of garlic administration on pulmonary arterial
vascular tone.

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Fig. 2.
Typical tracings of acetylcholine
(A)- and garlic extract
(B)-induced relaxation on isolated
rat intralobar pulmonary arteries. Rat intralobar pulmonary arteries
were isolated and pretreated with 5 µM indomethacin as described in
METHODS. Initial contractile tone was
induced with phenylephrine (PE) before addition of cumulative doses of
either acetylcholine or garlic extract (arrows). Similar experiments
were performed in at least 8-12 other different pulmonary arterial
ring preparations.
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|
Mechanism of garlic effect on isolated pulmonary
arterial rings. To assess the endothelium dependence of
the effect of garlic on the pulmonary arterial system, we repeated
studies in isolated arterial segments after pretreatment with the
specific nitric oxide synthase inhibitor
L-NAME and after endothelium
disruption. Pretreatment of endothelium-intact rat pulmonary arterial
segments with L-NAME completely
abolished the acetylcholine-induced relaxation as expected (Fig.
3), and abolition of acetylcholine-induced
relaxation was also used to ensure complete endothelial disruption in
studies with mechanically denuded segments.
L-NAME pretreatment resulted in
an 80% inhibition of garlic-induced relaxation (Fig.
4). The pulmonary arterial relaxation
response to 100 µg/ml of garlic was reduced from
35 ± 2 (n = 10 rings) to
7 ± 1%
(n = 12 rings) in the presence of
L-NAME. A similar reduction in
garlic-induced relaxation was observed in endothelium-disrupted rat
pulmonary arterial segments (
16 ± 2%;
n = 10 rings). However, in both
conditions, a degree of garlic-induced relaxation remained
(20-30%) despite the inhibition of nitric oxide production or
mechanical removal of the endothelium. Together, these data demonstrate
that the effect of garlic on pulmonary arterial segments is
predominately but not completely endothelium dependent and involves the
production of nitric oxide.

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Fig. 3.
Effects of
NG-nitro-L-arginine
methyl ester (L-NAME)
pretreatment on acetylcholine-induced endothelium-dependent relaxation
in isolated rat intralobar pulmonary arteries. Pulmonary arteries were
isolated and pretreated with 5 µM indomethacin as described in
METHODS. For inhibition of endothelial
nitric oxide synthesis, 0.3 mM
L-NAME was added to incubation
20 min before preparations were tested with acetylcholine. Data are
means ± SE of 8-10 different pulmonary ring preparations
obtained from 3-4 rats. Control rings relax in a normal fashion to
acetylcholine, demonstrating presence of intact functional endothelium.
This response is completely inhibited by
L-NAME pretreatment. Abolition
of acetylcholine response was also used to document complete
endothelial removal in endothelium-disrupted ring studies (data not
shown).
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Fig. 4.
Effects of L-NAME pretreatment
and endothelium disruption on garlic extract-induced relaxation in
isolated rat intralobar pulmonary arteries. Pulmonary arteries were
isolated and pretreated with 5 µM indomethacin as described in
METHODS. For inhibition of endothelial
nitric oxide synthesis, 0.3 mM
L-NAME was added to incubation
20 min before preparations were tested with garlic extract. For
endothelium-disrupted group, intimal endothelium was denuded with a
wooden applicator before being tested. , Vessels with intact
endothelium; , vessels with disrupted endothelium; , vessels with
intact endothelium pretreated with
L-NAME. Data are means ± SE
of 8-12 different pulmonary ring preparations obtained from
4-5 different rats.
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|
 |
DISCUSSION |
In this study, we have demonstrated that garlic powder administered
enterally prevents the acute hypoxic increase in pulmonary pressure
in an animal model of pulmonary hypertension without causing
significant effects on systemic blood pressure or heart rate. In
addition, we show that garlic causes a significant dose-dependent relaxation of isolated rat intralobar pulmonary arteries predominantly through endothelium-dependent effects on pulmonary vascular smooth muscle. These studies suggest that garlic may prevent hypoxic pulmonary
vasoconstriction through effects on the pulmonary arterial system.
This is the first in vivo animal study that has investigated the
effects of garlic on the pulmonary vasculature in the setting of
alveolar hypoxia. We utilized garlic powder manufactured from the
dehydration of fresh garlic bulbs. In our animals with a metabolic rate
two to three times that of humans, the daily dose of garlic administered was approximately equivalent to a human consuming 2 g of
garlic powder or 4 large garlic cloves. We chose to administer garlic
by gavage for 5 days before performing hypoxic challenges to assess the
effects in a relative "steady state" based on previous animal and
human studies (9, 14, 17) that have demonstrated effects on vascular
tone over 5-24 h after oral administration of garlic. The
administration of our aqueous extract of garlic powder by gastric
gavage to rats for 5 days before hypoxic exposure significantly
inhibited hypoxic pulmonary vasoconstriction in all animals and thereby
preserved normal mean pulmonary pressures. In contrast, all control
animals had significant elevations in pulmonary pressures in response
to low alveolar oxygen tension. The observation that MSAP and HR in the
garlic-fed animals did not differ from MSAP and HR in the control
animals is most consistent with a preferential effect on the pulmonary
vasculature. Other studies have demonstrated a modest decrease in
systemic blood pressure in animals (2, 4) and humans (1, 7, 10, 19)
receiving garlic, although this effect has not been uniformly observed
(16). Marked differences in dosage and route of garlic administration,
differences in methods of preparation (water, oil, or ethanol extracts
vs. rehydrated garlic powder or fresh garlic) and differences in the
timing of the assessment of effects on systemic pressure in these
studies may have influenced the components of garlic which were
evaluated and the magnitude of effects observed.
Our aqueous extract of garlic powder causes a significant
dose-dependent relaxation in intralobar pulmonary arterial rings both
in the presence and absence of nitric oxide synthase blockers and
intact endothelium. This observation indicates that at least two
mechanisms contribute to the vasodilatory effect. First,
L-NAME pretreatment of
endothelium-intact intralobar pulmonary arteries resulted in an 80%
inhibition of garlic-mediated vasodilatation, establishing that a major
component of the garlic effect on smooth muscle is mediated through the
production of nitric oxide in endothelial cells. This finding is
confirmed by a corresponding decrease in the effect of garlic in
endothelium-disrupted pulmonary arterial segments and is consistent
with recent work (6) demonstrating that garlic administration may
result in activation of calcium-dependent endothelial nitric oxide
synthase in certain tissues. Second, a degree of garlic-induced
vasorelaxation was maintained in both L-NAME-treated intact pulmonary
arterial segments and endothelium-disrupted pulmonary arterial
segments, indicating an additional direct effect on vascular smooth
muscle cells. This finding is compatible with studies in isolated
vascular strips that demonstrate that garlic can induce vasodilatation
via smooth muscle cell membrane hyperpolarization and/or
inhibition of the opening of calcium channels (18).
The components in garlic that influence vascular tone are not well
characterized. Much interest has focused on the numerous sulfur-containing compounds that appear to be important for a number of
the medicinal actions of garlic (3). Cysteine sulfoxides such as
alliin, which are transformed into thiosulfinates, comprise a
significant portion of these sulfur compounds (16). Intra-arterial administration of synthesized allicin (2-propenethiosulfinate), the
predominant thiosulfinate in garlic, resulted in mesenteric arterial
vasodilatation in the cat (13). Ku et al. (12) initiated and reported on preliminary studies focused on determining the role of
allicin in altering pulmonary vascular tone by assessing the vasoactive
efficacy of a number of garlic preparations with varying allicin
yields. The degree of pulmonary vasorelaxation correlated directly with
the allicin yield in each preparation. In addition, we have recently
investigated a specially prepared garlic powder in which alliin (kindly
provided by Dr. Larry Lawson, Murdock, Madaus, Schwabe Group;
Springville, UT), the parent compound of allicin, was removed. This
specific preparation of garlic had no effect on pulmonary vascular tone
(Ku, unpublished data). Taken together, these studies
suggest that allicin and/or other thiosulfinates derived from
alliin are important mediators of the vasorelaxation induced by garlic
in isolated pulmonary arterial segments. Future studies are needed to
determine the molecular mechanisms by which thiosulfinates cause
vasorelaxation in pulmonary arterial segments and to define whether the
effects observed in isolated pulmonary arterial segments in vitro
account for the alterations observed in the entire pulmonary
vasculature in vivo.
 |
ACKNOWLEDGEMENTS |
The study was funded by Pure-Gar Company.
 |
FOOTNOTES |
G. A. Abrams is a consultant for Pure-Gar Company.
Address for reprint requests: M. B. Fallon, UAB Liver Center and
Division of Gastroenterology and Hepatology, Univ. of Alabama at
Birmingham, 410 Lyons-Harrison Research Bldg., 701 South 19th St.,
Birmingham, AL 35294-0007.
Received 25 November 1997; accepted in final form 13 April 1998.
 |
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