Potential of garlic (Allium sativum) in lowering high blood pressure: Mechanisms of action and clinical relevance

Abstract

Garlic supplements have shown promise in the treatment of uncontrolled hypertension, lowering blood pressure (BP) by about 10 mmHg systolic and 8 mmHg diastolic, similar to standard BP medication. Aged garlic extract, which contains S-allylcysteine as the bioactive sulfur compound, in particular is standardizable and highly tolerable, with little or no known harmful interaction when taken with other BP-reducing or blood-thinning medication. Here we describe biologically plausible mechanisms of garlic's BP-lowering effect. Garlic-derived polysulfides stimulate the production of the vascular gasotransmitter hydrogen sulfide (H2S) and enhance the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation, vasodilation, and BP reduction. Several dietary and genetic factors influence the efficiency of the H2S and NO signaling pathways and may contribute to the development of hypertension. Sulfur deficiency might play a part in the etiology of hypertension, and could be alleviated with supplementation of organosulfur compounds derived from garlic.

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http://dx.doi.org/10.2147/IBPC.S51434
Potential of garlic (Allium sativum) in lowering
high blood pressure: mechanisms of action
and clinical relevance
Karin Ried
Peter Fakler
National Institute of Integrative
Medicine, Melbourne, VIC, Australia
Correspondence: Karin Ried
National Institute of Integrative
Medicine, 21 Burwood Road,
Hawthorn, VIC 3122, Australia
Tel +61 3 9912 9545
Fax +61 3 9804 0513
Email karinried@niim.com.au
Abstract: Garlic supplements have shown promise in the treatment of uncontrolled hypertension,
lowering blood pressure (BP) by about 10 mmHg systolic and 8 mmHg diastolic, similar to stan-
dard BP medication. Aged garlic extract, which contains S-allylcysteine as the bioactive sulfur
compound, in particular is standardizable and highly tolerable, with little or no known harmful
interaction when taken with other BP-reducing or blood-thinning medication. Here we describe
biologically plausible mechanisms of garlic’s BP-lowering effect. Garlic-derived polysulfides
stimulate the production of the vascular gasotransmitter hydrogen sulfide (H
2
S) and enhance
the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation,
vasodilation, and BP reduction. Several dietary and genetic factors influence the efficiency of
the H
2
S and NO signaling pathways and may contribute to the development of hypertension.
Sulfur deficiency might play a part in the etiology of hypertension, and could be alleviated with
supplementation of organosulfur compounds derived from garlic.
Keywords: garlic, S-allylcysteine, hydrogen sulfide (H
2
S), nitric oxide (NO), redox signaling,
hypertension
Hypertension
Hypertension, or chronically elevated blood pressure (BP) (systolic/diastolic BP [SBP/
DBP] $140/90 mmHg at the brachial artery), is a multifactorial condition implicated
in the development and progression of cardiovascular disease. Hypertension is among
the most important modifiable risk factors for cardiovascular disease.
1
High BP affects nearly 1 billion people globally and about 30% of adults in
Western countries.
1
An estimated 70% heart attacks, strokes, and chronic heart failure
are attributed to hypertension, leading to 37% of cardiovascular deaths in Western
countries and 13.5% globally.
2,3
Epidemiological studies have indicated a continuous association between BP and
cardiovascular risk, suggesting that a reduction of high systolic BP (SBP.140 mmHg)
by 20 mmHg or a reduction of high diastolic BP (DBP.90 mmHg) by 10 mmHg is
associated with a 50% risk reduction in developing cardiovascular disease.
4
However, a steady increase of SBP with age is expected, whereas DBP tends to
fall after middle age, with studies in elderly and middle aged populations suggesting
a nonlinear J- or U-shaped relationship between BP and mortality.
5,6
Therefore, appropriate assessment of an individual’s BP status is important
to guide whether antihypertension therapy is indicated or to avoid potential
overtreatment. While office BP monitoring is most practical – with improved accu-
racy achieved after 5–10 minutes rest, repeated automated measures, ideally on
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Ried and Fakler
both arms
7,8
– sustained elevated readings using a 24-hour
ambulatory BP monitoring (24-h ABPM) independently pre-
dict increased cardiovascular risk of 27% for every 10 mmHg
increase in 24-h ABPM SBP.
9
Elevated nighttime BP, in partic-
ular, has been associated with increased risk of cardiovascular
events including stroke and myocardial infarction.
9
Twenty percent of individuals demonstrate white-coat
hypertension, defined as elevated office BP but normotensive
24-h ABPM.
10
White-coat hypertension, however, has been
associated with functional and structural cardiovascular
abnormalities, including reduced arterial elasticity, left ven-
tricular diastolic dysfunction, and enlarged arteries, similar to
persistent hypertension.
11
Therefore, treatment of individuals
with white-coat hypertension may still be of benefit.
While management of BP in family practice has increased
in the past 20 years, a large proportion (23%) remain uncon-
trolled with persisting SBP $140 mmHg or DBP $90 mmHg
independent of the treatment.
7,12–14
Current guidelines for treatment of hypertension recommend
starting monotherapy with any of the standard BP medication
classes, including angiotensin-converting enzyme inhibitors,
angiotensin II-receptor blockers, calcium-channel blockers,
or diuretics in patients with uncomplicated hypertension.
15,16
While guidelines are clear about when to consider treatment
with BP medication, they are less clear about which BP medica-
tion class to start treatment with in patients with uncomplicated
hypertension and no comorbidities; treatment is dependent on
personal preference and experience of the treating doctor.
Guidelines further recommend follow-up after at least
6 weeks to check the effectiveness of treatment and poten-
tial change of BP medication regime by adding other BP
medication classes, increasing dosage, or changing BP
medication type, depending also on tolerability and potential
side effects.
15
Approximately 40% of hypertensive patients can achieve
the target BP of ,140/90 mmHg with monotherapy, inde-
pendent of the type of antihypertensive medication used.
About 40% require combination therapy with two agents,
and 20% need to take three or more antihypertensive
medications to achieve BP control.
14,17
However, adverse
reactions from antihypertensive medication may occur in
a significant number of patients and are more likely when
multiple drugs are prescribed.
18
Adverse reactions include
fatigue, dizziness, cough, headache, myalgia, angioedema,
renal impairment, gastrointestinal upsets, hyperglycemia,
and electrolyte disturbances.
18
Long-term patient persistence with antihypertensive
treatment is unsatisfactory,
19,20
with only 44% of patients
adhering to the treatment regimen in the long term.
20,21
While physician-related barriers to effective management
of uncontrolled hypertension, such as therapeutic inertia,
contribute to this problem,
22,23
patient motivation and satis-
faction are equally important.
24
Persistence varies with the
type of medication
20,21
and is associated with the severity and
frequency of adverse events,
18
as well as with the complexity
of treatment.
24
Several factors play a role in the development of hyper-
tension, including genetic variability, lifestyle, and dietary
influences. While genetic variability is estimated to contrib-
ute about 30% to individuals’ BP profiles,
25,26
lifestyle and
dietary choices play an important role in BP modulation
and control.
13
Research suggests a body mass index (=weight/height
2
)
between 18.5 kg/m
2
and 25 kg/m
2
to be the desired range for
Caucasians. Reductions in SBP of 5–20 mmHg per 10 kg weight
loss can be achieved in overweight hypertensives.
13
In addi-
tion, 30 minutes of regular daily moderate aerobic exercise
(eg, brisk walk) can reduce SBP by 4–9 mmHg,
13
while opti-
mizing vitamin D levels (serum .75 nmol/L) can improve
SBP by 3–4 mmHg in hypertensives.
27,28
Other lifestyle factors influencing BP include smok-
ing, alcohol intake, and stress. Smoking cessation has been
estimated to lead to a BP reduction of up to 10 mmHg in
hypertensives,
29
alcohol consumption exceeding 1–2 stan-
dard drinks per day may influence BP by 2–4 mmHg,
13
and
continuous stress and insufficient quality sleep may push the
BP by up to 10 mmHg.
30
Diet plays an important role in BP control, with the
adoption of the dietary approaches to stop hypertension
or a Mediterranean diet achieving BP reductions between
8 mmHg and 14 mmHg systolic in hypertensives.
13,31
In
addition, a meta-analysis including 13 trials (n=543 hyper-
tensives) of vitamin C intake of 500 mg daily was associated
with a reduction of BP of up to 5 mmHg systolic.
32
While
moderation of sodium intake has been recommended, recent
research suggests a greater importance of an adequate ratio
between sodium and potassium (NaCl/KCl) intakes for
optimal cardiovascular health.
33,34
Other nutritional medical approaches to hypertension
management include increased consumption of lycopene,
mainly from tomato and watermelon,
35
cocoa,
36
and garlic,
discussed here.
Interest in complementary and nutritional medicine has
been increasing, with about 50% of Australians, includ-
ing those with cardiovascular conditions, regularly using
complementary therapies.
37–40
As motivation to self-care may

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73
Garlic for hypertension
influence patient compliance,
41
there is scope to explore the
integration of effective nutritional and other complementary
therapies in antihypertensive management.
Garlic and hypertension
Garlic (Allium sativum) has been used as a spice, food, and
medicine for over 5,000 years, and is one of the earliest
documented herbs utilized for the maintenance of health and
treatment of disease.
42
In some of the oldest texts on medi-
cine, eg, the Egyptian Ebers papyrus dating around 1500 BC
and the sacred books of India, “the Vedas” (1200–200 BCE),
garlic was recommended for many medicinal applications,
including circulatory disorders.
43
In ancient Greece, garlic
was used as a diuretic, as recorded by Hippocrates, the
father of modern medicine.
44
In addition to its cardiovascu-
lar benefits, garlic has traditionally been used to strengthen
the immune system and gastrointestinal health.
42
Today,
this intriguing herb is probably the most widely researched
medicinal plant.
More recently, garlic has been shown to have BP-lowering
properties. A meta-analysis including 20 clinical trials sug-
gested garlic to be superior to placebo in lowering BP in
hypertensive patients on average by 8–9 mmHg in SBP and
6–7 mmHg in DBP, P,0.0001).
45
Trials included in the meta-
analysis were considered high quality, reporting adequate allo-
cation concealment, randomization, double blinding, and low
attrition. This reduction in BP reported in the meta-analysis
is comparable to the BP-lowering effects of common anti-
hypertensive medications.
13,46
While garlic supplementation
reduced BP significantly in hypertensive patients, it did not
appreciably affect patients with normal BP.
45,47–49
In addi-
tion, response to and effectiveness of garlic supplementation
appears to be dependent on individual genetic and dietary
factors, with SBP reductions of up to 40 mmHg in responders
and a proportion of 25%–33% nonresponders, independent
of garlic dosage, in a 3-month trial.
50
Types and components
of garlic, tolerability, and safety
Several types of garlic preparations are available, including
raw and freshly cooked garlic, garlic oil, garlic powder, and
aged garlic extract. Functional sulfur-containing components
described in garlic include alliin, allicin, diallyl sulfide, dial-
lyl disulfide, diallyl trisulfide, ajoene, and S-allylcysteine.
51,52
Allicin, formed by enzymatic reaction from alliin, the main
compound found in fresh raw garlic and garlic powder, is
volatile and unstable. Allicin is destroyed by cooking, and
has the potential to trigger intolerance, gastrointestinal
complaints, and allergic reactions,
53–55
and raw garlic taken
in high doses can reduce red blood cell count.
56
Garlic
essential oil contains diallyl disulfide and diallyl trisul-
fide and no water-soluble allicin. Commercially available
garlic oil preparations often include only a small amount
of garlic essential oil in a vegetable oil base, complicating
comparability and standardization of products.
53
In contrast,
S-allylcysteine, the main active compound in aged garlic
extract, is stable and standardizable, and has been found to
be highly tolerable.
36,51,54,55,57,58
The majority of clinical trials studying the effect of garlic
on BP used either garlic powder or aged garlic extract.
45,48
Side effects of garlic supplements, reported by about a third
of the participants in these trials, were generally mild, and
included burping, flatulence, and reflux in the first few weeks
of the trial.
47,50
A small number of the population (4%–6%)
may experience more severe gastrointestinal disturbances
with therapeutic dosages of garlic supplements.
47,50,59,60
Lower tolerance of sulfur-containing foods such as garlic,
onion, and leek may be reversed by supplementation with
molybdenum and/or vitamin B
12
, often deficient in affected
individuals.
61,62
Despite the general advice, evidence is weak for gar-
lic preparations causing harmful interactions if taken in
addition to blood-thinning, blood-sugar-regulating, or
anti-inflammatory medications.
56,63,64
Physicians and patients
need to be mindful, however, of a potentially harmful inter-
action of garlic with protease inhibitors in antiretroviral
therapy.
63
It is generally recommended that high doses
(equivalent to .4 g of fresh garlic or 3 mg allicin) should be
avoided in patients taking antithrombotic medications includ-
ing warfarin, due to the antiplatelet properties of garlic.
65
However, a trial using higher concentrations of aged garlic
extract (10 mL/day, containing 14.7 mg S-allylcysteine) for
patients on warfarin therapy found no increase in the inci-
dence of hemorrhage compared with placebo.
64
Mechanisms for blood pressure-
lowering effect of garlic
Several mechanisms of action for the BP-lowering properties
of organosulfur compounds in garlic have been postulated,
including mediation of intracellular nitric oxide (NO) and
hydrogen sulfide (H
2
S) production as well as blockage of
angiotensin-II production, which in turn promotes vasodila-
tion and thus reduces the BP.
66–71
The strongest evidence of and insights into the mechanisms
of the BP-lowering effect of garlic supplementation involve
endothelium-dependent vasodilation, and thus, this review

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Ried and Fakler
will focus on the current knowledge of the physiological and
biochemical processes within blood vessels.
Vasorelaxation
The relaxation of vascular smooth muscle cells is an element
of the physiological mechanisms for lowering BP. Reduced
responsiveness of blood vessels to relax from constriction
following autonomic nervous, endocrine/prostanoid, or shear
stress signaling is thought to be an important factor in the
pathophysiology of hypertension, as indicated by experimen-
tal and clinical evidence.
72
NO, redox signaling, and the effect
of garlic on hypertension
The soluble gas NO is a well-known factor in the mechanism
for acetylcholine-induced (parasympathetic) vasodilation.
NO is synthesized from l-arginine by at least three isoforms
of NO synthase (NOS) in the endothelium by endothelial
NOS (eNOS), in nerve cells mainly by neuronal NOS, and
in macrophages by inducible NOS.
73
In some tissues and
organs, including the heart, both eNOS and neuronal NOS
are present.
Figure 1 illustrates vascular NO signaling pathways,
including the effect of NO on vasodilation, and a potential
influence of garlic organosulfur compounds.
eNOS-derived NO induces relaxation of smooth muscle
cells and, thus, increased dilation of all types of blood ves-
sels, via a guanylyl cyclase-dependent mechanism.
73
Lack
of NO production by eNOS is believed to be a major causal
factor in the development of vascular dysfunction and
hypertension.
74,75
eNOS, a highly regulated and complex enzyme, is inac-
tive while bound to caveolin, and can be activated through
calcium-responsive binding of calmodulin via hormonal or
neuronal activation or shear stress-induced phosphoryla-
tion (Figure 1). The production of NO requires l-arginine
as substrate and tetrahydrobiopterin (BH
4
) as a cofactor.
BH
4
levels have been reported to decrease with aging and
cardiovascular disease, and a lack of BH
4
results in so-called
eNOS uncoupling, resulting in the generation of high levels
of superoxide (O
2
-
) and low levels of NO.
73
Redox signaling involves reversible oxidation–reduction
of cysteinyl residues of proteins in cell membranes or within
cells in response to the redox potential of the extracellular
cysteine/cystine (CyS/Cys-S-S-Cys) pool.
76
Increased plasma
cystine concentration and/or oxidized plasma metabolites
have been associated with increased prevalence of human
pathologic conditions, including decreased flow-mediated
dilation, reversible myocardial perfusion defects, and
persistent atrial fibrillation.
77
Thus, dietary factors affecting
extracellular thiol/disulfide redox potential in human plasma
could be important in cardiovascular disease.
77
Oxidative stress, defined as “a disturbance in the
pro-oxidant/antioxidant balance in favor of the former” has
been an intensively researched field of inquiry in the past
few decades.
78
However, this definition has been challenged
by a number of authors following recent advances in the
understanding of redox signaling, and changes in the redox
status of tissues have been shown to be part of cellular signal
transduction.
76,79–81
It has been postulated that hypertension, too, may be a
result of a disruption in redox signaling rather than being
caused by an imbalance of oxidants and antioxidants.
82–84
It has been suggested that the redox status of the cellu-
lar milieu affects the activity of eNOS and thus modulates
NO-dependent pathways in the endothelium.
85,86
Aged garlic extract in cell culture prevented endothelial
cells from “oxidative stress” by increasing cellular concentra-
tions of thiol antioxidants, such as cysteine and glutathione
(GSH) while shifting the ratio of oxidized GSH to reduced
GSH (Figure 1).
87
Moreover, aged garlic extract was shown to normalize
NO output from endothelial cells by preventing the decline of
BH
4
levels.
87
Relevant levels of BH
4
prevent NO uncoupling
and superoxide generation, which are thought to improve
endothelial dysfunction, and potentially reducing the pro-
gression to atherosclerosis.
87
In addition, S-glutathionylation of eNOS at two
highly conserved cysteine residues reversibly decreases
NOS activity with an increase in superoxide generation,
resulting in impaired endothelium-dependent vasodilation.
86
S-glutathionylation can be reversed, however, by thiol agents.
S-glutathionylation of eNOS is thought to be a pivotal switch
providing redox regulation of cellular signaling, endothelial
function, and vascular tone.
86
Furthermore, while uncoupling
of eNOS leads to potent inactivation of NO through its reac-
tion with superoxide (O
2
-
), this reaction forms the potent
oxidant peroxynitrite (ONOO
-
) (Figure 1). Peroxinitrite
has long been considered to be a highly toxic metabolic
by-product, damaging biomolecules including proteins,
lipids, and DNA. However, there have been new insights
demonstrating that ONOO
–
is also involved in various
signaling pathways, including a mechanism of vasodilation
independent of cGMP.
88
While NO clearly is an important signaling molecule, its
overproduction has been implicated in various pathologies,

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Garlic for hypertension
O
2
eNOS
Folate
Calmodulin
BH
2
L-arginine
O
2
–
Mechanical
shear stress
PKB
Neuronal
acetylcholine
Ca
2+
Nitric oxide signaling
Glutathione
Hormonal
bradykinin
Reductive environment
Oxidative environment
uncoupling
BH
4
Garlic
sulfides
ONOO
–
NO
GTP
cGMP
Smooth muscle cell relaxation
vasodilation
blood pressure reduction
Guanyl
cyclase
Glutathionylation of
regulatory proteins
Ca
2+
GSH
GSSG
Garlic
sulfides
Figure 1 Effect of garlic on blood pressure via the NO pathway.
Notes: Blue rectangles illustrate metabolites, blue circles represent enzymes, orange circles are dietary cofactors, green star shapes are garlic and other organosulfur-
containing nutrients, red rectangle represents NO, and purple rectangles denote direct and indirect inuence of NO on vasodilation and blood pressure. NO pathway: in the
presence of BH
4
, eNOS produces NO, which triggers pathways leading to smooth muscle cell relaxation and vasodilation. eNOS uncoupling leads to the formation of O
2
-
.
NO and O
2
-
combine to form OONO
-
, which rapidly reacts with thiols and tyrosine residues of proteins, which in turn, leads to vasodilation and BP reduction independent
of cGMP. Garlic and other dietary organosuldes may play a role in the regulation of the NO signaling pathway by creating a more reductive environment and therefore
supporting NO production.
Abbreviations: BH
2
, dihypdrobiopterin; BH
4
, tetrahydrobiopterin; Ca
2+
, calcium ion; cGMP, cyclic-guanosyl-monophosphate; GSSG, oxidized glutathione; eNOS, endothelial-
nitric-oxide-synthase; GSH, reduced free glutathione; GTP, guanosyl-tri-phosphate; NO, nitric oxide (radical); ONOO, peroxynitrite; O
2
, oxygen; O
2
-
, superoxide anion
radical; PKB, protein kinase-B.

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Ried and Fakler
including angiogenesis, mitochondrial dysfunction, and heart
failure.
89,90
“Nitrosative stress” may cause hyper-nitrosylation
of various regulatory enzymes leading to dysregulation of
several cellular and physiological processes including inhibi-
tion of autophagy.
91
Moreover, hyperproduction of NO may also lead to
upregulation of mammalian target of rapamycin (mTOR), the
central regulating molecule of the major signaling pathways
for cell metabolism, growth, proliferation, and survival.
91
According to one theory of aging, the mTOR signaling
pathway, driving developmental growth early in life, leads
to age-related diseases through hyperfunction later in life.
92
In fact, there is a growing list of physiological malfunctions
linked to overstimulation of this NO-dependent signaling
pathway, ranging from insulin resistance to neurodegenera-
tive diseases to cancer, and even including hypertension itself.
If NO enhances rather than inhibits mTOR signaling, there
is cause for concern with pharmacological interventions
increasing NO bioavailability, and potentially introducing
unwanted effects.
The highly regulated NO signaling pathways described
earlier depend on organic thiols and other sulfur-containing
molecules, and thus may be impaired in sulfur deficiency.
Garlic and other alliums, such as leek and onion, with their
high content of polysulfides may help in providing the nutri-
ents needed for maintaining or restoring optimum redox bal-
ances for a number of eNOS-dependent signaling pathways
important in vascular relaxation.
H
2
S production and the effect
of garlic on hypertension
A second vascular gaseous signal transmitter is H
2
S.
93
H
2
S exists in micromolar concentrations in various mam-
malian tissues, including the brain, nervous system, vas-
cular smooth muscle cells, and in the heart.
93
Endogenous
H
2
S production is primarily the result of two enzymes:
cystathionine-β-synthase (CBS) and cystathionine-γ-lyase
(CSE), whereby the nonessential amino acid cysteine
is metabolized by desulfuration, releasing sulfur in a
reduced oxidation state and generating H
2
S. In addition,
3-mercaptopyruvate sulfur-transferase and cysteine ami-
notransferase localized to the endothelium of the tho-
racic aorta have also been reported to produce H
2
S from
cysteine and α-ketoglutarate.
94
Experiments with CSE
knock-out rodents have found reduced levels of H
2
S and
hypertension.
95
Also, spontaneously hypertensive rats have
reduced expression of CSE in aortic tissues and lowered
plasma levels of H
2
S.
24,96,97
Figure 2 illustrates the H
2
S production pathway, the
connection to the methylation cycle and homocysteine
(HCy), the effect of H
2
S on vasodilation, and influence of
garlic-derived polysulfides on this pathway.
The H
2
S-dependent BP-reducing effect is thought to be
primarily mediated through sulfhydration of ATP-sensitive
potassium (K
AT P
) channels, which in turn leads to voltage-
sensitive channel opening and relaxation of vascular smooth
muscle cells.
98
However, other potassium channels may also be affected
by H
2
S, and additional mechanisms have been suggested
in determining the opening/closing of K
+
channels, includ-
ing nitrosylation, and a possible cooperation between H
2
S
and NO.
98
While the relationship between NO and H
2
S in control-
ling vascular relaxation is still unclear (eg, both upregulation
and inhibition of eNOS by H
2
S have been reported),
99
there
is convincing evidence that H
2
S shares at least some of the
vasorelaxing signaling role with NO and H
2
S deficiency and
therefore can contribute to vascular dysfunction including
hypertension.
84,93,94,100,101
Nonenzymatic conversion of garlic-
derived organic polysuldes to H
2
S
In a series of elegant experiments, Benavides et al
69
showed
that garlic-derived polysulfides can produce H
2
S under physi-
ologically relevant O
2
conditions in rat aortic tissue. They
provided evidence for a mechanism involving reduced thiols.
While it is unknown which garlic bioactives can release H
2
S
nonenzymatically, it has been hypothesized that the major
bioactive S-allylcysteine found in aged garlic extract may also
act as a substrate for the enzyme CSE to produce H
2
S.
102
H
2
S deciency and supplementation
There is conflicting evidence about the potential age-related
decline in vascular H
2
S production, but any impairments of
H
2
S signaling may differ among tissues, with the liver being
less susceptible to functional changes with age than less vital
organs including the vasculature, which would be consistent
with the triage theory of nutritional deficiencies.
103,104
It is generally understood that most H
2
S gets oxidized
within mitochondria to thiosulfate and further to sulfate.
Thiosulfate formed from H
2
S through mitochondrial oxidation
can undergo reduction and thus recycling by an enzymatic
process dependent on dihydrolipoic acid (the reduced form
of lipoic acid).
105
While most H
2
S oxidation occurs within
mitochondria, extra-mitochondrial oxidation occurs by reac-
tive oxygen species and reactive nitrogen species.
106
Thus,

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Garlic for hypertension
Vit B
6
*
Vit B
2
CBS
Methionine
SAM
SAH
Homocysteine
Vit B
12
Vit B
6
*
H
2
S
Cystathionine
CSE
CBS
Vit B
6
*
Methionine-
synthase
CSE
Cysteine
Cystine (CysSSCys)
Diet
Redox
Garlic
sulfides
Non-enzymatic
3-mercapto-
pyruvate
CAT
MPST
Garlic
sulfides
eNOS
Tetrahydro-
folate
Methyl-
tetrahydro-
folate
MTHFR
Dihydro-
folate
Folate
Dihydrofolate-
reductase
Methylene-
tetrahydro-
folate
K
+
ion-channel
opening
Hydrogen sulfide
production & signaling
1
2
3
4
5
6
6
7
7
6
5
re-methylation
Glu+Gly
Glutathione (GSH)
GSSG
NADPH
Se
H
2
O
2
Smooth muscle cell relaxation
vasodilation
blood pressure reduction
Vit B
6
*
6
Figure 2 Effect of garlic on blood pressure via the hydrogen sulde (H
2
S) pathway, and inuence of dietary and genetic factors on homocysteine levels.
Notes: Blue rectangles illustrate metabolites, blue circles represent enzymes, orange circles are dietary cofactors, green star shapes show garlic and other polysulde-
containing nutrients, red rectangle indicates H
2
S, and purple rectangles represent direct and indirect inuence of H
2
S on vasodilation and blood pressure. Red circles 1–7:
Inuence of dietary and genetic factors on H
2
S pathway 1= genetic polymorphism, homozygous for deleterious allele, leads to impaired folate metabolism. 2= common
polymorphisms, some of which lead to increased homocysteine and decreased methylation and SAM levels; these respond well to folate supplementation. 3= genetic defects
lead to increased homocysteine levels. 4= low Vit B12 levels lead to increased homocysteine levels. 5= defect in CBS enzyme leads to increased homocysteine levels and
reduced H
2
S production. 6= low Vit B
6
* levels may increase homocysteine levels and reduce H
2
S production, and may respond to Vit B
6
supplementation. 7= dietary intake
of garlic polysuldes and thiosuldes can increase H
2
S nonenzymatically, and may ameliorate genetic defects in the CBS enzyme, or dietary deciencies in Vit B
6
and/or the
sulfur-containing amino acids cysteine and methionine.
Abbreviations: CAT, cysteine-amino-transferase; CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; CysSSCys, oxidized cysteine/cystine; eNOS, endothelial nitric
oxide synthase; Glu, L-glutamic acid; Gly, glycine; GSSG, oxidized glutathione; GSH, reduced glutathione; H
2
O
2
, hydrogen peroxide; K
+
, potassium ion; MPST, mercapto
pyruvate sulfur transferase; NADPH, nicotinamide adenine dinucleotide phosphate; MTHFR, methylene-tetra-hydro-folate reductase; SAH, S-adenosyl-homocysteine; SAM,
S-adenosyl-methionine; Se, selenium; Vit B
6
*, activated form of Vit B
6
= pyridoxal-phosphate; Vit B
2
, vitamin B
2
(riboavin); Vit B
12
, vitamin B
12
.

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Ried and Fakler
tissue concentrations of H
2
S can be expected to be lower in
more oxidative environments. On the other hand, high con-
centrations of H
2
S are toxic, and there is evidence that H
2
S
in high concentration itself causes formation of superoxide
by inhibiting mitochondrial oxidative phosphorylation. This
may be a possible negative feedback mechanism for limiting
excessive H
2
S concentrations.
107
This suggests that the H
2
S
signaling pathway in vasorelaxation has a similar effect to NO
signaling, without the potentially detrimental consequences
of chronic overproduction of the gasotransmitter.
Approximately two cloves of garlic per meal have been
estimated to release sufficient H
2
S for maintaining the bal-
anced blood vessel constriction.
93
Other dietary H
2
S donors
besides alliums include sulforafane from crucifers, some
fermented foods including “thousand year egg,” and the
infamous Asian durian fruit.
108
Garlic, hypertension,
and elevated HCy
Many clinical and epidemiological studies have found a
positive correlation between HCy plasma levels, endothe-
lial dysfunction, and cardiovascular disorders.
109–111
Conditions linked to endothelial dysfunction, such as
acute ischemic stroke with greater arterial stiffness and
stress-induced hypertension, have been reported in hyper-
homocysteinemia (HHCy).
112,113
Furthermore, serum con-
centrations of the sulfur-containing thiols HCy, cysteine,
and GSH have shown to be independently associated with
cardiovascular risk scores at the population level.
114
However,
whether elevated levels of HCy are primary or secondary risk
factors for cardiovascular disease is less clear.
115,116
There is a
clear negative correlation between elevated HCy levels and
brain and cognitive function.
117,118
Elevated levels of HCy might be a consequence
of impaired endothelial production of H
2
S.
119
The
transformation of HCy into cysteine is catalyzed
by the enzymes CBS and CSE as part of the trans-
sulfuration pathway (Figure 2).
94,120
CBS and CLE are
also among the few enzymes in mammals with the
capacity to produce H
2
S. The chemical reaction facili-
tated by CBS is a vitamin-B
6
-(pyridoxal-phosphate)-
dependent condensation of either serine or cysteine and
HCy.
119
CBS is the rate-limiting enzyme necessary for ter-
minal removal of HCy. Deficiencies in CBS activity caused
by genetic mutations of the CBS gene are the most frequent
cause of familial HHCy.
121
There are at least 153 mutations
known to exist in the CBS gene, with several significantly
reducing CBS activity.
121
These genetic CBS deficiencies
can be divided into two major allelic variance types: vita-
min B
6
responsive and vitamin B
6
nonresponsive.
122,123
Individuals with some of these genetic variants are likely
to have both decreased production of H
2
S and elevated
levels of HCy. While cases with a vitamin B
6
-responsive
variant can be treated with ongoing B
6
therapy, cases
affected by vitamin B
6
nonresponsive variants continue
to have impaired production of H
2
S, but may benefit from
supplementation with nutritional H
2
S donors, such as
garlic. Thus, consumption of garlic, which can produce
H
2
S nonenzymatically,
69
may benefit conditions related to
impaired production of H
2
S, such as hypertension, even
without lowering HCy.
On the other hand, in carriers of a deficient methylene-
tetra-hydro-folate-reductase (MTHFR) variant, elevated HCy
due to impaired remethylation may cause increased levels of
H
2
S, which has been linked to an increase in platelet activa-
tion and may contribute to the development of recurrent arte-
rial and venous thrombosis in these patients.
124
It is therefore
possible that supplementation with H
2
S-boosting nutrients,
such as garlic, may be counterproductive in individuals with
MTHFR deficiency.
Furthermore, both CBS enzyme deficiencies and
deficiencies in sulfur-containing amino acids (especially
methionine and cysteine) are known to result in low lev-
els of GSH, which plays important roles in cellular redox
status and signaling. Elevated levels of HCy and decreased
levels of cysteine and GSH have been found in a population
with a low dietary intake of protein and sulfur-containing
amino acids, and might be regarded as biomarkers of
sulfur deficiency.
125
A correlation between low red blood
cell GSH and increased plasma HCy has been linked to an
increased incidence of hypertension.
126
Garlic, with its high
content of sulfur compounds (including S-allylcysteine),
has the potential to alleviate sulfur deficiencies caused by
low-protein diets, which may also influence BP in these
individuals.
Garlic’s potential effect on HCy levels has been reported
in a small clinical trial of atherosclerosis patients randomized
to aged garlic extract (P=0.08).
127
Additionally, in an animal
model of HHCy, induced by a severely folate-depleted diet
in rats, aged garlic extract decreased plasma HCy concentra-
tions by 30%.
128
In contrast, elevated levels of HCy caused by
mild folate deficiency did not change significantly by garlic
supplementation.
128
Thus, garlic may have an effect on HCy metabolism
independent of the effect of B vitamins in addition to boost-
ing H
2
S production.

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Garlic for hypertension
Renin–angiotensin–aldosterone
system and the effect of garlic
on hypertension
Other potential mechanisms of action for garlic’s effect on
hypertension have been proposed, including the potential of
garlic blocking angiotensin-II production by inhibition of
the angiotensin-converting-enzyme (ACE), as suggested in
a number of cell culture and animal studies.
67,71,129
ACE is
a component in the renin–angiotensin–aldosterone system,
and inhibitors of ACE are used as standard BP-controlling
pharmaceuticals. However, animal and cell culture experi-
ments were mainly conducted with fresh garlic compounds,
containing allicin (S-allyl-cysteine sulfoxide), which has a very
low sustained bioavailability in human tissues.
55
Therefore, the
antihypertensive effect of garlic via the proposed angiotensin-
converting enzyme inhibitor mechanism seems less plausible
than its H
2
S-stimulating and NO-regulating properties.
Conclusion
Garlic, particularly in the form of the standardizable and
highly tolerable aged garlic extract, has the potential to
lower BP in hypertensive individuals similarly to standard
BP medication, via biologically plausible mechanisms of
action. Primarily, polysulfides in garlic have the potential
to upregulate H
2
S production via enzymatic and nonen-
zymatic pathways, which promote vasodilation and BP
reduction.
Several dietary and genetic factors, including folate,
vitamin B
6
, and vitamin B
12
deficiency, and known genetic
variants of the MTHFR and CBS genes, influence the effi-
ciency of H
2
S production, and could be important contributors
to hypertension in these individuals, which may also explain
individual responsiveness to garlic supplementation seen in
clinical trials.
Polysulfides in garlic may also influence regulation of NO
redox signaling pathways, including NO-mediated vasodila-
tion and reduction of BP. Future clinical trials could explore
the potential influence of nutritional status and genetic fac-
tors on the individual’s responsiveness to garlic therapy for
hypertension.
Disclosure
The authors report no conflicts of interest in this work.
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