Peer Reviewed Published Dosages for Supplementation for High Bloood Pressure

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 chance factors for cardiovascular affliction.¹

Loftier BP affects near 1 billion people globally and well-nigh xxx% of adults in Western countries.ⁱ 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.^ii,3

Epidemiological studies have indicated a continuous association between BP and cardiovascular adventure, suggesting that a reduction of high systolic BP (SBP>140 mmHg) past twenty mmHg or a reduction of high diastolic BP (DBP>90 mmHg) by 10 mmHg is associated with a 50% risk reduction in developing cardiovascular affliction.⁴

Nonetheless, a steady increase of SBP with age is expected, whereas DBP tends to fall later on middle age, with studies in elderly and middle anile populations suggesting a nonlinear J- or U-shaped relationship between BP and mortality.^5,6

Therefore, appropriate assessment of an individual'south BP status is important to guide whether antihypertension therapy is indicated or to avoid potential overtreatment. While part BP monitoring is near practical – with improved accuracy achieved after 5–10 minutes residue, repeated automated measures, ideally on both artillery^seven,eight – sustained elevated readings using a 24-hour ambulatory BP monitoring (24-h ABPM) independently predict increased cardiovascular risk of 27% for every ten mmHg increase in 24-h ABPM SBP.^ix Elevated nighttime BP, in particular, has been associated with increased risk of cardiovascular events including stroke and myocardial infarction.⁹

20 per centum of individuals demonstrate white-coat hypertension, defined as elevated office BP but normotensive 24-h ABPM.¹⁰ White-glaze hypertension, nevertheless, has been associated with functional and structural cardiovascular abnormalities, including reduced arterial elasticity, left ventricular 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 unit practice has increased in the past 20 years, a large proportion (23%) remain uncontrolled with persisting SBP ≥140 mmHg or DBP ≥90 mmHg independent of the treatment.^7,12–14

Current guidelines for handling of hypertension recommend starting monotherapy with whatsoever of the standard BP medication classes, including angiotensin-converting enzyme inhibitors, angiotensin 2-receptor blockers, calcium-channel blockers, or diuretics in patients with unproblematic hypertension.^fifteen,16 While guidelines are clear about when to consider treatment with BP medication, they are less clear about which BP medication class to start treatment with in patients with uncomplicated hypertension and no comorbidities; treatment is dependent on personal preference and feel of the treating doctor.

Guidelines further recommend follow-up after at least six weeks to check the effectiveness of handling and potential 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 furnishings.¹⁵

Approximately forty% of hypertensive patients tin can accomplish the target BP of <140/ninety mmHg with monotherapy, independent of the type of antihypertensive medication used. About forty% require combination therapy with two agents, and 20% need to have three or more than antihypertensive medications to achieve BP control.^14,17 Notwithstanding, adverse reactions from antihypertensive medication may occur in a pregnant number of patients and are more than likely when multiple drugs are prescribed.¹⁸ Adverse reactions include fatigue, dizziness, coughing, headache, myalgia, angioedema, renal impairment, gastrointestinal upsets, hyperglycemia, and electrolyte disturbances.^eighteen

Long-term patient persistence with antihypertensive treatment is unsatisfactory,^19,20 with merely 44% of patients adhering to the treatment regimen in the long term.^20,21 While physician-related barriers to constructive management of uncontrolled hypertension, such every bit therapeutic inertia, contribute to this problem,^22,23 patient motivation and satisfaction are equally important.²⁴ Persistence varies with the blazon of medication^20,21 and is associated with the severity and frequency of adverse events,¹⁸ likewise as with the complexity of treatment.²⁴

Several factors play a role in the development of hypertension, including genetic variability, lifestyle, and dietary influences. While genetic variability is estimated to contribute nigh 30% to individuals' BP profiles,^25,26 lifestyle and dietary choices play an important role in BP modulation and control.¹³

Research suggests a torso mass index (=weight/meridian²) between xviii.5 kg/m^two and 25 kg/m² 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.^thirteen In addition, thirty minutes of regular daily moderate aerobic exercise (eg, brisk walk) tin reduce SBP by 4–ix mmHg,¹³ while optimizing vitamin D levels (serum >75 nmol/L) can amend SBP by 3–4 mmHg in hypertensives.^27,28

Other lifestyle factors influencing BP include smoking, alcohol intake, and stress. Smoking abeyance has been estimated to lead to a BP reduction of upwards to 10 mmHg in hypertensives,²⁹ alcohol consumption exceeding 1–two standard drinks per twenty-four hours may influence BP by 2–iv mmHg,¹³ and continuous stress and insufficient quality sleep may push the BP by upwards to 10 mmHg.³⁰

Nutrition plays an important role in BP control, with the adoption of the dietary approaches to stop hypertension or a Mediterranean nutrition achieving BP reductions between 8 mmHg and 14 mmHg systolic in hypertensives.^13,31 In addition, a meta-analysis including 13 trials (due north=543 hypertensives) 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 acceptable ratio between sodium and potassium (NaCl/KCl) intakes for optimal cardiovascular wellness.^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 hither.

Involvement in complementary and nutritional medicine has been increasing, with about fifty% of Australians, including those with cardiovascular atmospheric condition, regularly using complementary therapies.^37–forty As motivation to self-care may influence patient compliance,⁴¹ there is scope to explore the integration of effective nutritional and other complementary therapies in antihypertensive direction.

Garlic and hypertension

Garlic (Allium sativum) has been used as a spice, food, and medicine for over five,000 years, and is one of the primeval documented herbs utilized for the maintenance of health and handling of disease.⁴² In some of the oldest texts on medicine, 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 Hellenic republic, garlic was used every bit a diuretic, as recorded by Hippocrates, the father of modern medicine.⁴⁴ In addition to its cardiovascular 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 constitute.

More recently, garlic has been shown to accept BP-lowering properties. A meta-assay including twenty clinical trials suggested garlic to exist superior to placebo in lowering BP in hypertensive patients on boilerplate by viii–9 mmHg in SBP and 6–vii mmHg in DBP, P<0.0001).⁴⁵ Trials included in the meta-analysis were considered loftier quality, reporting adequate allocation concealment, randomization, double blinding, and low attrition. This reduction in BP reported in the meta-assay is comparable to the BP-lowering effects of mutual antihypertensive medications.^13,46 While garlic supplementation reduced BP significantly in hypertensive patients, information technology did non appreciably affect patients with normal BP.^45,47–49 In addition, response to and effectiveness of garlic supplementation appears to exist dependent on individual genetic and dietary factors, with SBP reductions of up to twoscore mmHg in responders and a proportion of 25%–33% nonresponders, contained of garlic dosage, in a 3-month trial.^l

Types and components of garlic, tolerability, and condom

Several types of garlic preparations are available, including raw and freshly cooked garlic, garlic oil, garlic pulverization, and aged garlic extract. Functional sulfur-containing components described in garlic include alliin, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, ajoene, and South-allylcysteine.^51,52 Allicin, formed by enzymatic reaction from alliin, the main chemical compound establish 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 cherry blood cell count.⁵⁶ Garlic essential oil contains diallyl disulfide and diallyl trisulfide and no water-soluble allicin. Commercially available garlic oil preparations frequently include only a minor amount of garlic essential oil in a vegetable oil base, complicating comparability and standardization of products.⁵³ In contrast, South-allylcysteine, the main active compound in anile 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 issue of garlic on BP used either garlic powder or aged garlic excerpt.^45,48 Side effects of garlic supplements, reported by near a third of the participants in these trials, were more often than not mild, and included burping, flatulence, and reflux in the first few weeks of the trial.^47,50 A pocket-size number of the population (iv%–6%) may experience more severe gastrointestinal disturbances with therapeutic dosages of garlic supplements.^{47,50,59,threescore} Lower tolerance of sulfur-containing foods such as garlic, onion, and leek may be reversed by supplementation with molybdenum and/or vitamin B₁₂, often deficient in afflicted individuals.^61,62

Despite the general advice, bear witness is weak for garlic preparations causing harmful interactions if taken in improver 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 interaction of garlic with protease inhibitors in antiretroviral therapy.⁶³ Information technology is generally recommended that loftier doses (equivalent to >four g of fresh garlic or three mg allicin) should be avoided in patients taking antithrombotic medications including warfarin, due to the antiplatelet properties of garlic.⁶⁵ Still, a trial using higher concentrations of aged garlic extract (10 mL/solar day, containing fourteen.7 mg Due south-allylcysteine) for patients on warfarin therapy found no increase in the incidence of hemorrhage compared with placebo.⁶⁴

Mechanisms for blood force per unit area-lowering event of garlic

Several mechanisms of action for the BP-lowering properties of organosulfur compounds in garlic accept been postulated, including mediation of intracellular nitric oxide (NO) and hydrogen sulfide (H₂S) production also as blockage of angiotensin-II production, which in turn promotes vasodilation and thus reduces the BP.^66–71

The strongest show of and insights into the mechanisms of the BP-lowering event of garlic supplementation involve endothelium-dependent vasodilation, and thus, this review will focus on the current knowledge of the physiological and biochemical processes within claret 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 experimental and clinical evidence.⁷²

NO, redox signaling, and the result of garlic on hypertension

The soluble gas NO is a well-known gene in the mechanism for acetylcholine-induced (parasympathetic) vasodilation. NO is synthesized from 50-arginine by at least iii isoforms of NO synthase (NOS) in the endothelium by endothelial NOS (eNOS), in nervus cells mainly by neuronal NOS, and in macrophages by inducible NOS.⁷³ In some tissues and organs, including the eye, both eNOS and neuronal NOS are present.

Effigy 1 illustrates vascular NO signaling pathways, including the event of NO on vasodilation, and a potential influence of garlic organosulfur compounds.

Figure ane Effect of garlic on claret pressure level 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, reddish rectangle represents NO, and purple rectangles announce direct and indirect influence of NO on vasodilation and blood pressure. NO pathway: in the presence of BH4, eNOS produces NO, which triggers pathways leading to smooth muscle cell relaxation and vasodilation. eNOS uncoupling leads to the formation of O2 −. NO and O2 − 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 organosulfides may play a function in the regulation of the NO signaling pathway by creating a more than reductive environment and therefore supporting NO production. Abbreviations: BH2, dihypdrobiopterin; BH4, tetrahydrobiopterin; Ca2+, 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; O2, oxygen; O2 −, superoxide anion radical; PKB, protein kinase-B.

eNOS-derived NO induces relaxation of smoothen musculus cells and, thus, increased dilation of all types of blood vessels, 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 inactive while bound to caveolin, and can be activated through calcium-responsive bounden of calmodulin via hormonal or neuronal activation or shear stress-induced phosphorylation (Figure 1). The production of NO requires 50-arginine every bit substrate and tetrahydrobiopterin (BH₄) as a cofactor. BH₄ levels have been reported to subtract with aging and cardiovascular disease, and a lack of BH_four results in so-called eNOS uncoupling, resulting in the generation of high levels of superoxide (O₂ ⁻) and depression 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-Due south-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 being plasma could be important in cardiovascular disease.⁷⁷

Oxidative stress, defined as "a disturbance in the pro-oxidant/antioxidant residuum in favor of the former" has been an intensively researched field of inquiry in the past few decades.⁷⁸ Even so, this definition has been challenged past a number of authors following contempo advances in the understanding of redox signaling, and changes in the redox status of tissues have been shown to be part of cellular betoken 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

Information technology has been suggested that the redox condition of the cellular milieu affects the activity of eNOS and thus modulates NO-dependent pathways in the endothelium.^85,86

Aged garlic extract in cell civilisation prevented endothelial cells from "oxidative stress" by increasing cellular concentrations 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 past preventing the refuse of BH_four levels.⁸⁷ Relevant levels of BH_four foreclose NO uncoupling and superoxide generation, which are thought to improve endothelial dysfunction, and potentially reducing the progression to atherosclerosis.⁸⁷

In improver, Due south-glutathionylation of eNOS at 2 highly conserved cysteine residues reversibly decreases NOS action with an increase in superoxide generation, resulting in impaired endothelium-dependent vasodilation.⁸⁶ S-glutathionylation can exist reversed, notwithstanding, by thiol agents. Southward-glutathionylation of eNOS is thought to be a pivotal switch providing redox regulation of cellular signaling, endothelial office, and vascular tone.⁸⁶ Furthermore, while uncoupling of eNOS leads to potent inactivation of NO through its reaction with superoxide (O₂ ⁻), this reaction forms the stiff oxidant peroxynitrite (ONOO⁻) (Effigy i). Peroxinitrite has long been considered to be a highly toxic metabolic by-product, dissentious biomolecules including proteins, lipids, and Deoxyribonucleic acid. However, there have been new insights demonstrating that ONOO^– is also involved in various signaling pathways, including a mechanism of vasodilation contained of cGMP.⁸⁸

While NO clearly is an important signaling molecule, its overproduction has been implicated in various pathologies, including angiogenesis, mitochondrial dysfunction, and heart failure.^89,90 "Nitrosative stress" may crusade hyper-nitrosylation of various regulatory enzymes leading to dysregulation of several cellular and physiological processes including inhibition of autophagy.⁹¹

Moreover, hyperproduction of NO may also atomic number 82 to upregulation of mammalian target of rapamycin (mTOR), the cardinal regulating molecule of the major signaling pathways for jail 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, at that place is a growing list of physiological malfunctions linked to overstimulation of this NO-dependent signaling pathway, ranging from insulin resistance to neurodegenerative diseases to cancer, and even including hypertension itself. If NO enhances rather than inhibits mTOR signaling, there is crusade 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 exist impaired in sulfur deficiency. Garlic and other alliums, such equally leek and onion, with their high content of polysulfides may help in providing the nutrients needed for maintaining or restoring optimum redox balances for a number of eNOS-dependent signaling pathways important in vascular relaxation.

H_iiS production and the effect of garlic on hypertension

A second vascular gaseous signal transmitter is H₂Southward.⁹³ H_twoS exists in micromolar concentrations in diverse mammalian tissues, including the encephalon, nervous system, vascular smooth muscle cells, and in the middle.⁹³ Endogenous H₂S production is primarily the effect 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 H₂S. In addition, iii-mercaptopyruvate sulfur-transferase and cysteine aminotransferase localized to the endothelium of the thoracic aorta have also been reported to produce H₂Southward from cysteine and α-ketoglutarate.⁹⁴ Experiments with CSE knock-out rodents have found reduced levels of H_iiSouth and hypertension.⁹⁵ Likewise, spontaneously hypertensive rats have reduced expression of CSE in aortic tissues and lowered plasma levels of H₂Southward.^24,96,97

Figure 2 illustrates the H₂S production pathway, the connection to the methylation cycle and homocysteine (HCy), the effect of H₂S on vasodilation, and influence of garlic-derived polysulfides on this pathway.

Effigy ii Result of garlic on blood pressure via the hydrogen sulfide (H2Due south) pathway, and influence of dietary and genetic factors on homocysteine levels. Notes: Blueish rectangles illustrate metabolites, blueish circles represent enzymes, orange circles are dietary cofactors, green star shapes bear witness garlic and other polysulfide-containing nutrients, ruby-red rectangle indicates H2S, and purple rectangles stand for direct and indirect influence of HtwoS on vasodilation and blood force per unit area. Crimson circles 1–7: Influence of dietary and genetic factors on H2South pathway i= genetic polymorphism, homozygous for deleterious allele, leads to impaired folate metabolism. two= mutual polymorphisms, some of which lead to increased homocysteine and decreased methylation and SAM levels; these answer 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 H2S production. vi= low Vit B6* levels may increment homocysteine levels and reduce H2Due south product, and may respond to Vit Bhalf-dozen supplementation. 7= dietary intake of garlic polysulfides and thiosulfides tin increase H2Due south nonenzymatically, and may ameliorate genetic defects in the CBS enzyme, or dietary deficiencies in Vit Bhalf dozen 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; H2O2, 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, Due south-adenosyl-methionine; Se, selenium; Vit B6*, activated course of Vit Bhalf-dozen =pyridoxal-phosphate; Vit Bii, vitamin B2 (riboflavin); Vit B12, vitamin B12.

The H₂Southward-dependent BP-reducing result is thought to be primarily mediated through sulfhydration of ATP-sensitive potassium (Grand_ATP) channels, which in plough leads to voltage-sensitive aqueduct opening and relaxation of vascular smooth muscle cells.⁹⁸

However, other potassium channels may too be affected by H₂S, and additional mechanisms have been suggested in determining the opening/closing of K⁺ channels, including nitrosylation, and a possible cooperation betwixt H_twoS and NO.⁹⁸

While the relationship betwixt NO and H_twoSouthward in controlling vascular relaxation is still unclear (eg, both upregulation and inhibition of eNOS by H_iiS have been reported),⁹⁹ at that place is convincing evidence that H_twoSouthward shares at least some of the vasorelaxing signaling role with NO and H₂S deficiency and therefore tin contribute to vascular dysfunction including hypertension.^{84,93,94,100,101}

Nonenzymatic conversion of garlic-derived organic polysulfides to H_twoSouthward

In a serial of elegant experiments, Benavides et al⁶⁹ showed that garlic-derived polysulfides can produce H_twoDue south under physiologically relevant O₂ atmospheric condition in rat aortic tissue. They provided evidence for a mechanism involving reduced thiols. While it is unknown which garlic bioactives can release H₂Due south nonenzymatically, it has been hypothesized that the major bioactive S-allylcysteine plant in anile garlic extract may also human activity as a substrate for the enzyme CSE to produce H₂S.¹⁰²

H₂S deficiency and supplementation

At that place is conflicting bear witness almost the potential age-related decline in vascular H₂Due south production, but any impairments of H₂S signaling may differ among tissues, with the liver existence less susceptible to functional changes with historic period than less vital organs including the vasculature, which would be consistent with the triage theory of nutritional deficiencies.^103,104

Information technology is generally understood that most H₂S gets oxidized within mitochondria to thiosulfate and farther to sulfate. Thiosulfate formed from H_twoS through mitochondrial oxidation can undergo reduction and thus recycling past an enzymatic procedure dependent on dihydrolipoic acid (the reduced class of lipoic acid).¹⁰⁵ While well-nigh H₂S oxidation occurs inside mitochondria, extra-mitochondrial oxidation occurs by reactive oxygen species and reactive nitrogen species.¹⁰⁶ Thus, tissue concentrations of H_twoS can exist expected to be lower in more oxidative environments. On the other hand, loftier concentrations of H_iiS are toxic, and there is evidence that H₂S in high concentration itself causes germination of superoxide by inhibiting mitochondrial oxidative phosphorylation. This may be a possible negative feedback mechanism for limiting excessive H_iiSouthward concentrations.¹⁰⁷ This suggests that the H₂S signaling pathway in vasorelaxation has a like 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 H₂Due south for maintaining the balanced blood vessel constriction.⁹³ Other dietary H₂S 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 establish a positive correlation between HCy plasma levels, endothelial 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 hyperhomocysteinemia (HHCy).^112,113 Furthermore, serum concentrations of the sulfur-containing thiols HCy, cysteine, and GSH have shown to be independently associated with cardiovascular risk scores at the population level.¹¹⁴ Nonetheless, whether elevated levels of HCy are primary or secondary risk factors for cardiovascular disease is less clear.^115,116 At that place is a articulate negative correlation between elevated HCy levels and brain and cognitive function.^117,118

Elevated levels of HCy might be a upshot of impaired endothelial production of H_twoSouth.¹¹⁹ The transformation of HCy into cysteine is catalyzed by the enzymes CBS and CSE as role of the trans-sulfuration pathway (Figure 2).^94,120 CBS and CLE are too amid the few enzymes in mammals with the capacity to produce H₂Due south. The chemical reaction facilitated by CBS is a vitamin-B_{half dozen}-(pyridoxal-phosphate)-dependent condensation of either serine or cysteine and HCy.¹¹⁹ CBS is the rate-limiting enzyme necessary for last removal of HCy. Deficiencies in CBS activeness caused by genetic mutations of the CBS gene are the most frequent cause of familial HHCy.¹²¹ In that location are at least 153 mutations known to be in the CBS factor, with several significantly reducing CBS activity.¹²¹ These genetic CBS deficiencies tin can be divided into two major allelic variance types: vitamin B₆ responsive and vitamin B₆ nonresponsive.^122,123 Individuals with some of these genetic variants are likely to take both decreased production of H_twoS and elevated levels of HCy. While cases with a vitamin B₆-responsive variant can exist treated with ongoing B₆ therapy, cases affected by vitamin B₆ nonresponsive variants go along to have impaired production of H₂South, simply may benefit from supplementation with nutritional H₂Southward donors, such equally garlic. Thus, consumption of garlic, which tin produce H₂S nonenzymatically,⁶⁹ may do good weather related to dumb product of H₂S, 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 H₂Due south, which has been linked to an increase in platelet activation and may contribute to the development of recurrent arterial and venous thrombosis in these patients.¹²⁴ It is therefore possible that supplementation with H₂S-boosting nutrients, such as garlic, may exist 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 depression levels 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 equally biomarkers of sulfur deficiency.¹²⁵ A correlation between low ruby-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 Due south-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 concentrations past xxx%.¹²⁸ In contrast, elevated levels of HCy caused by mild folate deficiency did non change significantly by garlic supplementation.¹²⁸

Thus, garlic may accept an upshot on HCy metabolism independent of the result of B vitamins in add-on to boosting H_twoS production.

Renin–angiotensin–aldosterone system and the issue of garlic on hypertension

Other potential mechanisms of activity for garlic'due south effect on hypertension take 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 jail cell civilization and animal studies.^67,71,129 ACE is a component in the renin–angiotensin–aldosterone organization, and inhibitors of ACE are used as standard BP-controlling pharmaceuticals. Even so, animal and cell culture experiments were mainly conducted with fresh garlic compounds, containing allicin (S-allyl-cysteine sulfoxide), which has a very low sustained bioavailability in homo tissues.⁵⁵ Therefore, the antihypertensive issue of garlic via the proposed angiotensin-converting enzyme inhibitor mechanism seems less plausible than its H₂S-stimulating and NO-regulating properties.

Determination

Garlic, peculiarly 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 H₂Due south production via enzymatic and nonenzymatic pathways, which promote vasodilation and BP reduction.

Several dietary and genetic factors, including folate, vitamin B₆, and vitamin B₁₂ deficiency, and known genetic variants of the MTHFR and CBS genes, influence the efficiency of H₂S production, and could exist of import contributors to hypertension in these individuals, which may also explain individual responsiveness to garlic supplementation seen in clinical trials.

Polysulfides in garlic may likewise influence regulation of NO redox signaling pathways, including NO-mediated vasodilation and reduction of BP. Future clinical trials could explore the potential influence of nutritional condition and genetic factors on the individual's responsiveness to garlic therapy for hypertension.

Disclosure

The authors report no conflicts of involvement in this work.

---

References

one.	World Heart Federation. Fact Canvas: Cardiovascular Disease Risk Factors. Geneva: Earth Heart Federation; 2012. Available from: http://www.world-heart-federation.org/printing/fact-sheets/cardiovascular-disease-take a chance-factors/. Accessed Nov 12, 2014.
2.	Lawes CM, Vander Hoorn S, Rodgers A. Global brunt of blood-pressure-related illness, 2001. Lancet. 2008;371(9623):1513–1518.
three.	Martiniuk AL, Lee CM, Lawes CM, et al. Hypertension: its prevalence and population-attributable fraction for mortality from cardiovascular illness in the Asia-Pacific region. J Hypertens. 2007;25(ane):73–79.
4.	Lewington Due south, Clarke R, Qizilbash North, Peto R, Collins R. Age-specific relevance of usual blood force per unit area to vascular mortality: a meta-analysis of individual information for ane million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–1913.
5.	Denker MG, Cohen DL. What is an appropriate blood pressure goal for the elderly: review of recent studies and applied recommendations. Clin Interv Aging. 2013;8:1505.
6.	Bangalore S, Messerli FH, Wun CC, et al. J-bend revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial. Eur Heart J. 2010;31(23):2897–2908.
7.	Briganti EM, Shaw JE, Chadban SJ, et al. Untreated hypertension among Australian adults: the 1999-2000 Australian Diabetes, Obesity and Lifestyle Written report. Med J Aust. 2003;179(3):135–139.
eight.	Myers MG. The great myth of role blood pressure measurement. J Hypertens. 2012;thirty(10):1894–1898.
ix.	Conen D, Bamberg F. Noninvasive 24-h ambulatory blood pressure and cardiovascular disease: a systematic review and meta-analysis. J Hypertens. 2008;26(7):1290–1299.
10.	Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true normotension: a meta-assay. J Hypertens. 2007;25(11):2193–2198.
11.	Glen SK, Elliott HL, Curzio JL, Lees KR, Reid JL. White-coat hypertension as a cause of cardiovascular dysfunction. Lancet. 1996;348(9028): 654–657.
12.	Centers for Disease Command and Prevention. Vital signs: prevalence, treatment, and control of hypertension – United States, 1999–2002 and 2005–2008. MMWR Morb Mortal Wkly Rep. 2011;60(4):103.
13.	Chobanian AV, Bakris GL, Black HR, et al. The 7th report of the joint national commission on prevention detection evaluation and treatment of high blood pressure level. JAMA. 2003;289(nineteen):2560–2572.
14.	Calhoun DA, Jones D, Textor Southward, et al. Resistant hypertension: diagnosis, evaluation, and treatment a scientific statement from the American Heart Association Professional person Instruction Committee of the Council for High Blood Force per unit area Enquiry. Hypertension. 2008;51(6):1403–1419.
15.	National Heart Foundation of Australia (National Blood Pressure and Vascular Disease Advisory Committee). Guide to management of hypertension 2008. Updated Dec 2010.
16.	Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Strength for the direction of arterial hypertension of the European Society of Hypertension (ESH) and of the European Lodge of Cardiology (ESC). J Hypertens. 2013;31(seven):1281–1357.
17.	Hobbs F, Irwin P, Rubner J. Evidence-based treatment of hypertension: what'southward the function of angiotensin II receptor blockers? Br J Cardiol. 2005;12(ane):65–seventy.
18.	Olsen H, Klemetsrud T, Stokke HP, Tretli Southward, Westheim A. Adverse drug reactions in current antihypertensive therapy: a full general do survey of 2586 patients in Norway. Blood Printing. 1999;8(ii):94–101.
xix.	Hasford J, Mimran A, Simons WR. A population-based European cohort report of persistence in newly diagnosed hypertensive patients. J Hum Hypertens. 2002;sixteen(8):569–575.
20.	Simons LA, Ortiz M, Calcino G. Persistence with antihypertensive medication: Australia-wide experience, 2004-2006. Med J Aust. 2008;188(4):224–227.
21.	Caro JJ, Speckman JL, Salas M, Raggio Yard, Jackson J. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. Can Med Assoc J. 1999;160(1):41–46.
22.	Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Salubrious People 2010 blood pressure level control goals. Hypertension. 2006;47(3):345–351.
23.	Oliveria SA, Lapuerta P, McCarthy BD, L'Italien GJ, Berlowitz DR, Asch SM. Doc-related barriers to the effective management of uncontrolled hypertension. Arch Intern Med. 2002;162(4):413–420.
24.	Burnier M. Long-term compliance with antihypertensive therapy: another facet of chronotherapeutics in hypertension. Blood Press Monit. 2000;5(Suppl 1):S31–S34.
25.	Korner PI. Essential Hypertension and its Causes: Neural and Not-Neural Mechanisms. Oxford: Oxford University Press; 2007.
26.	Mo R, Omvik P, Lund-Johansen P. The Bergen blood force per unit area written report: offspring of two hypertensive parents accept significantly college blood pressures than offspring of ane hypertensive and one normotensive parent. J Hypertens. 1995;13(12 pt 2):1614–1617.
27.	Witham Physician, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009;27(10):1948.
28.	Souberbielle JC, Body JJ, Lappe JM, et al. Vitamin D and musculoskeletal health, cardiovascular affliction, autoimmunity and cancer: recommendations for clinical practice. Autoimmun Rev. 2010;9(xi):709–715.
29.	Groppelli A, Giorgi DM, Omboni Southward, Parati K, Mancia 1000. Persistent blood force per unit area increase induced by heavy smoking. J Hypertens. 1992;ten(5):495–499.
30.	McCraty R, Atkinson 1000, Tomasino D. Impact of a workplace stress reduction plan on blood pressure and emotional health in hypertensive employees. J Altern Complement Med. 2003;9(3):355–369.
31.	Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular adventure: a study of the American College of Cardiology/American Center Association Chore Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 pt B):2960–2984.
32.	Juraschek SP, Guallar East, Appel LJ, Miller ER 3rd. Effects of vitamin C supplementation on claret pressure: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012;95(5):1079–1088.
33.	Mente A, O'Donnell MJ, Rangarajan S, et al. Association of urinary sodium and potassium excretion with claret pressure. N Engl J Med. 2014;371(seven):601–611.
34.	O'Donnell G, Mente A, Rangarajan S, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med. 2014;371(7):612–623.
35.	Ried K, Fakler P. Protective effect of lycopene on serum cholesterol and blood pressure level: meta-analyses of intervention trials. Maturitas. 2011;68(4):299–310.
36.	Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Issue of chocolate on blood force per unit area. Cochrane Database Syst Rev. 2012;viii: CD008893.
37.	MacLennan AH, Myers SP, Taylor AW. The continuing apply of complementary and alternative medicine in S Australia: costs and behavior in 2004. Med J Aust. 2006;184(i):27–31.
38.	Harris P, Rees R. The prevalence of complementary and culling medicine utilize among the general population: a systematic review. Complement Ther Med. 2000;8(two):88–96.
39.	Yeh GY, Davis RB, Phillips RS. Employ of complementary therapies in patients with cardiovascular disease. Am J Cardiol. 2006;98(5): 673–680.
40.	Lin MC, Nahin R, Gershwin ME, Longhurst JC, Wu KK. State of complementary and culling medicine in cardiovascular, lung, and blood research executive summary of a workshop. Apportionment. 2001;103(16):2038–2041.
41.	Gohar F, Greenfield SM, Beevers DG, Lip GY, Jolly One thousand. Self-care and adherence to medication: a survey in the hypertension outpatient clinic. BMC Complement Altern Med. 2008;8:4.
42.	Rivlin RS. Historical perspective on the apply of garlic. J Nutr. 2001; 131(Suppl iii):951S–954S.
43.	Petrovska BB, Cekovska South. Extracts from the history and medical properties of garlic. Pharmacogn Rev. 2010;4(7):106.
44.	Moyers SB. Garlic in Health, History, and Globe Cuisine. St Petersburg: Suncoast Press; 1996.
45.	Ried Thou. Effect of garlic on blood pressure, serum cholesterol and immunity: updated meta-analyses and review. J Nutr. 2014.
46.	McInnes GT. Lowering claret force per unit area for cardiovascular risk reduction. J Hypertens Suppl. 2005;23(i):S3–S8.
47.	Ried K, Frank OR, Stocks NP. Aged garlic extract lowers claret pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial. Maturitas. 2010;67:144–150.
48.	Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure level: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2008;8:13.
49.	Reinhart KM, Coleman CI, Teevan C, Vachhani P, White CM. Effects of garlic on claret pressure level in patients with and without systolic hypertension: a meta-analysis. Ann Pharmacother. 2008;42(12):1766–1771.
50.	Ried K, Frank OR, Stocks NP. Aged garlic extract reduces claret force per unit area in hypertensives: a dose-response trial. Eur J Clin Nutr. 2013;67:64–70.
51.	Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr. 2006;136(Suppl 3):716S–725S.
52.	Yun HM, Ban JO, Park KR, et al. Potential therapeutic furnishings of functionally agile compounds isolated from garlic. Pharmacol Ther. 2014;142(2):183–195.
53.	Amagase H, Petesch BL, Matsuura H, Kasuga South, Itakura Y. Intake of garlic and its bioactive components. J Nutr. 2001;131(iii):955S–962S.
54.	Lawson LD, Wang ZJ. Low allicin release from garlic supplements: a major problem due to the sensitivities of alliinase activeness. J Agric Food Chem. 2001;49(five):2592–2599.
55.	Lawson LD, Gardner CD. Composition, stability, and bioavailability of garlic products used in a clinical trial. J Agric Food Chem. 2005;53(16): 6254–6261.
56.	Harauma A, Moriguchi T. Aged garlic excerpt improves claret pressure in spontaneously hypertensive rats more safely than raw garlic. J Nutr. 2006;136(Suppl 3):769S–773S.
57.	Kodera Y, Suzuki A, Imada O, et al. Concrete, chemical, and biological properties of south-allylcysteine, an amino acrid derived from garlic. J Agric Food Chem. 2002;50(iii):622–632.
58.	Hoshino T, Kashimoto N, Kasuga S. Effects of garlic preparations on the gastrointestinal mucosa. J Nutr. 2001;131(3s):1109S–1113S.
59.	Brook Due east, Gruenwald J. Allium sativum in der Stufentherapie der Hyperlipidaemie. Med Welt. 1993;44:516–520.
60.	Borrelli F, Capasso R, Izzo AA. Garlic (Allium sativum L.): adverse furnishings and drug interactions in humans. Mol Nutr Food Res. 2007; 51(eleven):1386–1397.
61.	Waring RH, Klovrza LZ, Harris RM. Diet and individuality in detoxification. J Nutr Environ Med. 2007;16(2):95–105.
62.	Meletis CD. Cleansing of the human trunk. A daily essential process. Altern Complement Ther. 2001;7(4):196–202.
63.	Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13): 1777–1798.
64.	Macan H, Uykimpang R, Alconcel M, et al. Anile garlic excerpt may be safe for patients on warfarin therapy. J Nutr. 2006;136(Suppl 3):793S–795S.
65.	Braun L, Cohen M. Herbs and Natural Supplements: An Prove-Based Guide. Chatswood: Elsevier; 2007.
66.	Al-Qattan KK, Thomson M, Al-Mutawa'a South, Al-Hajeri D, Drobiova H, Ali M. Nitric oxide mediates the blood-pressure lowering effect of garlic in the rat two-kidney, 1-clip model of hypertension. J Nutr. 2006;136(Suppl 3):774S–776S.
67.	Sharifi AM, Darabi R, Akbarloo N. Investigation of antihypertensive machinery of garlic in 2K1C hypertensive rat. J Ethnopharmacol. 2003;86(2–3):219–224.
68.	Morihara N, Sumioka I, Moriguchi T, Uda Northward, Kyo Eastward. Anile garlic excerpt enhances production of nitric oxide. Life Sci. 2002;71(five):509–517.
69.	Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U Southward A. 2007; 104(46):17977–17982.
seventy.	Chuah SC, Moore PK, Zhu YZ. Due south-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol. 2007;293(5):H2693–H2701.
71.	Shouk R, Abdou A, Shetty K, Sarkar D, Eid A. Mechanisms underlying the antihypertensive furnishings of garlic bioactives. Nutr Res. 2014;34:106–115.
72.	Kirby BS, Crecelius AR, Voyles WF, Dinenno FA. Vasodilatory responsiveness to adenosine triphosphate in ageing humans. J Physiol. 2010;588(xx):4017–4027.
73.	Förstermann U, Sessa WC. Nitric oxide synthases: regulation and part. Eur Heart J. 2012;33(vii):829–837.
74.	Panza JA, García CE, Kilcoyne CM, Quyyumi AA, Cannon RO. Impaired endothelium-dependent vasodilation in patients with essential hypertension evidence that nitric oxide abnormality is not localized to a single point transduction pathway. Circulation. 1995;91(6): 1732–1738.
75.	Montezano AC, Touyz RM. Reactive oxygen species and endothelial function–part of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol. 2012;110(one):87–94.
76.	Jones DP. Redefining oxidative stress. Antioxid Redox Indicate. 2006; 8(nine–10):1865–1879.
77.	Jones DP, Park Y, Gletsu-Miller N, et al. Dietary sulfur amino acrid furnishings on fasting plasma cysteine/cystine redox potential in humans. Nutrition. 2011;27(2):199–205.
78.	Sies H. Oxidative stress: oxidants and antioxidants. Exp Physiol. 1997;82(2):291–295.
79.	Linnane AW, Kios M, Vitetta L. Good for you crumbling: regulation of the metabolome past cellular redox modulation and prooxidant signaling systems: the essential roles of superoxide anion and hydrogen peroxide. Biogerontology. 2007;8(5):445–467.
80.	Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011;194(i):7–15.
81.	Halliwell B. Free radicals and antioxidants – quo vadis? Trends Pharmacol Sci. 2011;32(3):125–130.
82.	Lee MY, Griendling KK. Redox signaling, vascular function, and hypertension. Antioxid Redox Signal. 2008;10(6):1045–1059.
83.	Touyz RM, Briones AM. Reactive oxygen species and vascular biological science: implications in man hypertension. Hypertens Res. 2011;34(1): 5–14.
84.	Majzunova M, Dovinova I, Barancik M, Chan J. Redox signaling in pathophysiology of hypertension. J Biomed Sci. 2013;20(1):69.
85.	Sugiyama T, Michel T. Thiol-metabolizing proteins and endothelial redox state: differential modulation of eNOS and biopterin pathways. Am J Physiol (Cell Physiol). 2010;22(ane):H194.
86.	Chen C-A, Wang T-Y, Varadharaj South, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular office. Nature. 2010;468(7327):1115–1118.
87.	Weiss N, Papatheodorou L, Morihara North, Hilge R, Ide Northward. Aged garlic extract restores nitric oxide bioavailability in cultured human endothelial cells even nether conditions of homocysteine elevation. J Ethnopharmacol. 2013;145(1):162–167.
88.	Cohen RA, Adachi T. Nitric oxide induced vasodilatation: regulation by physiologic S-glutathiolation and pathologic oxidation of the sarcoplasmic endoplasmic reticulum calcium ATPase. Trends Cardiovasc Med. 2006;16(iv):109–114.
89.	Foster MW, Hess DT, Stamler JS. Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med. 2009;xv(ix): 391–404.
90.	Mantle ML. The NO/ONOO-cycle every bit the central cause of heart failure. Int J Mol Sci. 2013;14(11):22274–22330.
91.	Sarkar S, Korolchuk Half dozen, Renna M, et al. Complex inhibitory effects of nitric oxide on autophagy. Mol Cell. 2011;43(1):xix–32.
92.	Blagosklonny MV. Answering the ultimate question "what is the proximal cause of crumbling?". Aging (Albany NY). 2012;4(12):861.
93.	Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92(2):791–896.
94.	Zhang Y, Tang Z-H, Ren Z, et al. Hydrogen sulfide, the side by side stiff preventive and therapeutic agent in aging and age-associated diseases. Mol Prison cell Biol. 2013;33(6):1104–1113.
95.	Lake-Bruse KD, Faraci FM, Shesely EG, Maeda North, Sigmund CD, Heistad DD. Gene transfer of endothelial nitric oxide synthase (eNOS) in eNOS-scarce mice. Am J Physiol (Middle Circ Physiol). 1999;277(2):H770–H776.
96.	Yan H, Du J, Tang C. The possible part of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun. 2004;313(1):22–27.
97.	Zhao X, Zhang L-K, Zhang C-Y, et al. Regulatory effect of hydrogen sulfide on vascular collagen content in spontaneously hypertensive rats. Hypertens Res. 2008;31(viii):1619–1630.
98.	Jiang B, Tang Thousand, Cao Yard, Wu L, Wang R. Molecular machinery for H2S-induced activation of KATP channels. Antioxid Redox Point. 2010;12(10):1167–1178.
99.	Kolluru GK, Shen X, Kevil CG. A tale of two gases: NO and H2S, foes or friends for life? Redox Biol. 2013;ane(ane):313–318.
100.	Predmore BL, Lefer DJ, Gojon Grand. Hydrogen sulfide in biochemistry and medicine. Antioxid Redox Signal. 2012;17(1):119–140.
101.	Kashfi K, Olson KR. Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Biochem Pharmacol. 2013;85(v):689–703.
102.	Chuah SC, Moore PK, Zhu YZ. S-allylcysteine mediates cardioprotection in an astute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol. 2007;293(v):H2693–H2701.
103.	Predmore BL, Alendy MJ, Ahmed KI, Leeuwenburgh C, Julian D. The hydrogen sulfide signaling organisation: changes during aging and the benefits of caloric restriction. Historic period. 2010;32(four):467–481.
104.	Ames BN. Low micronutrient intake may accelerate the degenerative diseases of crumbling through allocation of deficient micronutrients by triage. Proc Natl Acad Sci U S A. 2006;103(47):17589–17594.
105.	Yoshinori M, Norihiro S, Yuka G, Noriyuki North, Yuki O, Hideo Yard. Thioredoxin and dihydrolipoic acid are required for iii-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem J. 2011;439(3): 479–485.
106.	Nikolaidis MG, Jamurtas AZ. Claret as a reactive species generator and redox status regulator during practice. Arch Biochem Biophys. 2009;490(2):77–84.
107.	Olson KR. A practical wait at the chemistry and biology of hydrogen sulfide. Antioxid Redox Betoken. 2012;17(1):32–44.
108.	Wang R. Is H2S a stinky remedy for atherosclerosis? Arterioscler Thromb Vasc Biol. 2009;29(2):156–157.
109.	Schalinske KL, Smazal AL. Homocysteine imbalance: a pathological metabolic marker. Adv Nutr. 2012;iii(6):755–762.
110.	Moat SJ, McDowell IF. Homocysteine and endothelial function in man studies. Semin Vasc Med. 2005;5(2):172–182.
111.	Weiss Due north, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in balmy hyperhomocysteinemia. Vasc Med. 2002;seven(3):227–239.
112.	Tayama J, Munakata Chiliad, Yoshinaga K, Toyota T. Higher plasma homocysteine concentration is associated with more advanced systemic arterial stiffness and greater blood force per unit area response to stress in hypertensive patients. Hypertens Res. 2006;29(6):403.
113.	Mizrahi EH, Noy South, Sela B-A, Fleissig Y, Arad M, Adunsky A. Further show of interrelation between homocysteine and hypertension in stroke patients: a cross-sectional written report. Isr Med Assoc J. 2003;v(xi):791–794.
114.	Mangoni AA, Zinellu A, Carru C, Attia JR, McEvoy M. Serum thiols and cardiovascular risk scores: a combined assessment of transsulfuration pathway components and substrate/production ratios. J Transl Med. 2013;11(one):i–ix.
115.	Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular affliction: causal or casual? Arch Intern Med. 2000;160(four):422–434.
116.	Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR example-control studies, avoiding publication bias. PLoS Med. 2012;9(2):e1001177.
117.	Smith AD. The worldwide challenge of the dementias: a function for B vitamins and homocysteine? Food Nutr Balderdash. 2008;29(Suppl 1): 143–172.
118.	Smith Advertizing, Smith SM, De Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated encephalon cloudburst in balmy cognitive impairment: a randomized controlled trial. PLoS Ane. 2010;five(ix):e12244.
119.	Beard RS, Bearden SE. Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide enquiry. Am J Physiol Heart Circ Physiol. 2011;300(ane): H13–H26.
120.	Finkelstein JD, Martin JJ. Homocysteine. Int J Biochem Cell Biol. 2000;32(iv):385–389.
121.	Kraus JP, Janošik M, Kožich V, et al. Cystathionine β-synthase mutations in homocystinuria. Hum Mutat. 1999;13(5):362–375.
122.	Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet. 1985;37(1):1.
123.	Skovby F, Gaustadnes One thousand, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency. Mol Genet Metab. 2010;99(1):1–three.
124.	d'Emmanuele di Villa Bianca R, Mitidieri E, Di Minno MN, et al. Hydrogen sulphide pathway contributes to the enhanced human platelet assemblage in hyperhomocysteinemia. Proc Natl Acad Sci U S A. 2013;110(39):15812–15817.
125.	Ingenbleek Y, McCully KS. Vegetarianism produces subclinical malnutrition, hyperhomocysteinemia and atherogenesis. Nutrition. 2012;28(ii):148–153.
126.	Muda P, Kampus P, Zilmer M, et al. Homocysteine and red blood cell glutathione as indices for middle-aged untreated essential hypertension patients. J Hypertens. 2003;21(12):2329–2333.
127.	Budoff MJ, Takasu J, Flores FR, et al. Inhibiting progression of coronary calcification using Aged Garlic Extract in patients receiving statin therapy: a preliminary study. Prev Med. 2004;39(five): 985–991.
128.	Yeh YY, Yeh SM. Homocysteine-lowering activity is another potential cardiovascular protective factor of anile garlic extract. J Nutr. 2006;136(Suppl 3):745S–749S.
129.	Al-Qattan KK, Khan I, Alnaqeeb MA, Ali M. Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible arbitration of Na/H exchanger isoform-1. Prostaglandins Leukot Essent Fatty Acids. 2003;69(4):217–222.

ortizvirstal.blogspot.com

Source: https://www.dovepress.com/potential-of-garlic-allium-sativum-in-lowering-high-blood-pressure-mec-peer-reviewed-fulltext-article-IBPC

Share this post