Trends in Food Science & Technology 39 (2014) 104e115

Review

* Corresponding author.

http://dx.doi.org/10.1016/j.tifs.2014.06.0020924-2244/� 2014 Elsevier Ltd. All rights reserved.

Therapeutic

potential of

mushrooms in

preventing and

ameliorating

hypertension

Noor Fazila Mohamed Yahayaa,

Mohammad Azizur Rahmana,b

and Noorlidah Abdullaha,*aMushroom Research Centre, Institute of Biological

Sciences, Faculty of Science, University of Malaya,

Kuala Lumpur, Malaysia (e-mails: noorlidah@um.edu.

my; noorlidah@gmail.com) (Tel.: D60 3 79674371;fax: D60 3 79674178)

bDepartment of Biochemistry and Molecular Biology,

Jahangirnagar University, Savar, Dhaka, Bangladesh

Hypertension is a multi-aetiological, chronic pathophysiology

that leads to multi-organ dysfunctions like cardiovascular dis-

eases, strokes, and renal complications. Synthetic anti-

hypertensive drugs have been blamed for side effects of

various sorts. Thus, the search for natural, safe, and food-

based anti-hypertensive agents has gained momentum. Mush-

rooms, abundant in bio-active components, had been recog-

nized for its use as therapeutics in alternative and

complementary medicine as well as functional food. In the

present article, the potential of both culinary and edible-

turned-medicinal mushrooms is reviewed with respect to their

anti-hypertensive effects along with the respective bio-compo-

nent’s mode of action.

IntroductionHypertension is a multifactorial and chronic pathophysio-logical condition characterised by elevated arterial bloodpressure (Fig. 1). Normal blood pressure is maintained atan average systolic blood pressure (SBP) of 120 mmHgand an average diastolic blood pressure (DBP) of80 mmHg. National Health and Nutrition ExaminationSurveys (NHANES) defined hypertension asSBP � 140 mmHg and/or DBP � 90 mmHg (Egan &Zhao, 2013). Hypertension is known as the ‘silent killer’as it raises the risk of cardiovascular diseases (CVDs) andstrokes while remaining asymptomatic. Hypertension hasbecome an epidemic and the World Health Organization(WHO) marked it as the third ranked cause of disability-adjusted life-years (Ezzati, Lopez, Rodgers, Hoorn, &Murray, 2002). More than 1 billion people worldwide sufferfrom hypertension and this number may rise up to 1.56billion by the year 2025 (Kearny et al., 2005). Hypertensionhas been purported to cause 13.5% of global prematuredeaths (Lawes, Hoom, & Rodgers, 2008).

Hypertension is of two types: primary or essential(90e95%) and secondary (5e10%). Although the specificcause of primary hypertension is yet to be elucidated, path-ophysiological contributors include: stress-induced hyper-activities of the sympathetic nervous system;overproduction of vasoconstrictors and mineralocorticoidsthat retain excessive sodium ions; decreased productionof vasodilators such as prostacyclin, nitric oxide (NO),and natriuretic peptides; oxidative stress-induced endothe-lial dysfunction and vascular remodelling; obesity; and dia-betes mellitus (Oparil, Zaman & Callhoun, 2003).Secondary hypertension is caused by factors other thanthose for primary hypertension such as apnoea, drug-induced, neurological, and/or endocrinological abnormality(such as aldosteronism). Secondary hypertension developsmore rapidly compared with primary hypertension. It ema-nates from identifiable, often modifiable causes and if nottreated, evokes multi-organ dysfunction such as peripheralarterial diseases, renal failure, retinal haemorrhage, and vi-sual problems (Onusko, 2003).

Factors contributing to prevalence of hypertensionworldwide

Hypertension has become a global challenge because ofits higher frequency as well as being a progenitor of CVD,stroke, and kidney diseases. The most pronounced factors

Fig. 1. Pathophysiological mechanism of hypertension and factors mediating it.

105N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

underlying this global threat include changed lifestyles,rapid urbanisation, racial differences, malnutrition, andimbalanced dietary intake, as well as in utero malformation(Mittal & Singh, 2010). Hypertension alone does not posethe threat; rather, along with hypercholesterolaemia andatherosclerosis, it makes a person vulnerable to vasculardysfunctions (Kearney et al., 2005). All these health prob-lems are correlated to each other and frequently diagnosedin most of the patients (Ariyo et al., 2000; Egan & Zhao,2013). A report produced in 2008 based on a 3-year studyindicated that approximately one-third of adults in theUnited States have hypertension (Amy, 2012). Between2003 and 2010, the overall prevalence of hypertensionamong adults aged 18 and above reached 66.9 million orequal to 30.4%. Almost half of them were uncontrolledbecause they were either unaware or aware but untreated,while others were aware and treated, but still uncontrolled.

In Nepal, the prevalence of hypertension has increasedby 30 times in the urban population and 10 times in the ru-ral population (Chataut, Adhikari, & Sinha, 2012). Among527 volunteers aged 18 and above, 22.4% were detected tohave hypertension. Factors identified to be associated withhypertension included sex, age, physical activity, weight,and habits. Among them, the most prevalent factors wereweight and habits. Almost 40.5% of the overweight Nepal-ese involved in the study had hypertension. Besides, peoplehaving smoking and drinking habits, were found to be moreprone to hypertension compared to those not having suchhabits.

In Iran, a survey called the Golestan Cohort Study, apopulation-based study of 8998 men and women aged35e81 years from both urban and rural areas, was conduct-ed (Malekzadeh et al., 2013). Hypertension-associated riskfactors including body weight, gender, and diabetes werestudied. The results showed that female gender and diabetesmellitus were the top risk factors. However, body weightdid not show a significant association with hypertension.

A community-based cross-sectional study was conduct-ed in Gondar City, Northwest Ethiopia (Awoke, Awoke,Alemu, & Megabiaw, 2012). A total of 679 participantswere included in this study. One hundred and ninety-twoparticipants (28.3%) were hypertensive, of whom morethan a third (37.0%) did not know they had hypertension.Identified risk factors included age, diabetes status, phys-ical activity, and family history of hypertension.

A study conducted in Kedah, Malaysia, which focusedon socioeconomic factors in elderly people (�60 years),showed a high number of hypertension cases (Rashid &Azizah, 2011). The study concluded that the prevalenceof increased pulse pressure contributed to systolic hyperten-sion in elderly people. A previous study conducted in KualaLumpur, Malaysia, also reported that both systolic and dia-stolic hypertension increased with age among the respon-dents, which were aged 30 and above (Amplavar,Gurpreet, Salmiah, & Odhayakumar, 2010).

Another study conducted in the United States found thatemployment status was associated with hypertension(Eaker, Sullivan, Kelly-Hayes, D’Agostino, & Benjamin,2007). People with a good job had better health access, di-etary habits, and awareness. Moreover, marriage was alsocited to be a protective factor for hypertension, since itaffected biological, neuroendocrine, and immune systems.

Studies involving affluent male subjects in north Indiareported elevated body mass index (BMI), waist-hip ratio,and impaired glucose tolerance (IGT) or diabetes to bethe crucial factors of hypertension (Yadav et al., 2008).Other CVD factors such as serum triglycerides and smok-ing also showed an increment as the population movedfrom a normotensive to a hypertensive state. In addition,heredity, obesity, high intake of sodium/potassium salts,reduced consumption of fruit and vegetables, and a seden-tary lifestyle have been identified as the most prominentcausative factors of hypertension in a Chinese population(Zeng et al., 2011).

106 N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

Strategies for controlling hypertensionEvolution of concepts involving hypertension dates back

to mid-19th century when the measurement of blood pres-sure had been correlated with various diseases (Bakris &Frohlich, 1989; Kotchen, 2011). Thenceforth, numerousstrands of strategies for its remedy have been elucidatedand updated. Life style changes including appropriate die-tary intake stand as the first line of defence against hyper-tension. However, drug treatment becomes inevitable inaddition to or in parallel with life style modifications in se-vere cases (Appel, 2003). Initiated from the extraction andvalidation of alkaloids from the plant Rauwolfia serpentina,the last half a century has witnessed the research and devel-opment of chemically synthesized anti-hypertensive agents(Bakris & Frohlich, 1989; Kotchen, 2011). The evolu-tionary trends in developing antihypertensive agents havebeen depicted in Fig. 2.

The seventh report of the Joint National Committee(JNC) on Prevention, Detection, Evaluation and Treatmentof High Blood Pressure (Chobanian et al., 2003) recom-mended the use of diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptorblockers (ARBs), and/or calcium channel blockers(CCBs) for the treatment of hypertension in patients whoare at increased risk for coronary complications or stroke(White, 2005).

Diuretics are used to remove excessive water and saltfrom the body through urine with a view to reducing bloodpressure (Fuchs, 2001). Beta-blockers bind to the beta re-ceptors in heart muscle and reduce the tissue stress

Fig. 2. Historical breakthroughs in anti-hypertensive agents research.

stimulated by the hormone adrenaline (Bangalore,Sawhney & Messerli, 2008). ACE inhibitors act by inhibit-ing the ACE that reduces the activity of the renin-angiotensin-aldosterone system (RAAS). This system isactivated when there is a fall in blood pressure (Van derHorst, Voors, & Van Veldhuisen, 2007). The ARBs alsointerrupt the RAAS and cause vasodilation. However,ARB is prescribed for patients who are intolerant to ACEinhibitors (Nishida, Takahashi, Nakayama, & Asai, 2012).CCBs work by blocking voltage-gated calcium channels(VGCCs) in cardiac muscle and blood vessels. Since cal-cium is crucial for muscle contraction, the blocking byCCBs relaxes and dilates the artery muscle. In addition,some patients may need combination therapy of these drugsfor better healing. The target organ and mode of action ofthese anti-hypertensive drugs currently prescribed world-wide, has been depicted in Fig. 3.

However, anti-hypertensive drugs have been reported ashaving various adverse effects. Diuretics cause frequent uri-nation, arrhythmia, muscle cramps, nausea, and vomiting.Beta-blockers can worsen asthma and diabetes and causestomach cramps, blurred vision, confusion, dizziness,depression, and nightmares (Ko et al., 2004). ACE inhibi-tors such as captopril and enalapril cause dry cough, skinrashes, hyperkalaemia, renal failure, foetal anomalies, an-gioedema and allergic reactions (Brown & Douglas,1998). The side effects of ARBs and CCBs also coincidewith each other (Alomar, 2014). In addition, adverse drugreactions (ADRs) are always encountered with multiplediseases and the use of many drugs. If hypertension isaccompanied by other diseases, these diseases may havean impact on the response of the body to anti-hypertensive drugs and the metabolic processes of thebody may be affected negatively. Later on, increased dos-ages may be required, which in turn would only worsenthe ADRs.

Mushrooms as medicinal-functional food againsthypertension

The conflict between the merits and demerits of syn-thetic anti-hypertensive drugs demands the search forsafe, efficacious, and novel therapeutic agents of a naturalsource. The term ‘functional food’ has been coined inthis context and is defined as “a natural or processed foodthat contains known biologically-active compounds whichwhen in defined quantitative and qualitative amounts pro-vides a clinically proven and documented health benefit,and thus, an important source in the prevention, manage-ment and treatment of chronic diseases of the modernage” (Martirosyan, 2011). Mushrooms (macrofungi),mostly members of the Basidiomycetes class of macro-fungi, fulfil the requirement of functional foods. The termi-nology can be extended to ‘medicinal-functional foods’and/or expressed as ‘functional-medicinal foods’, due tothe fact that some culinary/edible mushrooms possessimmense medicinal values while several medicinally

Fig. 3. Mechanism of action of the anti-hypertensive drugs at different organs of the human body.

107N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

important species are of high culinary demand (Abdulla,Noor, Wong, & Ali, 2008; Abdullah, Ismail, Aminudin,Shuib, & Lau, 2012; Paterson, 2006).

A plethora of bioactive compounds present in mush-rooms confer antioxidant, antitumor/anticancer, antimicro-bial, immunomodulatory, antiatherogenic, andhypoglycemic properties (Wasser, 2002, 2011). The hypo-cholesterolaemic effect of mushrooms has been attributedto their inhibitory effect on cholesterol biosynthesis and ab-sorption and stimulatory effect on faecal excretion(Guillam�on et al., 2010). The dietary fibres present inmushrooms further reinforce their suitability as hypolipi-daemic agents (Fukushima et al., 2000; Hsing-Hsien,Wen-Chi & Mei-Ling, 2002). They have also been highlyregarded for possessing natural free radical scavengers ofvarious sorts including polysaccharides (e.g., b-D-glucan),polyphenols (e.g., phenolic acids and flavonoids), vitamins(e.g., tocopherol, ascorbic acid, and niacin), ergosterol, andcarotenoids (Guillam�on et al., 2010). From as early as 100B.C., culinary-medicinal usage of mushrooms has rangedfrom simple and common diseases to presenteday complexand pandemics like AIDS (Paterson, 2006).

Mushrooms, as alternative and complementary medici-nal foods, stand out as being excellent for treating hyper-tension. Hong et al. (2008) demonstrated that ACEinhibitory peptides present in mushrooms lowered bloodpressure with no adverse effect. This finding was supportedby further research upon both culinary and medicinal mush-rooms of different categories (Abdullah et al., 2012). Jao,Huang, and Hsu (2012) elucidated the mode of action ofthese hypertension-ameliorating bioactive peptides alongwith their bioavailability. Numerous studies and findingson the anti-hypertensive properties of both edible and me-dicinal mushrooms have attracted scientists all over theworld to further their studies on these ‘gifts from God’.

Among the highly studied species are Tricholoma gigan-teum (giant mushroom), Marasmius androsaceus (horsehairparachute mushroom), Grifola frondosa (maitake mush-room), Pleurotus species (oyster mushroom), Lentinula ed-odes (shiitake mushroom), Ganoderma lucidum (reishi orlingzhi mushroom), Sparassis crispa (cauliflower mush-room), Pholiota adiposa (black tiger’s paw mushroom)and Sarcodon aspratus (yellow cap mushroom), Hypsizygusmarmoreus (shimeji/buna shimeji mushroom), Flammulinavelutipes (enoki mushroom), Hericium erinaceus (lion’smane mushroom), and Agaricus bisporus (buttonmushroom).

T. giganteum (giant mushroom)T. giganteum is found mainly in Japan, Korea, and trop-

ical areas of Asia and Africa. Hyoung Lee, Ho Kim, SikPark, Jun Choi, and Soo Lee (2004) reported the ACEinhibitory effect of 61.03% at 1 mg concentration of thehot water extract of T. giganteum with IC50 value of0.74 mg. They then extracted a novel ACE inhibitor(ACEI) peptide from T. giganteum, purified it, and testedits efficacy on spontaneously hypertensive rats (SHRs).The peptide competitively inhibited ACE and showed apotent anti-hypertensive effect in the SHRs at the dosageof 1 mg/kg body weight. The blood pressure reduction po-tential was similar to that of captopril, one of the most com-mon anti-hypertensive drugs (Fig. 4).

The ACEI peptide derived from T. giganteum is a uniquetripeptide consisting of the amino acids proline (40%), glu-tamic acid (30%), and glycine (30%), and the sequence wasdeduced as Gly-Glu-Pro (Hyoung Lee et al., 2004). Itshows very low sequence homology with other ACEIsand its molecular weight is small enough (301 Da) for ab-sorption through the intestine. It demonstrated an anti-hypertensive effect without any adverse side effects. The

Fig. 4. Effect of orally administrated ACE inhibitor extracted from Tri-choloma giganteum on blood pressure in SHRs (Lee & Rhee, 1990).

108 N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

ACE inhibitory pattern was similar to that of other anti-hypertensive agents derived from mushrooms such as G.fondosa and non-mushroom origins such as fibrinogen pen-tapeptides, milk protein casein fragment, tuna muscle octa-peptide, and porcine plasma tripeptides (Ariyosh, 1993).The purified ACEI peptide from T. giganteum maintainedits inhibitory activity even after incubation with proteases(Hyoung Lee et al., 2004).

M. androsaceus (horsehair parachute mushroom)M. androsaceus is a traditional Chinese edible-

medicinal mushroom. Zhang et al. (2009) extracted thebio-active component 3,3,5,5-tetramethyl-4-piperidone(TMP) from M. androsaceus and demonstrated its consis-tent anti-hypertensive effect. The SBP of spontaneously hy-pertensive rats (SHR) was significantly lowered in 30 minafter TMP administration and lasted for 4 h at the dosagesof 2.5, 5 and 10 mg/kg (p.o) body weight (Zhang et al.,2009).

The chemical structure of TMP closely resembles that ofmecamylamine, the first available oral anti-hypertensiveagent (Table 1). At low dosage (2.5e10 mg, p.o.), meca-mylamine can cross the blood brain barrier and TMP’smode of action was supposed to mimic that of the meca-mylamine (Zhang et al., 2009).

In addition, the anti-hypertensive effect of M. androsa-ceus is supposed to be achieved through the partial gangli-onic blocking action of TMP, since nictitating membranecontraction was prominently attenuated in 5 min and wastotally blocked after TMP administration to the

experimental animals (Zhang et al., 2009). Typically, gan-glion blockers dilate blood vessels, resulting in reducedblood pressure.

To further substantiate the claim, this group put forwardevidence that TMP at the same dosage reduced blood pres-sure of 2K1C rats in a 2-week study. TMP at 30 mg/kg(intravenously [i.v.]) counteracted preganglionicstimulation-induced nictating membrane responses (Zhanget al., 2009). Haemodynamic studies in dogs confirmedthe results and further proved that TMP-mediated bloodpressure reduction was independent of any adverse effect.Even the sympathetic-vagal balance was uninterrupted afterTMP administration, as revealed by heart rate variabilitystudies.

G. frondosa (maitake mushroom)The anti-hypertensive effect of G. frondosa was first

demonstrated by Kabir & Kimura, 1989. They fed a dietcontaining 5% G. frondosa powder (w/w) to SHRs andcompared their blood pressure pattern with that of normo-tensive rats. Nine weeks of observation revealed signifi-cantly lowered blood pressure. Later on, Talpur et al.(2002) reported similar findings while comparing the effectof whole maitake mushroom to that of its two sol-ventesolvent partitioned fractions (ether and water). Theyconducted experiments on two rat strains: Zucker fattyrats (ZFRs) and SHRs. After 35 days, they observed thatSBP was significantly decreased (mean SBP 176 vs.197 mmHg, p < 0.001) in the SHRs that ingested the etherfraction compared with control SHRs. However, in ZFRs,both the whole maitake powder and water fraction couldreduce SBP (120 vs. 138 mm Hg, respectively,p < 0.001) (Talpur et al. 2002). In the meantime, a peptidewith ACE inhibitory activity was isolated from the hot wa-ter extract of G. frondosa and its amino acid sequence wasdeciphered to be Val-Ile-Glu-Lys-Tyr-Pro (Choi, Cho,Yang, Ra, & Suh, 2001). The ACEI peptide is supposedto interrupt the RAAS by competitive interaction at theactive site of the ACE (Choi et al., 2001; Talpur et al.2002).

Recently, Preuss, Echard, Bagchi, and Perricone (2010)evaluated the protective role of G. frondosa active fractions,SX and D, in age-onset hypertensive SpragueeDawley rats.Data obtained after 4 months of intensive experimentsenabled them to opine that G. frondosa fractions reducedage-mediated hypertension via the RAAS, along withenhanced insulin sensitivity and reduced inflammatory as-pects that ultimately led to a normal blood pressure andlonger life span.

Pleurotus species (oyster mushrooms)Oyster mushrooms (Pleurotus species) are important

both in tropical and temperate countries in respect of theirculinary status. The mostly noted species having anti-hypertensive effects include Pholiota ostreatus, Pleurotuscornucopiae, Pholiota nebrodensis, and Pholiota

Table 1. Anti-hypertensive mushroom bio-components and their mode of actions.

Anti-hypertensive agent Structure Mode of action Source Reference

Tripeptide Gly-Glu-Pro Competitive inhibition of ACE Tricholoma giganteum Hyoung Lee et al., 20043,3,5,5-tetramethyl-4-piperidone (TMP)

N

H3C

H3C

CH3

CH3

O

(A)

CH3

3

H3C

NHCHH3C

(B)

NH CH3

CH3

CH3

CH3

(C) Mecamylamine

Partial ganglionic blocking-mediated vasodilation

Marasmius androsaceus Zhang et al., 2009

Hexapeptide Val-Ile-Glu-Lys-Tyr-Pro Inhibition of ACE Grifola frondosa Choi et al., 2001D-mannitol

OHO

OHOH

HO Competitive inhibition of ACE Pleurotus cornucopiae Hagiwara et al., 2005

Oligo peptides Arg-Leu-Pro-Ser-Glu-Phe-Asp-Leu-Ser-Ala-Phe-Leu-Arg-Ala Competitive inhibition of ACE Pleurotus cornucopiae Jang et al., 2011Oligo peptides Arg-Leu-Ser-Gly-Gln-Thr-Ile-Glu-Val-Thr-Ser-Glu-Tyr-

Leu-Phe-Arg-HisCompetitive inhibition of ACE Pleurotus cornucopiae Jang et al., 2011

Potassium K+ Hyperpolarization of Na+-K+

pump and/or Kir channelsLentinula edodes Haddy, 2006; Julita, 2007

Lentinan

OO

HO

HO O

OH

OHO

HO

HO O

OH

O

HO

HO

HO

OH

O

HO O

OHO

O

HO O

OH

HO

O

HO O

OH

O

HO

OH

HO

Vasodilation Lentinula edodes Bisen et al., 2010

(continued on next page)

109

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Table 1 (continued )

Anti-hypertensive agent Structure Mode of action Source Reference

Chitin

O

O

NH

CH2OH O

NH

CH2OH

CH3

CH3O

O

n

Yet to be discovered Lentinula edodes Je et al., 2006; Vetter, 2007

Ganoderics CH2OH1

Ganoderol AO

CH2OH

HO

2

Ganoderol B

CHO3

Ganoderal AO

COOH

HO

4

Ganoderic acid Y

Inhibition of ACE Ganoderma lucidum Morigiwa et al., 1986

110

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Unkn

ownco

mponen

tStructure

unkn

own

increa

sedNO

productionthrough

Akt/N

OSsign

aling

Sparassiscrispa

Yoshitomiet

al.,2011

Pentapep

tide

Gly-G

lu-G

ly-G

ly-Pro

Pholiota

adiposa

(Koo,2006)

L-pipecolicac

id

H N

O

OH

Stereo

selectivean

dco

mpetitive

inhibitionofACE

Sarcodonaspratus

(Kiyoto,2008)

Oligo

pep

tide

Ala-H

is-G

lu-Pro-Val-Lys

CompetitiveinhibitionofACE

Agaricu

sbisporus

Lauet

al.,2014

Oligo

pep

tide

Arg-Ile-G

ly-Leu

-Phe

CompetitiveinhibitionofACE

Agaricu

sbisporus

Lauet

al.,2014

Oligo

pep

tide

Pro-Ser-Ser-Asp-Lys

Non-competitiveinhibitionofACE

Agaricu

sbisporus

Lauet

al.,2014

111N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

cystidiosus (Hagiwara et al., 2005; Jang et al., 2011). Theirameliorating effect on elevated blood pressure has beenattributed to their inhibitory effect on ACE. Hagiwaraet al. (2005) reported D-mannitol, a sugar alcohol, as theACE inhibitory bioactive component of the tamogi-takemushroom, Pholiota cornucopia. They compared the ACEinhibitory effect of hot water extract of tamogi-take mush-roosm (WETM), D-mannitol derived from the hot waterextract of tamogi-take mushroom, and pure D-mannitol(authentic D-mannitol) in SHR/Hos male rats. AuthenticD-mannitol decreased SBP from 178 to 157 mmHg after4 h of administration. WETM also significantly decreasedSBP from 180 to 165 mm Hg after 4 h. At the concentrationof 3 mg/ml, the ACE inhibitory effects of both authentic D-mannitol and D-mannitol derived from tamogi-take mush-room were almost the same. The authors further comparedthe ACE inhibitory activities of monosaccharides (D-glucose, D-galactose, and D-mannose), monosaccharide-based sugar alcohols (D-mannitol, D-sorbitol, and D-dulci-tol), and disaccharides (D-maltose and a-lactose). The re-sults showed that the sugar alcohol D-mannitol was thebest ACE inhibitor, followed by the monosaccharides con-taining D-glucose, D-galactose, and D-mannose, whereas thedisaccharides had the lowest ACE inhibitory potency.

Jang et al. (2011) isolated and purified two ACEI pep-tides from the fruiting bodies of P. cornucopiae and re-ported their anti-hypertensive effects in SHR at a dosageof 600 mg/kg body weight. The molecular mass of thesetwo oligo peptides were 1.62 and 2.03 kDa, respectively,with the respective amino acid sequence of Arg-Leu-Pro-Serine-Glu-Phe-Asp-Leu-Ser-Ala-Phe-Leu-Arg-Ala andArg-Leu-Ser-Gly-Gln-Thr-Ile-Glu-Val-Thr-Ser-Glu-Tyr-Leu-Phe-Arg-His. Their mode of inhibition was non-competitive, unlike the ACEIs of T. giganteum and G. fron-dosa. Besides, simultaneous treatment of gastric and intes-tinal fluids with the ACEI peptide increased its ACEinhibitory potential, indicating its easy absorption underphysiological conditions.

Research findings of comparative ACE inhibitorystudies of culinary-medicinal mushrooms have receivedappreciable attention. Based on the IC50 values (mg/ml)of in vitro ACE inhibitory activities, Abdullah et al.(2012) reported the following order of potency as ACE in-hibitors for Pleurotus species: Pholiota eryngii (IC50

0.067 mg/ml) > Pholiota flabellatus (IC50 0.058 mg/ml) > Pholiota sajor-caju (IC50 0.056 mg/ml) > P. cysti-diosus (IC50 0.054 mg/ml) > Pholiota florida (IC50

0.050 mg/ml). The probability of the presence of a similartype of bioactive components with a similar structure andmode of action was suggested as the basis of the very closeproximate IC50 values, which are indicative of the respec-tive ACE inhibitory effects (Abdullah et al., 2012). Howev-er, experimental conditions such as the separationtechnique, solvents used and time and temperature appliedmight have had a considerable effect on the ACE inhibitionpattern of the mushrooms.

112 N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

L. edodes (shiitake mushroom)L. edodes is the second most popular edible-medicinal

mushroom worldwide (Bisen, Baghel, Sanodiya, Thakur,& Prasad, 2010). Blood pressure reduction studiesinvolving L. edodes date back to as early as 1989 when Ka-bir and Kimura, through comparative studies of anti-hypertensive and plasma lipid-lowering effects of shiitakeand maitake mushrooms upon SHR, reported the amelio-rating effects of both the mushrooms (Fig. 5). However,the anti-hypertensive agent and mechanism of blood pres-sure reduction were not investigated in that study.

The pathogenesis of hypertension includes an intricaterelationship among physiological levels of sodium and po-tassium ions and aldosterone (B€ussemaker, Hillebrand,Hausberg, Pavenst€adt, & Oberleithne, 2010). Increasedplasma sodium levels worsen, while higher potassiumlevels ameliorate the hypertensive state. Excessive sodiumions impair the endothelial vasculature by reducing produc-tion of the vasodilator NO. Thus, to overcome hyperten-sion, it is important to maintain plasma sodium ions andaldosterone at lower levels and potassium ions at higherlevels (B€ussemaker, et al., 2010).

The potassium content of L. edodes had been found to beas high as 31.55 mg/kg dry weight (Manzi, Gambelli,Marconi, Vivanti, & Pizzoferrato, 1999). Increased potas-sium ions hyperpolarise vascular smooth muscle cellsthrough the voltage-gated Naþ-Kþ pump and/or Kir chan-nel that causes vasodilation (Haddy, Vanhoutte, &Feletou, 2006). Thus, L. edodes aids in maintaining lowblood pressure. Besides, lentinan, a polysaccharide ob-tained from L. edodes, has been reported as having multi-factorial effects including vasodilation (Bisen et al., 2010;Chihara, 1992). In addition, Lau, Abdullah, Shuib, andAminudin (2012) reported L. edodes to be the second

Fig. 5. Systolic blood pressure changes in SHRs fed mushroom in thediet. Each point represents the mean � SE for five rats (SD from control

*p < 0.05, **p < 0.01) (Kabir & Kimura, 1989).

best ACE inhibitory agent among nine edible mushroomspecies. The hot water extract of L. edodes showed 90.1%ACE inhibition in vitro, second only to F. velutipes(95.6% ACE inhibition) at 10 mg/ml concentration.

Moreover, the chitin content of L. edodes has been foundto be as much as 8.07% of the dried mass (Vetter, 2007).Manzi, Marconi, Aguzzi, and Pizzoferrato (2004) foundthat the levels of chitin and its derivatives increased duringcooking. Chitin derivatives act as potent anti-hypertensiveagents (Je, Park, Kim, & Kim, 2006). Chitin derivativeswith 50% deacetylation at C-6 showed a dose-dependentSBP-lowering effect through inhibiting ACE (Ki 0.02 mM,IC50 0.038 mM) (Je et al., 2006). At the cellular level, theanti-hypertensive effects of L. edodes might be medicatedby one or more of the mechanisms stated so far.

G. lucidum (reishi or lingzhi mushroom)G. lucidum has been ascribed as the ‘magic mushroom’

for healing numerous physiological and psychologicalcomplications (Paterson, 2006; Wasser, 2002, 2011).Among the myriad of bioactive components present in G.lucidum, the triterpenoids and the polysaccharides havebeen reported to be medicinally most potent (Boh,Berovic, Zhang, & Zhi-Bin, 2007). Morigiwa, Kitabatake,Fujimoto & Ikekawa (1986) observed the ACE inhibitoryeffect of the methanolic extract of G. lucidum and identifiedfive novel triterpenes in the extract: ganoderal A; ganoder-ols A and B; and ganoderic acids K and S (Table 1).

Time-course required for lowering blood pressure mayvary from mushroom species to species. Kabir, Kimura &Tamura (1988), through a 4-week study upon the SHR,described the SBP lowering effect of G. lucidum (Fig. 6).Feeding of G. lucidum for the first two weeks had no

Fig. 6. Changes in systolic blood pressure (SBP) of spontaneously hy-pertensive rats fed Ganoderma lucidum in the diet in a 4-week studyperiod. During the first 2 weeks, SBP remained almost the same asthat of control. However, after 2 weeks of G. lucidum intake, SBPwas significantly lower in the SHRs compared with control. This rep-resents the time course of action and accumulation of G. lucidumbioactive components. Each point represents the mean � SE for sevenrats, “*p” means significantly different from control (Kabir, Kimura and

Tamura, 1988).

113N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

ameliorating effect; however, continued feeding for moretwo weeks significantly lowered SBP of the treated ani-mals. This plummeting pattern sustained for the rest ofthe study period. This might also be due to the loweramount of bio-active components accumulation during thefirst two weeks that afterwards increased in amount capableenough to combat the raised blood pressure (Kabir, Kimuraand Tamura, 1988).

Abdullah et al. (2012) reported the best ACE inhibitoryeffect of the hot water extracts of G. lucidum compared toother culinary-medicinal mushrooms. Multitudes ofphenolic substances present in G. lucidum were supposedto contribute to this inhibitory action. The anti-ACE activi-tiy of the hot water extract of G. lucidum became moreenhanced (57.01% inhibition at 2 mg/ml concentration),when grown on the germinated brown rice (Hasnat,Pervin, & Lim, 2013).

However, Lee and Rhee (1990) proposed an alternativemechanism of G. lucidum hot water extract mediated-hypotension. According to them, G. lucidum extract in-hibited the sympathetic nerve actions in the CNS whose sec-ondary effect was hypotension without any altered heart rate.

S. crispa (cauliflower mushroom)Hypertension is one of the prominent causative factors

of stroke. Thus, mushrooms capable of maintainingnormo-tensive state along with preventing stroke, are ofhigh medicinal-functional values. S. crispa has been foundto serve the dual benefit. Stroke-prone spontaneously hy-pertensive rats (SHRsSP) orally administered with diet con-taining 1.5% S. crispa powder, showed significantinhibition of the rise in blood pressure along with stroke-amelioration (Yoshitomi, Iwaoka, Kubo, Shibata, & Gao,2011). The underlying mechanism of reduced blood pres-sure involved the improvement of endothelial dysfunctionvia increment in NO production through activation of theAkt/NOS signalling pathway in the cerebral cortex(Yoshitomi et al., 2011).

P. adiposa (yellow cap mushroom)Koo et al. (2006) described the ACE inhibitory effect of

the hot water extract of P. adiposa, followed by the extrac-tion and characterization of the inhibitor. The purified ACEinhibitory peptide was a novel penta-peptide with molecu-lar weight of 414 Da (Koo et al., 2006). Its sequence wasrevealed as Gly-Glu-Gly-Gly-Pro and had very little simi-larity to other ACE inhibitory peptides (Koo et al., 2006).

S. aspratus (black Tiger’s paw mushroom)The aqueous extract of the edible mushroom S. aspratus

had been found to possess ACE inhibitory effect. L-pipe-colic acid (1-piperidine-2-carboxylic acid) was identifiedto be the main bioactive component of this function(Kiyoto et al., 2008). It inhibited in a stereoselectivefashion through competitive mode of inhibition whereasthe D-isomer was inactive (Kiyoto et al., 2008).

H. marmoreus (shimeji/buna shimeji/brown beechmushroom)

Kang et al. (2013) reported the anti-ACE effect of thehot water extract of H. marmoreus, followed by the identi-fication of the responsible oligopeptide. Its sequencededuced was Leu-Val-Asn-Asp-Leu-Val-Thr-Pro-Val-Phe-Asp with the molecular weight of 567.3 Da. Administeredto the SHR at 800 mg/kg body weight; this ACE inhibitor’spotency was similar to that of the synthetic antihyperten-sive drugh, captopril (Kang et al., 2013).

A. bisporus, F. velutipes and H. erinaceusComparative ACE inhibitory pattern of mushrooms de-

termines their respective antihypertensive potential. Insuch a study, Lau et al. (2012) determined the relative anti-hypertensive strength of three most common edible mush-rooms based on percentage ACE inhibition at 1 mg/mlconcentration and their gradation was as follows:

F. velutipes (95.65%) > H. erinaceus (90.1%) > A. bis-porus (87.2%)

In a separate study, Lau, Abdullah, Shuib, and Aminudin(2014) identified three separate bio-active peptides from A.bisporus having the amino acid sequences Ala-His-Glu-Pro-Val-Lys, Arg-Ile-Gly-Leu-Phe and Pro-Ser-Ser-Asp-Lys. The ACE inhibitory mode of the first two peptideswas competitive while that of the last one was non-competitive.

ConclusionAdverse side effects of synthetic anti-hypertensive drugs

warrant quick removal from the market giving space to thenatural, safe and alternative therapeutic approaches. Nutri-tional analysis has revealed mushrooms to be rich in high-quality protein, polysaccharides, vitamins and minerals(potassium, calcium, and magnesium), fibre and otherbioactive compounds but low in sodium and fat. Such adiet supports the recommendations of the Joint NationalCommittee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (Chobanian et al., 2003).

Apart from consumption of culinary mushrooms as veg-etables, the approach in using mushrooms to alleviate hy-pertension necessitates the use of composite formulaeobtained by a specific method of extraction. Hot waterextract of various mushrooms studied so far was deemedmost potent identifying several peptides, D-mannitol, D-glucose, D-galactose, D-mannose, triterpenes and potassiumas the active constituents. Thus, this composite formulaecomprising of several different components together couldact in concert to prevent and ameliorate hypertension basedon various mechanisms, predominantly via inhibiting theRAAS by interaction at the active site of the ACE enzyme.

The effectiveness of various mushroom species extractsand active compounds has been confirmed by numerouslaboratory experiments and animal trials. However, clinicaltrials are desirable not only for single compounds but alsofor extracts. The consistency of the “extracts” both in terms

114 N.F. Mohamed Yahaya et al. / Trends in Food Science & Technology 39 (2014) 104e115

of the overall chemical composition and in the actual levelsof active components between different batches and in eachmushroom species used could be standardized on the basisof one or two of the active component(s). This will spurhigh for better development of dietary supplement or nutra-ceuticals from mushrooms as remedy of hypertension.

AcknowledgementsThe authors gratefully thank University of Malaya and

the Ministry of Education, Malaysia for the High ImpactResearch MoE Grant UM.C/625/1/HIR/MoE/SC/02 andMohammad Azizur Rahman is grateful for the fellowshipsupported by the Bright Sparks Unit, University of Malaya.

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