Ntu 2: 3-Hydroxyphenylacetic Acid: Ntshav Siab Txo Flavonoid Metabolite

Yog xav paub ntxiv, thov hu rau:tina.xiang@wecistanche.com

Nyem qhov link hauv qab no kom tau txais part 1:https://www.xjcistanche.com/news/part1-3-hydroxyphenylacetic-acid-a-blood-pre-54725426.html

4. Kev sib tham

Kev tshuaj ntsuam ntawm txawv phenolic metabolites ntawmflavonoidsqhia tau tias 4 ntawm 22 yog cov muaj zog vasodilators. Ua raws li los ntawm cov txiaj ntsig no, lubmob plawvCov teebmeem ntawm 3-(3-hydroxyphenyl)propionic acid, 34-dihydroxyphenylacetic acid (DHPA), thiab 4-methyl catechol tau lees paub hauv vivo, thiab cov txheej txheem ua tau ntawm lawv cov kev ua tau raug kawm ex vivo [14,15]. Lwm cov flavonoid metabolite, 3-HPAA, tau raug tshem tawm ib ntus los ntawm kev tshawb nrhiav ntxiv vim nws tsis tuaj yeem ua kom muaj kev so tag nrho hauv kev tshuaj ntsuam thawj zaug ntawm nas aorta. Hauv txoj haujlwm no, peb txiav txim siab txuas ntxiv peb cov kev tshawb fawb yav dhau los thiab tsom mus rau 3-HPAA ib yam. Peb tsom mus rau (1) paub meej tias nws cov nyhuv vasodilatory ob qho tib si hauv vivo hauv spontaneously hypertensive nas thiab ex vivo nyob rau hauv lwm yam kev sim qauv (porcine coronary arterial rings), thiab (2) kawm lub mechanism ntawm qhov kev txiav txim.

Nyem kom paub ntau ntxiv cov ntaub ntawv khoom.

Qhov cuam tshuam ntawm 3-HPAA ntawm Ntshav Siab thiab Lub Plawv Lub Plawv Hauv Vivo hauv SHR

Thaum 3-HPAA yog qhov muaj zog vasodilator tsawg dua nyob rau hauv kev tshuaj ntsuam ex vivo yav dhau los [14], hauv txoj haujlwm no, nws tau lees paub meej tias muaj peev xwm txo qisntshav siabnyob rau hauv vivo nyob rau hauv spontaneously hypertensive nas tom qab intravenous tswj. Thaum siv raws li bolus, qhov nruab nrab, systolic thiab diastolic ntshav siab poob qis. Tsis tau xav txog heev, qhov cuam tshuam tseem ceeb ntawm cov ntshav siab diastolic twb tau pom tom qab qhov koob tshuaj tsawg heev ntawm 10 ugs.kg-1.Cov lus teb no kuj siab heev (kwv yees li 20 feem pua). Nrog nce koob tshuaj ntawm 3-HPAA, cov nyhuv tau nce me ntsis mus rau kwv yees li 25 feem pua. Ib yam no muaj tseeb nyob rau hauv cov ntaub ntawv ntawm systolic ntshav siab thaum ib tug tseem ceeb txo (kwv yees li 15 feem pua) yog tam sim no tom qab koob tshuaj ntawm 100ug.kg-I, thiab qhov siab tshaj plaws txo qhov pom yog kwv yees li 25 feem pua. Muaj qhov sib txawv ntawm cov tsiaj uas ua rau muaj qhov sib txawv; Txawm li cas los xij, qhov koob tshuaj-dependency ntawm cov nyhuv yog pom tseeb. Hauv qhov sib piv, tsis muaj kev hloov pauv hauv lub plawv dhia tau pom tom qab siv cov tshuaj bolus. Qhov no tuaj yeem txhais tau tias lub plawv tsis cuam tshuam nrog cov ntshav siab-txo cov nyhuv thiab cov nyhuv tsuas yog ua raws li peripheral so. Tsis muaj kev hloov pauv hauv lub plawv yog qhov tseem ceeb los ntawm qhov kev nyab xeeb ntawm qhov pom txij li cov lus tawm tswv yim nce hauv lub plawv dhia los ntawm lub paj hlwb, uas ua raws li kev txo qis hauv cov ntshav siab, yog qhov tsis zoo, raws li tau tshaj tawm nrog cov calcium. channel blocker nifedipine [24].

Hauv qhov xwm txheej tiag tiag, cov kab mob metabolites ntawm kev noj cov flavonoids txuas ntxiv nqus los ntawm GIT. Txhawm rau ua raws li qhov no, kev tso dej qeeb qeeb ntawm 3-HPAA ntawm tus nqi sib txawv tau muab rau hauv lwm qhov kev sim. Analogously rau daim ntawv thov bolus yav dhau los, qhov txo qis hauv qhov ntsuas, systolic, thiab diastolic ntshav siab tau pom. Cov nyhuv yog nyob ntawm koob tshuaj, thiab cov txiaj ntsig tseem ceeb tau tshwm sim los ntawm koob tshuaj ntawm 1 thiab 5mg.kg-1· min-Ireaching qhov siab tshaj plaws kwv yees li 50 feem pua ​​​​ntawm cov ntshav siab. Ib zaug ntxiv, tsis muaj kev hloov pauv tseem ceeb hauv lub plawv dhia tau pom thaum lub sij hawm 5 min-ntev-infusion, lossis hauv 10 feeb tom ntej ntawm kev saib xyuas tsiaj.

Cov nyhuv no ntawm cov ntshav siab tuaj yeem muaj kev cuam tshuam tiag tiag. Flavonoids los ntawm kev noj haus yog qhov tsis zoo absorbed hauv cov hnyuv. Lawv ncav cuag txoj hnyuv thiab ua rau cov metabolism hauv microbial. Cov txheej txheem degradation ntawm cov kab mob muaj qhov txo qis ntawm ob daim ntawv cog lus hauv 2, 3- txoj hauj lwm ua raws li C-ring fission. Cov kauj ruam tom ntej yog nyob ntawm qhov muaj lossis tsis muaj ntawm 3- pawg hydroxyl. Flavones uas tsis muaj hydroxyl no muab keeb kwm rau hydroxyphenylpropionic acid derivatives, thaum flavonols nrog cov 3-hydroxyl muab keeb kwm rau derivatives ntawm hydroxyphenyl acetic acids [25]. Txawm li cas los xij, 3-HPAA tshwm sim raws li lub nplhaib-fission khoom tau los ntawm microbial catabolism ntawm ntau niam txiv flavonoids, tsis tsuas yog flavonols xws liquercetin. Ntxiv mus, ib qho tseem ceeb metabolite nrog vasodilatory kev ua ub no, DHPA, muab keeb kwm rau 3-HPAA tom qab nws dehydroxylation thiab rau ib tug me me rau lwm vasorelaxant compound, 3, 4-dihydroxybenzoic acid / protocatechuic acid.{{3} }HPAA ntxiv catabolized rau hauv vaso-inactive hippuric thiab benzoic acids (Daim duab 1)[15,26]. Feem ntau, me me flavonoid metabolites qhia plasma ntau dua li lawv niam txiv flavonoids thiab tuaj yeem ncav cuag qhov siab tshaj plaws feem ntau nyob rau hauv thaj tsam ntawm 1 txog 615 nM lossis txawm 42.9 uM hauv qee kis [17]. Ib yam zoo li yuav muaj tseeb rau 3-HPAA. Hauv kev tshawb fawb tsiaj, kev tswj hwm ntawm Calafate berries extract (muab ~ 2.6 mg ntawm phenolics) los ntawm gavage rau gerbils ua rau cov ntshav siab tshaj plaws ntawm 3-HPAA ntawm kwv yees. 300nM tom qab 4h[27]. Lwm tus kws sau ntawv tau tshaj tawm tias ib zaug 3-HPAA cov tshuaj bolus ntawm 2 thiab 4 mg. kg-Ito nas ua rau cov plasma siab tshaj plaws ntawm approx.6mg.L-1(~ 40 uM thiab 16 mg.L-1 (~ 100 μM) 【28】.Nyob rau hauv peb txoj kev tshawb fawb, cov koob tshuaj ntau tshaj Kev siv tshuaj intravenously raws li ib qho bolus yog 10 mg.kg-1. Yog li, peb tuaj yeem kwv yees [28] tias qhov siab tshaj plaws plasma ua tiav tuaj yeem yog nyob nruab nrab ntawm 100 thiab 200 μM, uas yog 11-22 zaug siab dua li lub cev. kuaj pom [17]. Qhov tseem ceeb, cov txiaj ntsig tseem ceeb ntawm cov ntshav siab diastolic tau pom nyob rau ntawm qhov koob tshuaj ntawm 10 ug.kg-1, uas tuaj yeem sib npaug rau qhov ua tau tiav ntawm 100-200 nM. Analogous muaj tseeb Rau kev tswj hwm ntawm infusion, koob tshuaj ntawm 1 mg·kg-I.min- tuaj yeem ua rau cov ntshav plasma ntawm kwv yees li 10 μM 【28】, uas yog nyob rau hauv qhov ntau ntawm tag nrho cov qib uas tsim los ntawm kev noj haus [17]. koob tshuaj ntawm 5 mg.kg-.min-Kuv yuav nyuaj rau kev ua tiav los ntawm kev noj zaub mov nplua nuj nyob rau hauv polyphenols, thiab qhov no, 3-HPAA tej zaum, es tsis txhob, siv tau los ua tshuaj lossis ntxiv. cov ntaub ntawv rau tib neeg tsis yooj yim; Txawm li cas los xij, cov kev xav tau no tuaj yeem ua tiav hauv tib neeg tom qab noj zaub mov nplua nuj nyob hauv flavonoids thiab tej zaum yuav cuam tshuam nrog kev cuam tshuam ntawm vascular system [17]. Hmoov tsis zoo, cov ntaub ntawv kinetic ntawm 3-HPAA tseem txwv. Ib qho 8-lub limtiam kev sim tshuaj placebo-tswj nrog 72 tus neeg koom tau pom tias muaj kev nce qib hauv plasma ntau ntawm 3-HPAA (los ntawm ~ 180 txog ~ 250 nM) tom qab noj cov txiv hmab txiv ntoo, uas muab txog 837 mg ntawm polyphenols ib hnub. Ntxiv mus, kuj tseem muaj qhov nce ntawm 87 feem pua ​​​​ntawm cov zis tawm ntawm 3-HPAA [29]. Lwm txoj kev tshawb nrhiav pom 60 qhov sib txawv phenolic metabolites hauv ntshav thiab zis hauv 10 tus neeg tuaj yeem pab dawb tom qab noj cov kua txiv cranberry uas muaj 787 mg ntawm polyphenols. 3-HPAA yog ib qho ntawm cov metabolites txiav txim siab hauv plasma thiab mus txog qhov siab tshaj plaws ntawm ~ 600 nM tom qab 10 teev kwv yees li [17]. Lwm txoj kev tshawb fawb kinetic nrog cuaj tus txiv neej noj qab haus huv tau pom tias bioavailability ntawm (poly) phenols tsis yog nyob ntawm tus nqi noj xwb. Tus nqi ntawm 766 mg ntawm polyphenols coj mus rau qhov siab tshaj plaws 3-HPAA plasma concentrations ntawm ~ 260 nM, thaum noj ntau tshaj ob npaug ntawm cov nyiaj tau nce mus rau theem qis (~ 240 nM) [30]. Txawm li cas los xij, hauv ob qho xwm txheej, cov ntshav plasma nce mus txog kwv yees li 250 nM.

Mechanism of the Vascular Effects of 3-HPAA Studied Ex Vivo

Peb tau ua cov ntaub ntawv tshawb fawb hauv PubMed database nrog lo lus tseem ceeb "3-hydroxyphenyl acetic acid".Kev tshuaj xyuas ntawm 110 kab lus pom tau tso cai rau peb los txiav txim siab tias cov ntaub ntawv ntawm 3-HPAA pharmacokinetics muaj kev txwv thiab kev tshawb fawb pharmacodynamic, rau peb qhov kev paub zoo tshaj plaws, tsis muaj nyob. Tsuas yog ib txoj kev tshawb fawb pom tau tias 3-HPAA txo qis COX-2 cov protein ntau hauv cov qog nqaij hlav hauv plab, tab sis tsis muaj kev cuam tshuam rau PGE2 ntau lawm [31].

Raws li nyob rau hauv peb cov kev sim vivo, 3-HPAA txo cov ntshav siab koob tshuaj-raws li thiab tsis muaj kev cuam tshuam rau lub plawv dhia, peb xav tias cov txheej txheem ntawm kev soj ntsuam cov teebmeem tuaj yeem dag hauv qhov ncaj qha ntawm 3-HPAA ntawm lub vasculature. Yog li ntawd, peb tau ua ntau yam ntxiv ex vivo thwmsim los tshawb txog cov txheej txheem ntawm kev ua. Raws li muaj kev pom zoo hauv Czech koom pheej kom txo qis kev siv cov tsiaj sim hauv txoj kab nrog 3Rs (Hloov, Txo, thiab Kho Kom Zoo), peb tau xaiv lwm cov qauv uas suav nrog kev siv cov porcine coronary hlab ntsha los ntawm lub siab tshiab, uas yog tau los ntawm ib lub tsev tua tsiaj hauv zos. Cov qauv no tsis zoo. Ua ntej, vasodilation tau pom ntawm qhov ntau dua qhov siab dua hauv cov nas aorta, thiab qhov thib ob, qhov concentration no yog kwv yees li 100 npaug ntau dua li qhov concentration tau los ntawm kev noj haus [17]. Txawm hais tias qhov kev txwv no, qhov teeb tsa no tau tso cai rau peb pom qhov sib txawv ntawm cov pab pawg sim thiab, yog li, nws tau txais txiaj ntsig txaus rau kev txiav txim siab ntawm cov txheej txheem ntawm kev ua. Ntawm qhov tod tes, qhov zoo dua yog tias npua thiab tib neeg pom tau tias muaj ntau qhov sib xws ntawm cov hlab plawv [32]. Nws tau pom tias 3-HPAA tsim cov tshuaj vasodilation ntawm npua coronary hlab ntsha ex vivo. Cov nyhuv no yog tsawg kawg yog ib feem ntawm kev sib kho los ntawm endothelium nrog kev koom tes ntawm endothelium-derived NO. Hauv qhov sib piv rau TSIS TAU, peb tsis tau lees paub qhov kev koom tes ntawm endothelial M receptors, COX, SKca, thiab IKca raws, thiab tsis muaj kev cuam tshuam ncaj qha rau cov leeg nqaij Cay1.2 raws (L-hom).

TSIS tau yav tas los hu ua qhov endothelium-derived so kom txaus thiab nws lub luag haujlwm hauv vascular physiology paub zoo. Luv luv, tom qab raug tsim los ntawm eNOS nyob rau hauv cov hlwb endothelial, TSIS tau diffuses mus rau vascular du leeg hlwb uas nws activates soluble guanylate cyclase (sGC) thiab txoj kev cGMP-PKG (Daim duab 8). PKG, nyob rau hauv lem, activates ntau yam Kt raws tam sim no nyob rau hauv cov nqaij du, uas yog loj-conductance calcium-activated (BKca), ATP-sensitive (KATP), sab hauv rectifier (KIR), thiab voltage-gated (Kv), yog li cia lub Hloov ntawm K ntxiv ions. Qhov no ua rau muaj kev nce hauv qhov tsis zoo ntawm daim nyias nyias nrog qhov ua rau inhibition ntawm voltage-gated calcium channels (feem ntau L-hom) thiab thaiv ntawm extracellular Ca2 ntxiv influx. Cov theem ntawm intracellular Ca2 ntxiv kuj raug tswj los ntawm kev ua kom SERCA los ntawm PKG los yog ncaj qha los ntawm TSIS [33], thiab los ntawm inhibition ntawm IP3R raws. Qhov tsis muaj NO-mediated teebmeem cuam tshuam nrog ntau yam pathologies. Ib qho kev txo qis thiab kev ua haujlwm ntawm eNOS tau pom nyob rau hauv aortas los ntawm SHR 34 thiab ua tsis taus NO ntau lawm tau pom nyob rau hauv endothelial thiab vascular du leeg hlwb los ntawm mesenteric hlab ntsha thiab aorta ntawm genetic modified hypertensive nas [35]. Hauv tib neeg kev tshawb fawb, qhov txawv txav endothelial muaj nuj nqi tau tshaj tawm hauv cov neeg mob uas muaj ntshav siab tseem ceeb [36]. Endothelial dysfunction tau cuam tshuam nrog kev ua haujlwm tsis zoo ntawm vascular bioavailability ntawm NO [37] yam tsis tau qhia meej tias cov txheej txheem no yog raws li kev txo qis hauv kev sib txuas, tso tawm, lossis nthuav tawm NO. Tsis ntev los no, cov txheej txheem postulated kuj suav nrog kev nce hauv cov txheej txheem oxidant uas txhawb tsis muaj kev tawg [38,39]. Yog li, cov txheej txheem tau piav qhia saum toj no tuaj yeem ua rau muaj kev cuam tshuam vasodilatory ntawm 3-HPAA (Daim duab 8), thiab nws muaj peev xwm tiv thaiv kab mob vascular. Qhov tseem ceeb, qhov no tuaj yeem yog vim li cas rau qhov sib txawv loj ntawm SHR rhiab heev rau 3-HPAA vasodilatory teebmeem thiab tsis muaj kev nkag siab zoo ntawm cov hlab ntsha ntawm cov hlab ntsha ntawm lub plawv npua, txawm hais tias qhov kev xav no yuav tsum tau lees paub hauv kev tshawb fawb ntxiv.

Yog tias qhov no muaj tseeb, cov lus nug ntawm 3-HPAA-induced NOsynthesis tshwm sim. Tus nqi pKa ntawm 3-HPAA yog 4, uas txhais tau hais tias nyob rau hauv lub cev pH, cov tshuaj feem ntau yog ionized. Qhov no hinders passive transmembrane thauj; Txawm li cas los xij, lub xub ntiag ntawm kev thauj mus los tsis tau txheeb xyuas thiab tsis tuaj yeem raug cais tawm. Kev ua kom eNOS feem ntau tshwm sim los ntawm kev nce hauv cytosolic Ca2t.Nyob hauv peb qhov kev sim, 3-HPAA vasodilation tsis yog nyob ntawm kev ua ntawm endothelial IKCa thiab SKCa channels. Raws li ob qho tib si cov channel no yog Ca2 ntxiv -sensitive [40, qhov nce yav dhau los hauv cytoplasmatic Ca2 ntxiv rau qib tsis yog qhov tshwm sim. Raws li qhov no, endothelial M-receptors, uas yog GPCRs ua ke rau tus xa xov thib ob DAG ntxiv rau IP, / PKC ntxiv rau cytosolic Ca2 ntxiv, tsis tau koom nrog, vim lawv qhov blockade los ntawm atropine tsis hloov pauv vasodilation los ntawm 3-HPAA . Qhov kev soj ntsuam no, nrog rau qhov tseeb tias tsis muaj kev hloov pauv hauv lub plawv dhia ntawm nas, qhia tias kev ua haujlwm ncaj qha cholinomimetic rau 3-HPAA tsis zoo li. Nco ntsoov, muaj homology loj hauv cov muscarinic receptors piav qhia ntawm cov tsiaj nyeg: M1 rau Ms hauv nas, thiab M1 rau M hauv npua, tau qhia txog homology ntau dua 90 feem pua ​​​​ntawm tib neeg amino acid sequences ntawm cov receptors [41]. Qhov kawg tab sis tsis kawg, ntxiv rau TSIS TAU, endothelial vasodilation kuj tuaj yeem kho los ntawm lwm cov khoom endothelial, ntawm lawv tus neeg nruab nrab los ntawm cyclooxygenase-pathway prostacyclin (PGI2). Qhov no tsis tshwm sim nyob rau hauv rooj plaub ntawm 3-HPAA vim tias muaj cov tshuaj indomethacin, cyclooxygenase blocker, tsis muaj txiaj ntsig.

Yav dhau los, peb tau kawm lwm qhov tseem ceeb ntawm cov colonic metabolite, DHPA, ntawm tus nas aorta ex vivo. Nws cov nyhuv vasodilatory kuj yog ib feem nyob ntawm endothelium, tab sis nrog kev koom tes ntawm endothelial IKc.channels thiab COX, yog li Cabling dependent [15]. Qhov no yuav qhia tau tias vasodilatory colonic metabolites ntawm flavonoids tuaj yeem ua los ntawm ntau yam kev ua haujlwm. Hauv cov xwm txheej tiag tiag, muaj cov txheej txheem sib txawv thiab kev sib cuam tshuam ntawm ntau lub plab zom mov tuaj yeem pab txhawb vasodilation. Qhov kev xav no yog ua raws li peb txoj kev tshawb fawb hauv vivo ntawm kev sib xyaw ntawm colonic metabolites [42]. Qhov zoo siab, qee qhov kev tshawb fawb tau pom tias niam txiv flavonoid, quercetin, kuj yog vasoactive. Nws qhib eNOS, thiab qhov kev txiav txim no yog kho los ntawm kev nce hauv cytosolic Ca2, ua kom tom qab ntawd Ca2 ntxiv -activated K raws, feem ntau yog SKca, thiab ua rau hyperpolarization ntawm endothelial hlwb [43,44]. Quercetin, li no, ua nyob rau hauv ib txoj kev sib txawv. Txawm li cas los xij, bioavailability ntawm niam txivquercetinyog tsawg [45,46] thiab, yog li, nws ncaj qha cuam tshuam rau vasodilation tej zaum tsis tseem ceeb.

Cov kev tshawb fawb luam tawm hauv daim ntawv no muaj ntau yam kev txwv. Piv txwv li, cov hlab ntsha porcine coronary artery tsis yog cov hlab ntsha tsis muaj zog, thaum cov hlab ntsha ntshav siab-txo cov nyhuv yuav cuam tshuam nrog kev nthuav dav ntawm cov hlab ntsha. Ib qho ivadministration ntawm ib qho bolus lossis txawm tias qeeb iv infusion tsis ua raws li qhov tshwm sim tiag tiag uas tib neeg noj ntau koob tshuaj ntawm flavonoids, feem ntau hauv daim ntawv ntawmglycosides, txhua hnub. Yog li, plasma profile ntawm metabolites yuav txawv. Qhov tseem ceeb, cov flavonoids noj yog metabolized tsis mus rau hauv ib qho tab sis mus rau hauv kev sib xyaw ntawm cov metabolites. Muaj ntau ntawm lawv yuav muaj vasoactive thiab kev sib cuam tshuam ntawm lawv cuam tshuam rau qhov kawg tshwm sim. Tsis tas li ntawd, ivapplication tsis tso cai rau kev ntsuam xyuas lub luag haujlwm ntawm plab hnyuv microbiota thiab kev hloov pauv hauv kev tsim tawm ntawm 3-HPAA thiab lwm yam metabolites los ntawm niam txiv flavonoids. Cov kev tshawb fawb yav tom ntej yuav tsum sim daws cov teeb meem no kom nkag siab zoo txog bioactivities thiab cov txheej txheem ntawm kev ua ntawm 3-HPAA hauv cov hlab plawv, suav nrog lub luag haujlwm ntawm NO.

5. Cov lus xaus

Cov ntaub ntawv muab pov thawj muaj zog tias covflavonoidmetabolite, 3-HPAA, tsim los ntawm tib neeg lub plab microbiota, yog vasoactive thiab txo cov ntshav siab. Tsis tas li ntawd, cov txiaj ntsig tau qhia tias qhov txo qis hauv ntshav siab tuaj yeem ua tiav ntawm qhov ua tiav tau. Nrog rau cov kev tshawb pom no, peb tau pom tias cov nyhuv hypotensive tsis yog tshwm sim los ntawm kev ua ncaj qha rau ntawm lub plawv, tab sis feem ntau yuav muaj vascular-based. Thaum kawg, qhov 3-HPAA-induced vasodilation yog, tsawg kawg yog ib feem, kho los ntawm endothelium, qhov uas tsis muaj kev cuam tshuam los yuav ua lub luag haujlwm.

Cov khoom siv ntxiv: Cov ntaub ntawv txhawb nqa hauv qab no tuaj yeem rub tawm ntawm: https://www.mdpi.com/article/1{{10}}.339{{20}}/nul4020328/s1. Daim duab S1.Kev hloov pauv hauv cov ntshav siab tom qab bolus ivadministration ntawm 3-HPAA. Daim duab S2. Kev hloov hauv lub plawv dhia tom qab bolus iv kev tswj hwm ntawm 3-HPAA.Figure S3. Cov txiaj ntsig ntawm 3-HPAA infusions (0.05,0.25,1 thiab 5 mg.kg-1min-1) ntawm systolic, diastolic thiab txhais tau tias ntshav siab hauv cov nas muaj ntshav siab. Daim duab S4. Cov txiaj ntsig ntawm 3-HPAA infusions (0.05, 0.25,1 thiab 5 mg.kg-1.min-l) ntawm lub plawv dhia hauv cov nas muaj ntshav siab.

Cov ntaub ntawv

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