CN104688750A - Purposes of polydatin in preparing anti-arrhythmic products - Google Patents
Purposes of polydatin in preparing anti-arrhythmic products Download PDFInfo
- Publication number
- CN104688750A CN104688750A CN201510126295.1A CN201510126295A CN104688750A CN 104688750 A CN104688750 A CN 104688750A CN 201510126295 A CN201510126295 A CN 201510126295A CN 104688750 A CN104688750 A CN 104688750A
- Authority
- CN
- China
- Prior art keywords
- hypertrophy
- polygonin
- purposes
- ventricular
- myocardial
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HSTZMXCBWJGKHG-UHFFFAOYSA-N (E)-piceid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(C=CC=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-UHFFFAOYSA-N 0.000 title abstract description 8
- 239000003416 antiarrhythmic agent Substances 0.000 title abstract description 8
- HSTZMXCBWJGKHG-CUYWLFDKSA-N trans-piceid Polymers O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-CUYWLFDKSA-N 0.000 title abstract description 8
- 229960003764 polydatin Drugs 0.000 title abstract description 7
- 230000003288 anthiarrhythmic effect Effects 0.000 title abstract description 4
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 27
- 230000006793 arrhythmia Effects 0.000 claims abstract description 22
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims abstract description 21
- 206010047295 Ventricular hypertrophy Diseases 0.000 claims abstract description 16
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Polymers C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 23
- 208000010125 myocardial infarction Diseases 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
- 108091006146 Channels Proteins 0.000 claims description 5
- 102000034573 Channels Human genes 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 abstract description 16
- 230000002107 myocardial effect Effects 0.000 abstract description 15
- 230000002861 ventricular Effects 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 10
- 239000000284 extract Substances 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 7
- 241000699670 Mus sp. Species 0.000 abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract description 6
- 230000008859 change Effects 0.000 abstract description 6
- 206010049418 Sudden Cardiac Death Diseases 0.000 abstract description 5
- 230000036982 action potential Effects 0.000 abstract description 5
- 208000028867 ischemia Diseases 0.000 abstract description 5
- 239000011591 potassium Substances 0.000 abstract description 5
- 229910052700 potassium Inorganic materials 0.000 abstract description 5
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 4
- 230000001052 transient effect Effects 0.000 abstract description 4
- 102000004310 Ion Channels Human genes 0.000 abstract description 3
- 238000007634 remodeling Methods 0.000 abstract description 3
- 210000004413 cardiac myocyte Anatomy 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 238000004904 shortening Methods 0.000 abstract description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract 2
- 208000033774 Ventricular Remodeling Diseases 0.000 abstract 2
- 241001648835 Polygonum cuspidatum Species 0.000 abstract 1
- 235000018167 Reynoutria japonica Nutrition 0.000 abstract 1
- 230000016507 interphase Effects 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 230000001681 protective effect Effects 0.000 abstract 1
- 230000000452 restraining effect Effects 0.000 abstract 1
- 230000002980 postoperative effect Effects 0.000 description 39
- 241000700159 Rattus Species 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 23
- 230000000694 effects Effects 0.000 description 17
- 206010020880 Hypertrophy Diseases 0.000 description 15
- 210000000709 aorta Anatomy 0.000 description 14
- 239000007788 liquid Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 230000000747 cardiac effect Effects 0.000 description 7
- 230000004217 heart function Effects 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 210000004165 myocardium Anatomy 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000011575 calcium Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000002336 repolarization Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 210000002064 heart cell Anatomy 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000007831 electrophysiology Effects 0.000 description 3
- 238000002001 electrophysiology Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 208000004731 long QT syndrome Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000005405 multipole Effects 0.000 description 3
- 230000003387 muscular Effects 0.000 description 3
- -1 stilbene compound Chemical class 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- 206010047302 ventricular tachycardia Diseases 0.000 description 3
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- 206010042434 Sudden death Diseases 0.000 description 2
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 210000002376 aorta thoracic Anatomy 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000037024 effective refractory period Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000013577 regulation of ventricular cardiomyocyte membrane repolarization Effects 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 235000021283 resveratrol Nutrition 0.000 description 2
- 229940016667 resveratrol Drugs 0.000 description 2
- 210000001013 sinoatrial node Anatomy 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 208000003663 ventricular fibrillation Diseases 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003671 Atrioventricular Block Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 102000004657 Calcium-Calmodulin-Dependent Protein Kinase Type 2 Human genes 0.000 description 1
- 108010003721 Calcium-Calmodulin-Dependent Protein Kinase Type 2 Proteins 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102000000254 Kv Channel-Interacting Proteins Human genes 0.000 description 1
- 108010041081 Kv Channel-Interacting Proteins Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- HSTZMXCBWJGKHG-CENDIDJXSA-N Piceid Natural products OC[C@@H]1O[C@@H](Oc2cc(O)cc(C=Cc3ccc(O)cc3)c2)[C@H](O)[C@H](O)[C@H]1O HSTZMXCBWJGKHG-CENDIDJXSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 244000153955 Reynoutria sachalinensis Species 0.000 description 1
- 235000003202 Reynoutria sachalinensis Nutrition 0.000 description 1
- 108010091462 Shal Potassium Channels Proteins 0.000 description 1
- 102000018404 Shal Potassium Channels Human genes 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 206010040741 Sinus bradycardia Diseases 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 208000018452 Torsade de pointes Diseases 0.000 description 1
- 208000002363 Torsades de Pointes Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 description 1
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000003126 arrythmogenic effect Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 229960000796 barbital sodium Drugs 0.000 description 1
- FTOAOBMCPZCFFF-UHFFFAOYSA-N barbitone sodium Natural products CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003601 intercostal effect Effects 0.000 description 1
- 210000002977 intracellular fluid Anatomy 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000008289 pathophysiological mechanism Effects 0.000 description 1
- 210000000062 pectoralis major Anatomy 0.000 description 1
- 210000000989 pectoralis minor Anatomy 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- HSTZMXCBWJGKHG-OUUBHVDSSA-N piceide Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(C=CC=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-OUUBHVDSSA-N 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229940126121 sodium channel inhibitor Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RGHFKWPGWBFQLN-UHFFFAOYSA-M sodium;5,5-diethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC1(CC)C([O-])=NC(=O)NC1=O RGHFKWPGWBFQLN-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 230000000213 tachycardiac effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Landscapes
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to purposes of polygonum cuspidatum extract, namely polydatin. Myocardial hypertrophy is the most important reason for triggering congestive heart failure. Ventricular hypertrophy usually involves ventricular structure change, namely ventricular remodeling. The ventricular remodeling is a complication of multiple cardiovascular diseases and a vital and decisive element in the development process of the congestive heart failure. The arrhythmia occurrence rate after the myocardial remodeling is increased by 28%, and cardiac sudden deaths caused in the end are increased by over five times. It is indicated that through in vitro study tests, the polydatin remarkably restrains heart ion channels caused by ischemia indury of mice from remodeling and has a great protective effect for arrhythmia, and therefore the polydatin can be used for preparing products resisting against arrhythmia caused by myocardial hypertrophy and/or ventricular hypertrophy. According to the method, the polydatin plays the anti-arrhythmic role by increasing the electric current density of transient outward potassium current (Ito), shortening the action potential duration (APD) of cardiac muscle cells and restraining the QT inter-phase from being prolonged.
Description
Technical field
The application of the active ingredient that the present invention relates to Chinese crude drug in clinical, relates generally to a kind of Chinese medicine extract and polygonin (piceid, the polydatin) purposes at the anti-myocardial hypertrophy of preparation and/or ventricular hypertrophy institute proarrhythmia product.
Background technology
1, arrhythmia
Heart disease has become one of fastest-rising disease of sickness rate in recent years.Arrhythmia is because the exciting exception of sinuatrial node or excitement result from beyond sinuatrial node; exciting conduction slowly, retardance or through abnormal passage conduction, namely the origin of cardiomotility and (or) conductive impairment cause frequency and (or) the allorhythmia of heartbeat.Arrhythmia is one group of disease important in cardiovascular disease.It can be fallen ill separately and also can occur together with cardiovascular diseases.Can break out and cause sudden death, also sustainablely involving heart and exhaustion.
Myocardial hypertrophy is then cause the most important reason of heart failure.Ventricular hypertrophy is usually secondary to hypertension and myocardial infarction.Ventricular hypertrophy is usually directed to ventricular structure and changes, i.e. remodeling ventricle.Myocardial remodelling is the complication of many cardiovascular disease, is the important determiner in heart failure evolution.After myocardial remodelling, incidence of arrhythmia improves 28 ﹪, finally causes cardiac sudden death to increase more than 5 times.Patient's fatal arrhythmia risk of chronic cardiac pathologic over loading (e.g., by hypertension, valvular heart disease, chronic ischemia) increases and has the tendency that severe heart failure occurs.Along with the progress of heart failure, the frequency that VEA occurs and complexity increase.For a long time, it has been recognized that pathologic ventricular hypertrophy is the independent hazard factor of sudden cardiac death.But, under Chronic Hemodynamics event of overload, cause ARR mechanism very complicated.Even if also there is different tachycardic mechanism in the patient with same pathological change.
Research finds to there is the structure of myocardial cell and electrophysiological reconstruction in the cardiac muscle (myocardial hypertrophy and heart failure) of over loading.No matter the myocardial hypertrophy what reason causes and heart failure, the feature of its electricity reconstruct is that vntricular action potential extends (CurrOpinCardiol.2010Jan; 25 (1): 29-36.).For human heart, lengthening of action potential not only can come across compensatory myocardial hypertrophy but also can come across in endstage cardiac insufficiency.Usually change with QT interval in other myocardial hypertrophy or heart failure patient in ischemic or Ischemic dilated cardiomyopathy.And these change, be usually to be in harmonious proportion Ca under K+ passage
2+environment homeostasis changes into basis.
Identical of viewsly at present to think, the important information lowered about K+ passage comes from nearest α subunit (Kv4.2, Kv4.3) down-regulated expression to ventricular repolarization ion channel Ito, Ito electric current density is reduced, by extending Single Cardiac Cell, cause long QT syndrome, thus cause the generation of ventricular arrhythmia.
The clinical treatment emphasis to muscular hypertrophy and/or ventricular hypertrophy uses Cardiac glycosides positive inotropic action medicine and diuretic in the past, often ignores the arrhythmia that myocardial hypertrophy brings.The antiarrhythmic drug used clinically at present and develop is according to the influence and effect mechanism classification to cardiac electrophysiology, four large classes can be divided into: I class is sodium channel inhibitor, however serious sinus bradycardia, atrioventricular block can be produced, QRS ripple is broadening brings out the side effect such as new torsades de pointes ventricular arrhythmia.II class is beta-blocker, and its side effect is severe hypotension, and also has the effect extending Q-T interval.III class is the medicine that selectivity extends Single Cardiac Cell time-histories (APD) and effective refractory period (ERP), and selectivity blocks the medicine of myocardium potassium-channel, has the side effect similar with I class medicine.IV class is calcium channel blocker.I II IV class medicines all have to reduce and pass to speed and even cause the effect of passing to retardance, and these effects can increase the probability of reciprocal excitation, and bring out arrhythmia.III class medicine has no significant effect self-disciplining.
2, Rhizoma Polygoni Cuspidati
Rhizoma Polygoni Cuspidati, originates in East Asia Region, is distributed in the ground such as Jiangsu, Jiangxi, Shandong, Sichuan of the area on the south Hokkaido, Japan western part, the Korea peninsula, TaiWan, China and China.Mildly bitter flavor, cold nature, containing polygonin, flavone etc.The polygonin used in the present invention can extract in conventional manner, and such as publication number is the extracting method disclosed in the patent in CN1546503A (publication date on November 17th, 2004).The polygonin aqueous solution used in the present invention is prepared in conventional manner, and such as publication number is the method disclosed in the patent of CN1709269A (publication date 2005 on December 21).The concentration of preparation is 6-150mg/ml, and preferred concentration is 20-100mg/ml, and most preferable concentrations is 40mg/ml.
It is found that Rhizoma Polygoni Cuspidati has good potential applicability in clinical practice in recent years, become new study hotspot gradually.In the traditional medicine treatment of motherland, Chinese medicine is owing to being taken from natural plants, and toxic and side effects is few, often has multiple action target spot, and in steady regulation and control, have at body that " high person presses down it, sinking of QI of ZANG FU-organs should be treated by elevation; Have Yu person to damage it, treating deficiency syndrome by tonifying " profoundness.
Polygonin is a kind of monomer extracted in Rhizoma Polygoni Cuspidati, and it is the product that resveratrol is combined with glucose, and they all belong to the stilbene compound in Rhizoma Polygoni Cuspidati composition, i.e. hydroxy stibene compounds.The pharmacological research progress of polygonin in cardiovascular comprises:
1) polygonin myocardial cell protection effect.Polygonin is found obviously to alleviate murine myocardium viral infection infringement (Song Junhua, Binzhou Medical College's journal 2008,31:95-98).Domestic scholars report polygonin has the function of the similar resveratrol such as antioxidation, antiinflammatory, and improves effect (the Hebei medicine 2010,32:1492-1493 of cardiac function that hemorrhagic shock causes and microcirculation disturbance; ClinHemorheolMicrocirc.2003,29:211-217).At present, polygonin injection is in IIb phase clinical human conceptual phase at home at present, and IIb phase clinical human progress is smooth.Domestic now current common dose is 50-40mg/kg.
2) polygonin atherosclerosis.Experiment shows, polygonin significantly can reduce the blood fat of Corn Bract Decotion, and can alleviate aorta and the coronary atherosclerosis course of disease.(Chinese tcm emergency, 2005,14:564-567) polygonin also can reduce the soft speckle quantity of the unstable plate of carotid artery, may have the effect (Beijing Chinese medicine, 2009,28172-175) of arteriosclerosis.
3) polygonin antithrombus formation.Polygonin has the Platelet Aggregation in Rabbit suppressing the induction of arachidonic acid, adenosine diphosphate (ADP) and epinephrine in vivo and in vitro, and inhibition strength weakens (Dan Chunwen along with the reduction of polygonin concentration, Acta Pharmacologica Sinica, 1990,11 (6): 527).
Summary of the invention
At present, all antiarrhythmic drugs all have arrhythmogenic effect, and its incidence rate is 6% ~ 36%, its mechanism and electrocardio get excited formed or conductive impairment relevant.Easily occur long Q-T interval syndrome except after myocardial infarction damage, causing in the medicine of long Q-T interval syndrome various, but the most often there is this side effect in antiarrhythmic drug.Object of the present invention, is application polygonin treatment myocardial infarction arrhythmia, significantly can reduces the Q-T interval of prolongation, reduce ARR generation.
The present invention includes:
Polygonin is preparing the purposes in arrhythmia product.Described arrhythmia is that caused by myocardial hypertrophy and/or ventricular hypertrophy, described myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia are caused by hypertension or myocardial infarction.
Polygonin suppresses the purposes in long Q-T interval syndrome product in preparation.Described long Q-T interval, is caused by myocardial infarction.
Polygonin is expressing the purposes in product for the preparation of increase Ito channel protein.Described Ito channel protein is one or more in Kv4.2, Kv4.3 and Kchip.
Polygonin has suppression myocardial infarction and causes Arrhythmia under low dosage (20mg/kg) condition.
The said goods comprises the one in medicine, reagent or food, its occupation mode comprise be used alone or with other chemical substance conbined usage.
The technique effect of invention is as follows:
1, in numerous treatment arrhythmia, particularly myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia, a kind of efficient, cheap and Chinese medicine of safety is chosen in medicine, this Chinese medicine (polygonin) can raise transient outward potassium, by potential duration under reach (APD), play antiarrhythmic effect.
2, provide a kind of and suppress the efficient, cheap of long Q-T interval syndrome and the Chinese medicine of safety, this Chinese medicine (polygonin) is by the adjustment to myocardial cell membrane potassium-channel, regulate the process of repolarization of myocardial cell AP, shorten APD, suppress the generation of long QT syndrome.
3, the efficient, cheap of a kind of protein expression of remarkable increase Ito passage is provided and the Chinese medicine of safety, this Chinese medicine (polygonin) has inhibitory action to myocardial cell membrane Transient Outward Potassium Current (Ito) electric current, significantly increases the protein expression of Ito passage.
4, provide a kind of low dosage concentration of use, 20mg/kg, under this concentration, there is antiarrhythmic effect.
Accompanying drawing explanation
Fig. 1 is the electrophoretogram of the protein expression representing Ito subunit Kv4.2 and Kchip.
Detailed description of the invention
1. materials and methods
1.1 material
1) polygonin used in reagent the present invention is provided by Hai Wang Pharma Inc. of Shenzhen, and concrete grammar is as follows:
Giant knotweed rhizome 100g, suitably pulverizes, and extracts with 800ml ethanol percolation, filter, concentrating under reduced pressure (50 DEG C, 0.07-0.1Mpa), to final volume 50ml, adds 100ml water, and extract 3 times with 200ml vinyl alcohol, extract concentrating under reduced pressure (50 DEG C, 0.07-0.1Mpa) is to 150ml, and Silon stirs, decompression volatilizes solvent, for subsequent use as loading sample.
Loading sample uses a dry method on a sample on polyamide column for subsequent use (cylinder is about 600ml), chromatographic elution is carried out for mobile phase successively with 1000ml water, 3000ml30% ethanol water, flow velocity 600ml/hr, collect 30% ethanol water elution effluent, and will wherein merge containing polygonin stream part, be evaporated to 100ml (60 DEG C, 0.07-0.1Mpa), sucking filtration, draws product 2g, and wherein Determination of Polydatin is 84%.
Head product is with 95-100% dissolve with ethanol, and filter, filtrate adds water to containing alcohol final concentration 30%, add 1% (ml/ml) medical active carbon dust and boil 3 minutes, filtered while hot, filtrate reduced in volume, to 50ml, leaves standstill 0.5 hour crystallize at 4 DEG C, filter, gained crystal vacuum drying 4 hours (100 DEG C, 0.08-0.1Mpa, phosphorus pentoxide desiccant), obtain end-product polygonin 1.5g, detect containing polygonin 99.82% through HPLC.
Gained polygonin is made into polygonin aqueous solution, and concentration is 40mg/ml.Concrete grammar is as follows: polygonin 11g, propylene glycol 18ml, ethanol 116ml, pure water 200ml, 40 DEG C of ultrasonic dissolutions, 0.45um filtering with microporous membrane, be packed as 100 for subsequent use.Concentrate during use or be diluted to aimed concn.
2) Animals Male C57 mice, body weight 25-30g, is provided by Guangdong Province's Experimental Animal Center, totally 60, is divided into sham operated rats, operation group and treatment group at random, often organizes 20 mices.Threading not ligation when sham operated rats is ligation; Operation group is ischemia-reperfusion group; Treatment group is ischemia-reperfusion and gives polygonin gavage treatment group.
3) liquid (mM) in operation of recording potential electrode: KCl 140, MgCl
21, K
2aTP 5, Hepes 5, Glucose 10, KOH adjust pH to 7.4, and 0.22 μm of filtering with microporous membrane subpackage-20 DEG C saves backup.
Record I
tothe preparation (mM) of electric current extracellular fluid: NaCl 126, KCl 4, MgCl
22.5, Hepes5, dextrose 5.5, CdCl
20.3, MnCl
22, TEACl 20 (pH 7.3 with NaOH).
1.2 method
1) experiment grouping
Preoperatively give atropine 0.01mg/kg intramuscular injection, with 2% without barbital sodium 60mg/kg, through intraperitoneal injection of anesthesia.Anaesthetize successfully, tracheal intubation, utilize toy respirator to maintain normal respiratory rate (130-150 beat/min) and tidal volume (150-200 ml/min).Upper limb flushes left side, place and rejects chaeta, alcohol disinfecting, and 0.5-1.0cm horizontal cut is done at suprasternal notch place, is separated crust.Cut off left side pectoralis major and pectoralis minor, open, bulldog clamp is fixed.Open thoracic cavity by the 2nd, 3 intercostal, visible white thymus, carefully down found by center edge portion on thymus, find aortic arch place, ophthalmic tweezers threading.Enclose No. 26 medicated pillows, positive and negative surgical knot knotting, fetches syringe needle, to reach the object of constriction aortic arch.Sew up.Except sham operated rats and model group adopt normal saline gavage, treatment group adopts the capable gavage treatment of the dosage of 20mg/kg, and second day after operation starts, once a day.Continuous treatment 4 weeks (28 days).
2) exercise stress test
Adopt the mouse test treadmill that Beijing Zhi Shuduobao biotechnology Co., Ltd provides, allow three groups of mices enter treadmill in test the 4th weekend (the 28th day), treadmill speed is 15 ms/min, and the running time is 10 minutes in batches.Complete recording ecg (QT interval), ultrasound detection cardiac function, leaves and takes serum, and myocardial cell protein extraction detects Ito protein content, another separating myocardium cell, detects AP, record Ito function.
3) electrocardiographic recorder and QT QT dispersion (AD company electrocardiographic recorder) are measured:
Simulation human body crosslinking electrode placement location, utilizes needling electrode to insert animal foot and front subcutaneous record 12 Lead Synchronous ECG.Record 12 lead electrocardiogram respectively at behind preoperative and postoperative 7 days, same continuous measurement 3 cardiac cycles that lead are averaged and are measured QT interval, and QT interval is measured from QRS starting point (as without Q ripple, then with R ripple starting point) to T ripple terminal.Measure difference and lead the longest QT (QTmax) and the shortest QT (QTmin), the QT (QTc) that heart rate corrects with Bazzets formula correction, QT=QT/ (R-R)
1/2, the QT QT dispersion QTcd=QTcmax-QTcmin that heart rate corrects.
4) Heart Brightness Mode Function detection:
Be fixed on after mouse anesthesia on operation panel, instrument adopts dimension victory 2000 toy Ultrasound Instrument.Get minor axis B ultrasonic and M to surpass, the Blind Test 3 times respectively of every mice, averages, calculates left ventricular ejection fraction (LVEF) and evaluate cardiac function.
5) myocardial cell is separated
Anesthesia fully, open rapidly breast and take out heart, be put in the calcium liquid of 0 DEG C and wash, isolate aorta, aorta is inserted gently with No. 7 syringe needles of the ready 10ml of being connected in syringe, aorta is fixed with surgical thread, threeway on Langendorff pipe is opened, liquid flows out, fixing heart No. 7 syringe needles are connected on Langendorff pipe, with there being calcium liquid perfusion, add without calcium liquid, until cardiac arrest, the collagenase and albumin mixed liquor that prepare in advance within 10 ~ 20 minutes, is added after stoping jumping, about 30min heart lighter, during quality deliquescing, getting a little right side myocardium tissue is put in krebs solution, in time having cell to get off, residual myocardium tissue is taken off, surrounding tissue is cut gently with shears, do not cut off, then tissue is put in krebs solution and blows and beats with suction pipe, during piping and druming, cell gets off, and tissue keeps intact form relatively good relatively, blow and beat cell, residue tissue is thrown away, myocardial cell is kept in krebs solution.To stablize after one hour stand-by. mouse cardiac myocytes digestion duration is greatly about 30 ~ 50 minutes.
6) Ito Function detection (full cell pattern recording film electric current)
Experiment glass microelectrode microelectrode draws instrument and divides five steps to draw, then carries out polishing operation, and tip diameter is 0.5-1 μm.Add the magnetic bead of CD8 antibody treatment after cell transfecting 24h, be placed in incubator and hatch 30min, clean for several times with the PBS liquid containing 0.6%FBS before magnetic bead uses.The cell (being the successful cell of transfection) cell membrane being stained with several magnetic bead is selected to carry out electro physiology experiment.Cell incubation liquid adopts tyrode, and electrode charges electrode solution.Electrode is slowly immersed extracellular fluid by operation narishige, imposes a little malleation before entering liquid level, to prevent the foreign material blocking eletrode tip in liquid.After electrode enters water, measurement electrode impedance is at 2-5M Ω proper (resistance excessive or too small be all unfavorable for the formation of full cell and cause rupture of membranes success rate to decline).Return to zero take whole-cell recording technique mode under voltage clamp under, after forming G Ω level high resistance seals, carry out fast capacitance compensation, then controlled underbalance a little, form duct in the plasma membrane of rupture of membranes rear electrode sealing-in, form high resistance seals.Run the protocol set and namely give different voltage stimulations, current signal guides through Ag-AgCl electrode, adopt Axon company of U.S. patch clamp amplifier Axopatch 200B, filtering (frequency 2kHz), at room temperature (22 ~ 25 DEG C) make off-line analysis with Clampex 7.0 acquisition channel current storage after computer.
7) AP detects (under full cell pattern operation of recording current potential)
After forming full cell sealing-in, after liquid in electrode and intracellular fluid balance 3-5min, the wide 1ms of ripple is set, frequency 1Hz, stimulates with the square wave of 800pA, 5ms, the generation of induction action potential.Pulse continued stimulus 10 times, stimulus intervals is 1s.Pulse signal is by clamp software control, by the glass microelectrode transfered cell of liquid in Ag-AgCl wire electrode and filling electrode after amplifier amplifies, the current signal produced is changed through amplifier and is stored in hard disc of computer, analyze the various parameters of action potential, comprise resting potential (RP), overshoot (OS), amplitude of action (APA), repolarization 50% (APD
50) and 90% (APD
90) time.
2. experimental result
2.1 aorta arch constrictions are preoperative and after postoperative 28 days, and after stress test, the change of each group QTcd is as shown in table 1, before cardiac aorta bow Constriction, and the more equal no significant difference of QTcd (p>0.05) between 3 treated animals.Ischemia group after surgery more preoperative QTcd obviously increases (p<0.05), and postoperative hypertrophy group comparatively matched group QTcd also obviously increases (p>0.05).Rhizoma Polygoni Cuspidati treatment group postoperative 28 days QTcd slightly increase, but not statistically significant (p>0.05).Postoperative Rhizoma Polygoni Cuspidati treatment group QTcd is also significantly less than loose group (p<0.05).The treatment of prompting Rhizoma Polygoni Cuspidati can obviously shorten QTcd interval.
Table 1 polygonin is on the impact (x ± s, ms) of mouse aorta bow constriction preoperative and postoperative QT dispersion
| Group | Preoperative | Postoperative (28 days) |
| Sham operated rats | 34.9±2.8 | 36.5±3.4 |
| Loose group | 35.2±3.3 | 67.2±5.8 *# |
| Polygonin treatment group | 35.1±3.2 | 45.7±6.6 |
Note: * p<0.05vs hypertrophy group is preoperative, and #p<0.05vs sham operated rats is postoperative and polygonin treatment group is postoperative
2.2 postoperative 28 days of ultrasonic cardiac function result displays, none is dead for postoperative 40 mices of aorta arch constriction, and survival rate is 100%.Through preoperative and postoperative 28th day ultrasound Evaluation, there is heart eccentric hypertrophy in prompting loose group mouse heart, and declines with obvious cardiac function, and Left Ventricular Ejection Fraction drops to 38% ± 3 (P<0.05) by preoperative 52% ± 2; Left ventricle obviously expands simultaneously, left room end-diastolic diameter is extended to (3.57 ± 0.44) mm (P<0.05) by (2.84 ± 0.13) mm, shrinks last diameter and is extended to (4.31 ± 0.07) mm (P<0.05) by (3.49 ± 0.14) mm.Compared to loose group, polygonin obviously improves left ventricular cardiac function (Left Ventricular Ejection Fraction postoperative 53% ± 2vs hypertrophy group postoperative 38% ± 3, p<0.05), simultaneously, left room end-diastolic diameter (3.58 ± 0.09vs 4.31 ± 0.07, P<0.05) and end-systole diameter (2.32 ± 0.11vs3.21 ± 0.09, P<0.05) all have improvement in various degree (seeing the following form 2).
Table 2 polygonin is on before mouse aorta bow Constriction and the impact (x ± s) of postoperative 28 days every parameters of left ventricular function
Note: * p<0.05vs hypertrophy group is preoperative and sham operated rats is postoperative, #p<0.05vs hypertrophy group is postoperative, LVEF: Left Ventricular Ejection Fraction
2.3 Ito
Report, during myocardial ischemia, Ito electric current density significantly reduces.Following table 3 shows the Ito electric current density of sham operated rats, loose group and polygonin treatment group.Result shows, three groups of preoperative Ito electric current densities are compared does not have significant difference (P=0.234).And the postoperative Ito electric current density of loose group is significantly lower than sham operated rats.When+60mV, sham operated rats, loose group and the preoperative Ito electric current density of polygonin treatment group are respectively (11.1 ± 1.0) pA/pF (n=27), (10.9 ± 1.1) pA/pF (n=24), (10.6 ± 1.2) pA/pF (n=29, P=0.14vs sham operated rats).And sham operated rats during+60mV, loose group and the postoperative Ito electric current density of polygonin treatment group are respectively (10.4 ± 0.8) pA/pF (n=31), (5.2 ± 0.3) pA/pF (n=33, P<0.05vs sham operated rats), (8.9 ± 0.7) pA/pF (the loose group of n=35, P<0.05vs).Result shows, and can significantly increase Ito electric current density after giving polygonin.
Table 3 polygonin is to rat aorta bow Constriction preoperative and postoperative Ito current detecting (+60mV)
Note: * p<0.05vs hypertrophy group is preoperative and sham operated rats is postoperative, #p<0.05vs hypertrophy group is postoperative, LVEF: Left Ventricular Ejection Fraction
2.4 AP
As shown 4-6 display, the AP of sham operated rats, loose group and polygonin treatment group.Preoperative and the postoperative AP multipole 20% (APD20) to three groups, the time-histories of APD multipole 50% (APD50) and multipole 90% (APD90) carries out statistical analysis, three groups of preoperative APD20, APD50 and APD90 does not relatively have significant difference (P=0.145).Sham operated rats postoperative APD20, APD50 and APD90 are respectively (3.2 ± 0.2) ms, (8.7 ± 0.6) ms and (31.2 ± 2.8) ms (n=20), the postoperative APD of loose group
20, APD
50and APD
90comparatively sham operated rats significant prolongation, be respectively (4.9 ± 0.3) ms (P=0.00vs sham operated rats), (12.2 ± 1.1) ms (P=0.00vs sham operated rats) and (45.1 ± 2.7) ms (P=0.01vs sham operated rats), n=40.And the postoperative APD20 of polygonin treatment group, looser group of APD50 and APD90 significantly shortens, be respectively (4.0 ± 0.5) ms (the loose group of P<0.05vs), (9.8 ± 0.8) ms (the loose group of P<0.05vs) and (34.2 ± 3.4) ms (the loose group of P<0.05vs), n=35.And the resting membrane electric potential of three groups (RMP) is respectively (-78.3 ± 0.6) mV, (-79.8 ± 0.3) mV and (-78.4 ± 0.5) mV, three groups relatively do not have remarkable significant difference, P=0.219.Result shows, and can significantly shorten AP time-histories after giving polygonin.
Table 4 polygonin is to rat aorta bow Constriction preoperative and postoperative AP
20detect
| Group | Preoperative | Postoperative (28 days) |
| Sham operated rats | 3.2±0.2 | 3.6±0.3 |
| Loose group | 3.8±0.4 | 4.9±0.3 * |
| Polygonin treatment group | 3.6±0.4 | 4.0±0.5 # |
Note: * p<0.05vs hypertrophy group is preoperative and sham operated rats is postoperative, #p<0.05vs hypertrophy group is postoperative, LVEF: Left Ventricular Ejection Fraction
Table 5 polygonin is to rat aorta bow Constriction preoperative and postoperative AP
50detect
| Group | Preoperative | Postoperative (28 days) |
| Sham operated rats | 8.7±0.6 | 9.5±0.7 |
| Loose group | 9.1±0.5 | 12.2±1.1 * |
| Polygonin treatment group | 8.9±0.7 | 9.8±0.8 # |
Note: * p<0.05vs hypertrophy group is preoperative and sham operated rats is postoperative, #p<0.05vs hypertrophy group is postoperative, LVEF: Left Ventricular Ejection Fraction
Table 6 polygonin is to rat aorta bow Constriction preoperative and postoperative AP
90detect
| Group | Preoperative | Postoperative (28 days) |
| Sham operated rats | 31.2±2.8 | 30.1±3.8 |
| Loose group | 32.0±2.6 | 45.1±2.7 * |
| Polygonin treatment group | 30.8±2.9 | 34.2±3.4 # |
[0077]note: * p<0.05vs hypertrophy group is preoperative and sham operated rats is postoperative, #p<0.05vs hypertrophy group is postoperative, LVEF: Left Ventricular Ejection Fraction
2.5 Ito subunit Kv4.2 and Kchip express as shown in Figure 1, and within 28 days, extract cardiac muscular tissue's albumen afterwards, western blotting detects the protein expression of α and β subunit Kv4.2 and Kchip of Ito passage.The myocardial cell reconstruct that myocardial hypertrophy causes, wherein main manifestations is the remarkable reduction of the expression of Ito protein subunit, but what is interesting is, polygonin is treated, and significantly can improve the minimizing of this expressing quantity, increases Kv4.2 and Kchip protein content.
In figure, LVH:Left ventricular hypertrophy refers to left ventricular hypertrophy.
4. discuss
It is one of very high disease of current fatality rate that myocardial hypertrophy and/or ventricular hypertrophy cause heart failure.Although Current therapeutic significantly improves the prognosis of patients with heart failure, the mortality rate in a year is still up to 20%.Wherein have the patient of 50% to die from sudden cardiac death, compared to other reasons, heart failure sudden death rate up to 6-9 doubly.Cardiac muscular tissue dissects and reinventing and can change cardiac electrophysiology functionally.The research display in past, all there is electrophysiological change (Curr Opin Cardiol.2010Jan in various degree in the atrium of myocardial hypertrophy or patients with heart failure and ventricular muscle cell; 25 (1): 29 – 36.).
As everyone knows, voltage gated potassium channels (K
v) play an important role in the formation of Single Cardiac Cell (AP) repolarization, AP repolarization extends and causes LQT syndrome.Compare with normal myocardial cells, loose myocardial cell shows the prolongation of early repolarization AP, thus causes ARR generation frequently.Meanwhile, the myocardial cell of heart failure can show the downward of potassium current.From current research display, the molecular mechanism that Ito lowers may be multifactorial.Test proves, in the pathophysiological mechanism of myocardial hypertrophy heart failure, and downward performance the most obviously (the Circ Res.1993 of transient outward potassium (Ito); 73:379 – 385.; Circulation.2006; 113:345 – 355).The steady-state level of Kv4 potassium channel mRNA reduces the downward height correlation with Ito.In the research of canine model, the downward that ventricular tachycardia simultaneous Ito expresses, its participation mechanism may be and Ca
2+protein kinase ii (CaMKII) path that/calmodulin, CaM relies on is relevant with calcineurin/NFAT path.(Circ Res.2008；103:733–742)
The Focal point and difficult point of clinical position for arrhythmia and sudden cardiac death after myocardial hypertrophy and/or ventricular hypertrophy always, although current antiarrhythmic drug is a lot, how to select with strong points, side effect is little, the medicine of highly effective and safe is still still unsolved clinical problem.For after myocardial infarction arrhythmia prevention research with and subsequent several clinical trials all fail, impel clinicist to recognize further, select importance and the urgency of rational antiarrhythmic drug.
This result of study shows, the postoperative QTcd of aorta arch constriction obviously increases, be easy to bring out the fatal arrhythmia such as ventricular tachycardia, ventricular fibrillation, and polygonin treatment obviously can shorten QTcd, improve room to quiver territory, thus can ecg stability be increased, that reduces the fatal arrhythmia such as ventricular tachycardia, ventricular fibrillation easily sends out tendency.Simultaneously, experimental result display Kv4.2 albumen raises, and the α subunit (Kv4.2) that the treatment of prompting polygonin significantly can increase ventricular repolarization ion channel Ito is expressed, and Ito electric current density is raised, by shortening Single Cardiac Cell, improve cardiac function.Our experimental result also supports this hypothesis, and polygonin treatment can obviously promote left room LVFS and Left Ventricular Ejection Fraction.In experimentation, do not find the arrhythogenic ill effect of other antiarrhythmic drugs of polygonin temporarily, prevent and treat myocardial hypertrophy and/or ventricular hypertrophy proarrhythmia and show the effect of its uniqueness.
Claims (10)
1. polygonin is preparing the purposes in arrhythmia product.
2. purposes as claimed in claim 1, is characterized in that, described arrhythmia is caused by myocardial hypertrophy and/or ventricular hypertrophy.
3. purposes as claimed in claim 2, it is characterized in that, described myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia are caused by hypertension or myocardial infarction.
4. polygonin suppresses the purposes in long Q-T interval syndrome product in preparation.
5. purposes as claimed in claim 4, it is characterized in that, described long Q-T interval is caused by myocardial hypertrophy and/or ventricular hypertrophy.
6. polygonin is expressing the purposes in product for the preparation of increase Ito channel protein.
7. purposes as claimed in claim 6, is characterized in that, described Ito channel protein is one or more in Kv4.2 and Kchip.
8. purposes as described in one of claim 1-7, is characterized in that, described product comprises the one in medicine, reagent or food.
9. purposes as described in one of claim 1-7, it is characterized in that its occupation mode comprise be used alone or with other chemical substance conbined usage.
10. purposes as described in one of claim 1-7, is characterized in that consumption is 20mg/kg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510126295.1A CN104688750B (en) | 2015-03-23 | 2015-03-23 | A kind of purposes of polygonin in preparing anti-arrhythmia product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510126295.1A CN104688750B (en) | 2015-03-23 | 2015-03-23 | A kind of purposes of polygonin in preparing anti-arrhythmia product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104688750A true CN104688750A (en) | 2015-06-10 |
| CN104688750B CN104688750B (en) | 2018-09-11 |
Family
ID=53336576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510126295.1A Expired - Fee Related CN104688750B (en) | 2015-03-23 | 2015-03-23 | A kind of purposes of polygonin in preparing anti-arrhythmia product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104688750B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110478363A (en) * | 2019-08-22 | 2019-11-22 | 北京大学 | The new medicine use of cIMP |
-
2015
- 2015-03-23 CN CN201510126295.1A patent/CN104688750B/en not_active Expired - Fee Related
Non-Patent Citations (5)
| Title |
|---|
| X-Y ZHAO等: "Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo", 《BRITISH JOURNAL OF PHARMACOLOGY》 * |
| 付国通等: "绣球提取物虎杖苷抗心律失常和抗心肌缺血的作用", 《哈尔滨医科大学学报》 * |
| 吴东: "浆果中活性多酚的生物功能", 《科技信息》 * |
| 王涛等: "白藜芦醇对豚鼠心室肌细胞钾离子通道的影响", 《哈尔滨医科大学学报》 * |
| 陈西敬: "《药物代谢动力学研究进展》", 30 September 2008 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110478363A (en) * | 2019-08-22 | 2019-11-22 | 北京大学 | The new medicine use of cIMP |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104688750B (en) | 2018-09-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Huang et al. | The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest | |
| KR20080034154A (en) | Medicinal composition containing ginseng secondary glycosides, its preparation method and application | |
| CN101311160B (en) | Method for preparing red sage root salviandic acid A | |
| CN101230003B (en) | Preparation method of salvia miltiorrhiza tanshinoate A | |
| Huang et al. | Antiarrhythmic effects and ionic mechanisms of allicin on myocardial injury of diabetic rats induced by streptozotocin | |
| WO2023065684A1 (en) | Application of sodium caprylate in preparation of drug for improving cardio-pulmonary resuscitation effect and multiple organ dysfunction syndrome after cardio-pulmonary resuscitation | |
| Song et al. | Apoptosis is not involved in the mechanism of myocardial dysfunction after resuscitation in a rat model of cardiac arrest and cardiopulmonary resuscitation | |
| CN102949708B (en) | Application of human sDR5 (soluble death receptor 5) protein or sDR5-Fc (fragment crystallizable) antibody fusion protein as pharmaceutical drugs for myocardial infarction | |
| CN102028700A (en) | Medicinal composition and preparation method thereof | |
| EP2476422B1 (en) | Pharmaceutical compositon comprising timosaponin a-iii and timosaponin b-ii | |
| Wang et al. | Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes | |
| CN101143157A (en) | Tyrosol and tyrosol bypass salidroside plant extraction and preparation and use thereof | |
| CN104688750A (en) | Purposes of polydatin in preparing anti-arrhythmic products | |
| CN101549014A (en) | Heart-protecting musk oral preparation and preparation method thereof | |
| Lu et al. | Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes | |
| CN106466317A (en) | Cepharanthine and its pharmaceutically acceptable salt and solvate are as the application preparing antiarrhythmic drug | |
| CN105012356B (en) | Purposes of the ganoderic acid A in depression | |
| CN104688751B (en) | Purposes of the polygonin in preparing anti-arrhythmia product | |
| CN108939052A (en) | Purposes of the Exenatide in the drug of preparation prevention or treatment atrial fibrillation | |
| CN103385995B (en) | Traditional Chinese medicine compound for treating arrhythmia and preparation method thereof | |
| WO2010009573A1 (en) | A pharmaceutical composition for regulating the potassium channel in cardiac muscle cell and its preparation method and its uses | |
| Hou et al. | Remifentanil functions in the adaptive protection of cardiac function following ischemia | |
| CN104059154B (en) | A kind of new natriuretic peptide chimera C with heart failure resistance effectNAAC | |
| Weerateerangkul et al. | Effects of Kaempferia parviflora Wall. Ex. Baker on electrophysiology of the swine hearts | |
| US11219613B2 (en) | Pharmaceutical composition for preventing and treating liver diseases, containing, as active ingredient, cromolyn or pharmaceutically acceptable salt thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20151124 Address after: 518060 Nanhai Road, Guangdong, Shenzhen, No. 3688, No. Applicant after: Shenzhen University Address before: 518000 room 714, South Medical College, Shenzhen University, Shenzhen, Guangdong, Nanshan District Applicant before: Liu Jie Applicant before: Dong Ming |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180911 |