CN104688750B - A kind of purposes of polygonin in preparing anti-arrhythmia product - Google Patents
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Abstract
The present invention relates to the purposes of Gentrin Knotweed P.E polygonin.Myocardial hypertrophy is then the most important reason for causing heart failure.Ventricular hypertrophy is usually directed to ventricular structure change, i.e. remodeling ventricle.Myocardial remodelling is the complication of many angiocardiopathies, is the important determinant in heart failure evolution.Incidence of arrhythmia improves 28 ﹪ after myocardial remodelling, and cardiac sudden death is finally caused to increase 5 times or more.It tests and shows through in vitro study, polygonin significantly inhibits the reconstruct of the cardiac ion channel caused by mouse ischemic injuries, has stronger protective effect to arrhythmia cordis, thus polygonin can be used for preparing anti-myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia product.In the present invention, polygonin shortens Single Cardiac Cell time-histories (APD), inhibits QT interval prolongations, play antiarrhythmic effect by increasing Transient Outward Potassium Current (Ito) current density.
Description
Technical field
The present invention relates to application of the active ingredient of Chinese medicine in clinic, a kind of Chinese medical extract i.e. giant knotweed is related generally to
Glycosides (piceid, polydatin) is in the purposes for preparing anti-myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia product.
Background technology
1, arrhythmia cordis
Heart disease has become one of fastest-rising disease of incidence in recent years.Arrhythmia cordis is due to sinoatrial node excitement
Exception or excitement result from other than sinoatrial node, and exciting conduction is slow, blocks or is conducted through abnormal passage, i.e. of cardiomotility
Source and (or) conductive impairment lead to the frequency and (or) allorhythmia of heartbeat.Arrhythmia cordis is important in angiocardiopathy
One group of disease.It can individually fall ill can also occur together with cardiovascular disease.Can break out and cause to die suddenly, also it is sustainable involve heart and
Failure.
Myocardial hypertrophy is then the most important reason for causing heart failure.Ventricular hypertrophy usually obstructs secondary to hypertension and cardiac muscle
Extremely.Ventricular hypertrophy is usually directed to ventricular structure change, i.e. remodeling ventricle.Myocardial remodelling is the complication of many angiocardiopathies,
It is the important determinant in heart failure evolution.Incidence of arrhythmia improves 28 ﹪ after myocardial remodelling, finally causes the heart
Dirty sudden death increases 5 times or more.The patient of chronic cardiac pathologic excess load (e.g., by hypertension, valvular heart disease, chronic ischemia) is fatal
Property arrhythmia cordis risk increase and have the tendency that occur severe heart failure.With the progress of heart failure, property dystopy in room is fought
The dynamic frequency occurred and complexity increase.For a long time, it has been recognized that pathologic ventricular hypertrophy is sudden cardiac death
Independent hazard factor.However, the mechanism for leading to arrhythmia cordis under Chronic Hemodynamics event of overload is very complicated.Even if
There is also different tachycardic mechanism in patient with same pathological change.
Research finds that there are the structures of cardiac muscle cell and electricity to give birth in the cardiac muscle (myocardial hypertrophy and heart failure) of excess load
The reconstruction of reason.No matter myocardial hypertrophy and heart failure caused by what reason, electric the characteristics of reconstructing is that vntricular action potential prolongs
Long (CurrOpinCardiol.2010Jan；25(1):29-36.).For human heart, lengthening of action potential can both go out
Now it may occur in which in endstage cardiac insufficiency again in compensatory myocardial hypertrophy.In ischemic or Ischemic dilated cardiomyopathy and
In other myocardial hypertrophies or heart failure patient between QT the phase it occur frequently that change.And these change, and are often lowered with the channels K+
And Ca2+Based on interior environment constancy changes.
Identical of views at present to think, the important information lowered about the channels K+ comes from recently to ventricular repolarization ion
α subunits (the Kv4.2, Kv4.3) expression of channel Ito is lowered, and the reduction of Ito current densities is made, by extending cardiomyocyte like action electricity
Position, causes long QT syndrome, so as to cause the generation of ventricular arrhythmia.
Previous clinic is to use Cardiac glycosides positive inotropic action drug to the treatment emphasis of myohypertrophia and/or ventricular hypertrophy
And diuretics, often ignore arrhythmia cordis caused by myocardial hypertrophy.The antiarrhymic for clinically using and developing at present
Object according to cardiac electrophysiology influence and mechanism of action classify, four major class can be divided into：I class is sodium channel inhibitor, however can
Generate that serious sinus bradycardia, atrioventricular block, QRS wave are broadening induces new torsades de pointes ventricular arrhythmia etc.
Side effect.II class is beta-blocker, and side effect is severe hypotension, and also plays the role of the phase between extension Q-T.III class
It is the drug that selectivity extends Single Cardiac Cell time-histories (APD) and effective refractory period (ERP), the myocardium potassium of selectivity retardance
The drug of ion channel has side effect similar with I class drug.IV class is calcium channel blocker.I II IV class drugs have drop
Low to pass to speed or even cause the effect for passing to retardance, these effects can increase the possibility of reciprocal excitation, and induce rhythm of the heart mistake
Often.III class drug has no significant effect self-disciplining.
2, giant knotweed
Giant knotweed originates in East Asia Region, be distributed in area on the south Hokkaido, Japan western part, the Korea peninsula, TaiWan, China and
The ground such as Jiangsu, Jiangxi, Shandong, the Sichuan of China.Mildly bitter flavor, cold nature contain polygonin, flavones etc..Used in the present invention it
Polygonin can extract in conventional manner, such as in the patent of Publication No. CN1546503A (publication date on November 17th, 2004)
Disclosed extracting method.Polygonin aqueous solution used in the present invention is prepared in conventional manner, such as Publication No.
The method disclosed in the patent of CN1709269A (publication date on December 21st, 2005).A concentration of 6-150mg/ml prepared, it is excellent
Select a concentration of 20-100mg/ml, most preferable concentrations 40mg/ml.
In recent years it is found that giant knotweed has good potential applicability in clinical practice, it is increasingly becoming new research hotspot.In ancestral
In the traditional medicine treatment of state, for Chinese medicine due to being taken from natural plants, toxic side effect is few, often has multiple action target spots, and
And with " high person presses down it, and Sinking disorders should be treated with drugs of raising property in the certainly steady regulation and control of body；There is Yu person to damage it, treating deficiency syndrome by tonifying " profoundness.
Polygonin is a kind of monomer extracted in giant knotweed, it is the product that resveratrol is combined with glucose, they belong to
Stilbene compound in giant knotweed ingredient, i.e. hydroxy diphenyl ethylene class compound.Pharmacological research of the polygonin in terms of angiocarpy
Progress includes：
1) polygonin myocardial cell protection acts on.Polygonin is found can substantially reduced murine myocardium virus infection damage
Evil (Song Junhua, Binzhou Medical College's journal 2008,31:95-98).Domestic scholars report that polygonin has the classes such as anti-oxidant, anti-inflammatory
Like the function of resveratrol, and improve effect (the Hebei medicine of heart function and microcirculation disorder caused by haemorrhagic shock
2010,32:1492-1493；ClinHemorheolMicrocirc.2003,29:211-217).Currently, giant knotweed glycoside injection liquid exists
The country is currently in IIb phase clinical human conceptual phases, and IIb phase clinical human progress is smooth.It passes through now normal the country
It is 50-40mg/kg with dosage.
2) polygonin antiatherosclerosis.Experiment shows that polygonin can significantly reduce Atherosclerosis in Rabbits mould
The blood fat of type, and aorta and the coronary atherosclerosis course of disease can be alleviated.(Chinese tcm emergency, 2005,14:564-
567) polygonin can also reduce the soft spot quantity of arteria carotis shakiness fixed board block, may there is anti arteriosclerosis (Beijing Chinese medicine
Medicine, 2009,28172-175).
3) polygonin antithrombus formation.Polygonin has in vivo and in vitro to be inhibited on arachidonic acid, adenosine diphosphate (ADP) and kidney
The Platelet Aggregation in Rabbit of parathyrine induction, and inhibition strength weakens (Dan Chunwen, middle traditional Chinese medicines with the reduction of polygonin concentration
Neo-Confucianism report, 1990,11 (6):527).
Invention content
For at present, it is 6%~36% that all antiarrhythmic drugs, which have arrhythmogenic effect, incidence,
Mechanism is got excited with electrocardio to be formed or conductive impairment is related.Easily there are long Q-T interval syndromes after being damaged except myocardial infarction, various
In the drug for causing long Q-T interval syndromes, but most often there is the side effect in antiarrhythmic drug.The purpose of the present invention is to answer
Myocardial infarction arrhythmia cordis is treated with polygonin, the phase between extended Q-T can be significantly reduced, reduce the generation of arrhythmia cordis.
The present invention includes：
Purposes of the polygonin in preparing anti-arrhythmia product.The arrhythmia cordis is myocardial hypertrophy and/or ventricle fertilizer
Caused by thickness, the myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia are caused by hypertension or myocardial infarction.
Polygonin is preparing the purposes in inhibiting long Q-T interval syndromes product.The phase is drawn by myocardial infarction between the long Q-T
It rises.
Polygonin is being prepared for increasing the purposes in Ito channel proteins expression product.The Ito channel proteins are
It is one or more in Kv4.2, Kv4.3 and Kchip.
Polygonin has under the conditions of low dosage (20mg/kg) inhibits myocardial infarction to cause Arrhythmia.
The said goods include one kind in drug, reagent or food, occupation mode include be used alone or with otherization
Agents in combination is learned to use.
The technique effect of invention is as follows：
1, it is selected in numerous treatment arrhythmia cordis, especially myocardial hypertrophy and/or ventricular hypertrophy institute proarrhythmia, drug
A kind of efficient, cheap and safe Chinese medicine is taken, which can raise transient outward potassium, pass through
Shorten Action Potential Duration (APD), to play antiarrhythmic effect.
2, a kind of efficient, cheap and safe Chinese medicine inhibiting long Q-T interval syndromes is provided, the Chinese medicine (tiger
Cane glycosides) by the adjusting to myocardial cell membrane potassium-channel, the process of repolarization of cardiac muscle cell AP is adjusted, APD is shortened, inhibits length
The generation of QT interval syndromes.
3, a kind of efficient, cheap and safe Chinese medicine for the protein expression dramatically increasing the channels Ito is provided, it should
Chinese medicine (polygonin) has inhibiting effect to myocardial cell membrane Transient Outward Potassium Current (Ito) electric current, dramatically increases the egg in the channels Ito
White expression.
4, a kind of low dosage concentration used is provided, 20mg/kg has antiarrhythmic effect under the concentration.
Description of the drawings
Fig. 1 is the electrophoretogram for the protein expression for indicating Ito subunits Kv4.2 and Kchip.
Specific implementation mode
1. material and method
1.1 material
1) polygonin used in the reagent present invention is provided by Hai Wang Pharma Inc.s of Shenzhen, and the specific method is as follows：
Giant knotweed rhizome 100g, it is appropriate to crush, it is extracted with 800ml ethanol percolations, filtering, be concentrated under reduced pressure (50 DEG C, 0.07-
0.1Mpa) to final volume 50ml, 100ml water is added, and extract 3 times with 200ml vinyl alcohols, extract liquor reduced pressure (50 DEG C,
0.07-0.1Mpa) to 150ml, Silon stirring, decompression volatilizes solvent, spare as loading sample.
Loading sample is used a dry method on a sample in (cylinder about 600ml) on spare polyamide column, successively with 1000ml water,
3000ml30% ethanol waters are that mobile phase carries out chromatographic elution, and flow velocity 600ml/hr collects 30% ethyl alcohol water elution efflux, and
It will wherein fraction containing polygonin merge, and be concentrated under reduced pressure into 100ml (60 DEG C, 0.07-0.1Mpa), filter, obtain product 2g, wherein
Determination of Polydatin is 84%.
Head product is dissolved with 95-100% ethyl alcohol, and filtering, filtrate adds water to containing alcohol final concentration 30%, and 1% (ml/ml) is added
Medical active carbon dust boils 3 minutes, filters while hot, and filtrate decompression is concentrated into 50ml, and 0.5 hour crystallization is stood at 4 DEG C, filtering,
Gained crystal is dried in vacuo 4 hours (100 DEG C, 0.08-0.1Mpa, phosphorus pentoxide drier), obtains final product polygonin 1.5g,
Contain polygonin 99.82% through HPLC detections.
Gained polygonin is made into polygonin aqueous solution, a concentration of 40mg/ml.The specific method is as follows：Polygonin 11g, the third two
Alcohol 18ml, ethyl alcohol 116ml, pure water 200ml, 40 DEG C of ultrasonic dissolutions, 0.45um filtering with microporous membrane, be packed as 100 it is spare.Make
Used time concentrates or is diluted to aimed concn.
2) Animals Male C57 mouse, weight 25-30g are provided by Guangdong Province's Experimental Animal Center, totally 60, are randomly divided into
Sham-operation group, operation group and treatment group, every group of 20 mouse.Sham-operation group is only threaded when being ligation and is not ligatured；Operation group is scarce
Blood Reperfu- sion group；Treatment group is ischemia-reperfusion and gives polygonin gavage treatment group.
3) liquid (mM) in operation of recording potential electrode：KCl 140、MgCl2 1、K2ATP 5, Hepes 5, Glucose 10,
KOH adjusts pH to 7.4, and 0.22 μm of filtering with microporous membrane dispenses -20 DEG C and saves backup.
Record ItoThe preparation (mM) of electric current extracellular fluid：NaCl 126, KCl 4, MgCl22.5, Hepes5, dextrose
5.5, CdCl20.3, MnCl22, TEACl 20 (7.3 with NaOH of pH).
1.2 method
1) experiment packet
It is preoperative to give atropine 0.01mg/kg intramuscular injection, with 2% without barbital sodium 60mg/kg, through intraperitoneal injection fiber crops
It is liquor-saturated.After anaesthetizing successfully, trachea cannula maintains normal respiratory rate (130-150 beats/min) and tidal volume using toy lung ventilator
(150-200 ml/mins).Upper limb flushes and rejects chaeta on the left of place, alcohol disinfecting, and 0.5-1.0cm levels are done at suprasternal notch
Notch detaches crust.Left side pectoralis major and musculus pectoralis minor are cut, is opened, artery clamp is fixed.Thoracic cavity is opened by the 2nd, 3 intercostal, it is seen that
White thymus gland is carefully found by center edge portion on thymus gland, is found at the arch of aorta down, ophthalmic tweezers threading.No. 26 pillows are enclosed,
Positive and negative surgeons' knot knots, and syringe needle is fetched, to achieve the purpose that the constriction arch of aorta.Suture.Except sham-operation group and model group use
Physiological saline gavage, treatment group are treated using the dosage row gavage of 20mg/kg, and second day after operation starts, once a day.Continuously control
It treats 4 weeks (28 days).
2) exercise stress test
The mouse test treadmill provided using Beijing Zhi Shuduobao biotechnologies Co., Ltd, in the 4th weekend of experiment
(the 28th day) allows three groups of mouse to enter treadmill in batches, and treadmill speed is 15 ms/min, and the running time is 10 minutes.Finish the record heart
Electrograph (phase between QT), ultrasound detection heart function leave and take serum, and cardiac muscle cell's protein extraction detects Ito protein contents, separately detaches the heart
Myocyte detects AP, records Ito functions.
3) electrocardiographic recorder and QT QT dispersions (AD companies electrocardiographicrecorder recorder) measure：
Human body crosslinking electrode placement location is simulated, animal foot and front subcutaneously 12 leads of record are inserted into using needling electrode
Electrocardiogram.12 lead electrocardiogram are recorded after preoperative and 7 days postoperative, same lead continuously measured for 3 cardiac cycle
It is averaged the phase between measuring QT, phase measurement is from QRS starting points (such as without Q waves, then with R waves starting point) to T wave terminals between QT.It measures different
Lead longest QT (QTmax) and most short QT (QTmin), the QT (QTc) of heart rate correction is with Bazzets formula corrections, QT=QT/
(R-R)1/2, the QT QT dispersions QTcd=QTcmax-QTcmin of heart rate correction.
4) Heart Brightness Mode Function detection：
It is fixed on operation panel after mouse anesthesia, instrument is using dimension 2000 toy Ultrasound Instruments of victory.Take short axle B ultrasound and M super,
Every mouse distinguishes Blind Test 3 times, is averaged, and calculates left ventricular ejection fraction (LVEF) and evaluates heart function.
5) cardiac muscle cell detaches
Anesthesia is abundant, opens chest rapidly and takes out heart, is put into 0 DEG C of calcium liquid and washs, isolate aorta, use is ready
No. 7 syringe needles for being connected in 10ml syringes be gently inserted into aorta, fix aorta with surgical thread, will be on Langendorff pipes
Threeway is opened, and liquid outflow is connected to No. 7 syringe needles of fixed heart on Langendorff pipes, with there is calcium liquid perfusion, is added
Without calcium liquid, until cardiac arrest, stops jumping latter 10~20 minutes and the clostridiopetidase A prepared in advance and albumin mixed liquor is added, greatly
When about 30min hearts lighter, quality soften, a little right side myocardium tissue is taken to be put into krebs solution, when thering is cell to get off,
Residual myocardium tissue is removed, surrounding tissue is gently cut with scissors, not cut, then tissue is put into krebs solution and uses suction pipe
Piping and druming, cell gets off when piping and druming, and organize it is opposite keep intact form relatively good, blown and beaten cell, residue tissue is thrown away, cardiac muscle
Cell is stored in krebs solution.For use mouse cardiac myocytes digest duration about at 30~50 minutes after stablizing one hour.
6) Ito Function detections (full cell pattern record membrance current)
Experiment glass microelectrode microelectrode draws five steps of instrument point and draws, then is polished operation, and tip diameter is
0.5-1μm.The magnetic bead of CD8 antibody processing is added in cell transfecting afterwards for 24 hours, is placed in incubator and is incubated 30min, magnetic bead is using preceding with containing
The PBS liquid cleaning of 0.6%FBS is for several times.The cell (as transfecting successful cell) for being stained with several magnetic beads on cell membrane is selected to carry out
Electro physiology is tested.Cell incubation liquid uses tyrode, electrode to charge electrode solution.Electrode is slowly immersed in cell by operation narishige
External solution imposes a little positive pressure before entering liquid level, to prevent the sundries in liquid from blocking eletrode tip.After electrode enters water, measuring electrode
Impedance is 2-5M Ω proper (resistance is excessive or the too small formation for being unfavorable for full cell and rupture of membranes success rate is caused to decline).
It takes under voltage clamp and returns to zero under whole-cell recording technique mode, carry out fast capacitance compensation after forming Ω grades of high resistance seals of G, then
Slightly controlled underbalance forms duct after rupture of membranes in the plasma membrane of electrode sealing-in, form high resistance seals.What operation had been set
Protocol is to give different voltage stimulations, and current signal is guided through Ag-AgCl electrodes, using Axon companies of U.S. patch-clamp
Amplifier Axopatch 200B are filtered (frequency 2kHz), use Clampex 7.0 acquisition channel electricity for (22~25 DEG C) at room temperature
Stream makees off-line analysis after being stored in computer.
7) AP detects (operation of recording current potential under full cell pattern)
After forming full cell sealing-in, after liquid in electrode and intracellular fluid balance 3-5min, the wide 1ms of wave, frequency are set
1Hz is stimulated with the square wave of 800pA, 5ms, induces the generation of action potential.Pulse continued stimulus 10 times, stimulus intervals 1s.Arteries and veins
It rushes signal to be controlled by clamp softwares, passes through the micro- electricity of glass of liquid in Ag-AgCl wire electrodes and filling electrode after amplifier amplifies
Pole imports cell, and the current signal of generation is converted through amplifier and is stored in hard disc of computer, and the various of action potential are analyzed
Parameter, including resting potential (RP), overshoot (OS), amplitude of action (APA), 50% (APD of repolarization50) and 90%
(APD90) time.
2. experimental result
After 2.1 aorta arch constrictions are preoperative and 28 days postoperative, the variation of each group QTcd is as shown in table 1 after load test,
Before cardiac aorta bends Constriction, the more equal no significant difference (p of QTcd between 3 groups of animals>0.05).Ischemia group is after surgery compared with art
Preceding QTcd significantly increases (p<0.05), postoperative loose group also significantly increases (p compared with control group QTcd>0.05).Giant knotweed treatment group art
28 days QTcd slightly increase afterwards, but not statistically significant (p>0.05).Postoperative giant knotweed treatment group QTcd is also significantly less than loose group
(p<0.05).Prompt giant knotweed treatment can be obviously shortened the phase between QTcd.
1 polygonin of table bends mouse aorta the influence (x ± s, ms) of constriction preoperative and postoperative QT dispersions
| Group | It is preoperative | Postoperative (28 days) |
| Sham-operation group | 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 groups are preoperative, #p<0.05vs sham-operation groups are postoperative and polygonin treatment group is postoperative
2.2 ultrasonic heart function results show that none is dead for postoperative 40 mouse of aorta arch constriction, survival for postoperative 28 days
Rate is 100%.By preoperative and postoperative 28th day ultrasound Evaluation, loose group mouse heart is prompted heart eccentric hypertrophy occur,
And decline with apparent heart function, Left Ventricular Ejection Fraction drops to 38% ± 3 (P by preoperative 52% ± 2<0.05)；It is left simultaneously
Ventricle obviously expands, and left room end-diastolic diameter is extended to (3.57 ± 0.44) mm (P by (2.84 ± 0.13) mm<0.05) it, shrinks
Last diameter is extended to (4.31 ± 0.07) mm (P by (3.49 ± 0.14) mm<0.05).Compared to loose group, polygonin obviously changes
Kind left ventricular cardiac function (postoperative postoperative 38% ± 3, the p of 53% ± 2vs hypertrophys group of Left Ventricular Ejection Fraction<0.05), meanwhile, left room diastole
Last 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) there is different degrees of improvement (see the table below 2).
2 polygonin of table is to the influence (x ± s) with postoperative 28 days every parameters of left ventricular function before mouse aorta bow Constriction
Note：*p<0.05vs hypertrophy groups are preoperative and sham-operation group is postoperative, #p<0.05vs hypertrophy groups are postoperative, LVEF：Left room is penetrated
Blood fraction
2.3 Ito
It has been reported that when myocardial ischemia, Ito current densities significantly reduce.The following table 3 shows sham-operation group, loose group and tiger
The Ito current densities of Zhang Gan treatment groups.The result shows that three groups of preoperative Ito current densities compare no significant difference (P=
0.234).And the loose postoperative Ito current densities of group are substantially less than sham-operation group.In+60mV, sham-operation group, loose group and tiger
The preoperative Ito current densities of Zhang Gan treatment groups are respectively (11.1 ± 1.0) pA/pF (n=27), (10.9 ± 1.1) pA/pF (n=
, and (10.6 ± 1.2) pA/pF (n=29, P=0.14vs sham-operation group) 24).And sham-operation group, loose group and tiger when+60mV
The postoperative Ito current densities of Zhang Gan treatment groups are respectively (10.4 ± 0.8) pA/pF (n=31), (5.2 ± 0.3) pA/pF (n=
33, P<0.05vs sham-operation groups), and (8.9 ± 0.7) pA/pF (n=35, P<0.05vs hypertrophys group).The results show that giving tiger
Ito current densities can be dramatically increased after cane glycosides.
3 polygonin of table is to rat aorta bow Constriction preoperative and postoperative Ito current detectings (+60mV)
Note：*p<0.05vs hypertrophy groups are preoperative and sham-operation group is postoperative, #p<0.05vs hypertrophy groups are postoperative, LVEF：Left room is penetrated
Blood fraction
2.4 AP
If table 4-6 is shown, sham-operation group, loose group and polygonin treatment group AP.Preoperative to three groups and postoperative AP multipoles
The time-histories of 20% (APD20), APD multipoles 50% (APD50) and multipole 90% (APD90) carries out statistical analysis, and three groups preoperative
APD20, APD50 and APD90 relatively without significant difference (P=0.145).Sham-operation group postoperative APD20, APD50 and
APD90 is respectively (3.2 ± 0.2) ms, (8.7 ± 0.6) ms and (31.2 ± 2.8) ms (n=20), and hypertrophy organizes postoperative APD20,
APD50And APD90Significantly extend compared with sham-operation group, respectively (4.9 ± 0.3) ms (P=0.00vs sham-operation groups), (12.2 ±
1.1) ms (P=0.00vs sham-operation groups) and (45.1 ± 2.7) ms (P=0.01vs sham-operation groups), n=40.And polygonin is controlled
Looser group for the treatment of group postoperative APD20, APD50 and APD90 significantly shortens, respectively (4.0 ± 0.5) ms (P<0.05vs is loose
Group), (9.8 ± 0.8) ms (P<0.05vs hypertrophys group) and (34.2 ± 3.4) ms (P<0.05vs hypertrophys group), n=35.And three groups
Resting membrane electric potential (RMP) be respectively (- 78.3 ± 0.6) mV, (- 79.8 ± 0.3) mV and (- 78.4 ± 0.5) mV, three groups are compared
There is no notable significant difference, P=0.219.The results show that can significantly shorten AP time-histories after giving polygonin.
4 polygonin of table is to rat aorta bow Constriction preoperative and postoperative AP20Detection
| Group | It is preoperative | Postoperative (28 days) |
| Sham-operation group | 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 groups are preoperative and sham-operation group is postoperative, #p<0.05vs hypertrophy groups are postoperative, LVEF：Left room is penetrated
Blood fraction
5 polygonin of table is to rat aorta bow Constriction preoperative and postoperative AP50Detection
| Group | It is preoperative | Postoperative (28 days) |
| Sham-operation group | 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 groups are preoperative and sham-operation group is postoperative, #p<0.05vs hypertrophy groups are postoperative, LVEF：Left room is penetrated
Blood fraction
6 polygonin of table is to rat aorta bow Constriction preoperative and postoperative AP90Detection
| Group | It is preoperative | Postoperative (28 days) |
| Sham-operation group | 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# |
Note：*p<0.05vs hypertrophy groups are preoperative and sham-operation group is postoperative, #p<0.05vs hypertrophy groups are postoperative, LVEF：Left room is penetrated
Blood fraction
2.5 Ito subunits Kv4.2 and Kchip expression are as shown in Figure 1, extract cardiac muscular tissue's albumen, western after 28 days
Blotting detects the protein expression of α and β the subunits Kv4.2 and Kchip in the channels Ito.Cardiac muscle cell's weight caused by myocardial hypertrophy
Structure, wherein it is mainly shown as the significant decrease of the expression of Ito protein subunits, but it is interesting that polygonin treatment, can significantly change
It is apt to the reduction of this expressing quantity, increases Kv4.2 and Kchip protein contents.
LVH in figure:Left ventricular hypertrophy refer to left ventricular hypertrophy.
4. discussing
It is one of very high disease of current lethality that myocardial hypertrophy and/or ventricular hypertrophy, which cause heart failure,.Although current
Treatment has significantly improved the prognosis of patients with heart failure, but the death rate in 1 year is still up to 20%.Wherein there is 50% patient dead
In sudden cardiac death, compared to other reasons, heart failure sudden death rate is up to 6-9 times.Cardiac muscular tissue dissects and weight functionally
Cardiac electrophysiology can be changed in modeling.The atrium and ventricle myocyte of past studies have shown that myocardial hypertrophy or patients with heart failure deposits
In different degrees of electrophysiological change (Curr Opin Cardiol.2010Jan；25(1):29–36.).
It is well known that voltage gated potassium channels (KV) lifting in the formation of Single Cardiac Cell (AP) repolarization
It acts on, the extension of AP repolarizations causes LQT syndromes.It is compared with normal myocardial cells, loose cardiac muscle cell shows early stage
The extension of repolarization AP, so as to cause the generation of frequent arrhythmia cordis.At the same time, the cardiac muscle cell of heart failure can express out potassium
The downward of ionic current.The molecular mechanism lowered from current studies have shown that Ito may be multifactor.Experiment proves, in the heart
In the pathophysiological mechanism of myohypertrophia heart failure, the downward performance (Circ the most apparent of transient outward potassium (Ito)
Res.1993；73:379–385.；Circulation.2006；113:345–355).The Stationary Water pancake of Kv4 potassium channels mRNA
The low downward with Ito is highly relevant.In the research of canine model, the downward of Ventricular Tachycardia simultaneous Ito expression,
Participation mechanism may be and Ca2+Protein kinase ii (CaMKII) access and calcineurin/NFAT that/calmodulin relies on
Access is related.(Circ Res.2008；103:733–742)
For arrhythmia cordis after myocardial hypertrophy and/or ventricular hypertrophy and sudden cardiac death be always clinical position emphasis and
How difficult point selects the drug of with strong points, Small side effects, highly effective and safe to be still although there are many antiarrhythmic drug at present
Still unsolved clinical problem.For after myocardial infarction arrhythmia cordis prevent research with and subsequent several clinical tests accuse
Failure, promotes clinician it is further recognized that selecting the importance and urgency of rational antiarrhythmic drug.
This result of study shows that the postoperative QTcd of aorta arch constriction is significantly increased, it is easy to induce Ventricular Tachycardia, the heart
Fatal arrhythmias such as room trembling, and polygonin treatment can be obviously shortened QTcd improve room and quiver domain, steady so as to increase electrocardio
It is qualitative, reduce the easy hair tendency of the fatal arrhythmias such as Ventricular Tachycardia, ventricular fibrillation.Meanwhile experimental result is shown
Kv4.2 albumen increases, and prompts polygonin treatment that can dramatically increase the α subunits (Kv4.2) of ventricular repolarization ion channel Ito
Expression makes Ito current densities increase, and by shortening Single Cardiac Cell, improves heart function.Our experimental result is also propped up
This is held it is assumed that polygonin treatment can be obviously improved left room shortening rate and Left Ventricular Ejection Fraction.In experimentation, tiger is not found temporarily
The ill-effect of other antiarrhythmic drug proarrhythmias of cane glycosides causes the rhythm of the heart in prevention myocardial hypertrophy and/or ventricular hypertrophy
Not normal its unique effect of display.
Claims (3)
1. polygonin is preparing the purposes in inhibiting long Q-T interval syndromes product, wherein the phase is by myocardium fertilizer between the long Q-T
Caused by big and/or ventricular hypertrophy, wherein polygonin dosage is 20mg/kg.
2. purposes as described in claim 1, which is characterized in that the product includes one kind in drug or reagent.
3. purposes as described in claim 1, it is characterised in that its occupation mode includes being used alone or joining with other chemical substances
It closes and uses.
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