CN106466312A - Application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for the Vitamin E - Google Patents
Application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for the Vitamin E Download PDFInfo
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- CN106466312A CN106466312A CN201510508034.6A CN201510508034A CN106466312A CN 106466312 A CN106466312 A CN 106466312A CN 201510508034 A CN201510508034 A CN 201510508034A CN 106466312 A CN106466312 A CN 106466312A
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- reperfusion
- arrhythmia
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Abstract
The present invention discloses a kind of application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for Vitamin E, belongs to pharmaceutical field.The result of the present invention shows that Vitamin E has ischemia resisting Reperfu- sion and leads to ARR effect, Vitamin E is used for QT interval prolongation and related ARR medicine after preparation preventing and treating heart ischemia reperfusion, this kind of medicine is that action target spot is clear and definite, the medicine of QT interval prolongation after new ischemia resisting Reperfu- sion known to molecular structure.Prove that this kind of medicine can reduce the QT interval prolongation that ischemia-reperfusion causes by isolated heart ischemia-reperfusion injury model, you can to reduce the risk that related arrhythmia occurs.
Description
Technical field
The present invention relates to Vitamin E is in the new application of pharmaceutical field, relate in particular to Vitamin E in preparation
Application in the antiarrhythmic medicament of prevention and/or treatment ischemia-reperfusion induction.
Background technology
Incidence of CHD rises year by year and is in rejuvenation trend in recent years, acute myocardial infarction (Acute
Myocardial infarction, AMI) it is a coronary heart disease type the most serious, China every year nearly million
Patient dies from acute myocardial infarction, and therefore, this disease is considered " human health first killer ".Acute myocardial
The maximally effective remedy measures of infarction are to realize filling again completely of cardiac muscular tissue on the basis of coronary artery is opened
Note, that is, realize Myocardial Microcirculation Reperfu- sion.The treatment meanss commonly used at present include thrombolytic method and coronary artery is situated between
Enter surgical therapy.But, after thrombolytic method and coronary intervention procedure treatment, often result in ischemia-reperfusion
Damage.How to prevent and treat ischemical reperfusion injury and improve cardiac muscular tissue's Reperfu- sion and become urgent need to solve the problem.
Myocardial ischemia reperfusion injury is an extremely complex pathophysiological change process, except leading to cardiac muscle
Infarct size increase, myocardial cell injury and ventricle myonecrosis, also result in serious arrhythmia, or even
Lead to cardiac sudden death.Research shows that QT interval prolongation can increase ARR incidence rate, so this can be adopted
The risk that individual index evaluation arrhythmia occurs.Clinic does not have effective medicine to be used for treating Ischemia Reperfusion at present
The arrhythmia of note induction, and conventional antiarrhythmic drug usually has arrhythmogenic effect.
Content of the invention
In order to overcome shortcoming and the deficiency of prior art, it is an object of the invention to provide a kind of Vitamin E exists
Application in the antiarrhythmic medicament of preparation prevention and/or treatment ischemia-reperfusion induction.
The purpose of the present invention is achieved through the following technical solutions：
The present invention provides a kind of Vitamin E in the arrhythmia of preparation prevention and/or treatment ischemia-reperfusion induction
Application in medicine.
Described arrhythmia is room property, room or sinus arrhythmia；
Described arrhythmia is the arrhythmia with QT interval prolongation；
Described arrhythmia can also be that the rhythm of the heart that the diseases such as diabetes, myocardial hypertrophy or hypertension cause loses
Often；
By reducing, active oxygen plays prevention to described Vitamin E to the suppression of hERG electric current and/or treatment is made
With；
Described Vitamin E can be made tablet, injection or suck preparation；
Described Vitamin E can be administered orally, intravenous injection, intramuscular injection or transpulmonary inhalation mode；
Described Vitamin E can also make combination with other medicines or food, answering for medicine for treatment thing
With.
A kind of composition of medicine or food, comprise Vitamin E.
The present invention, with respect to prior art, has such advantages as and effect：
(1) research shows that Vitamin E can reduce the area of infarcted myocardium, thus play protection to heart making
With.But Vitamin E causes QT interval prolongation and related ARR treatment or prevents to ischemia-reperfusion
Effect, is not reported so far.
(2) present invention is directed to the problems referred to above and finds that Vitamin E has ischemia resisting Reperfu- sion and leads to the heart through research
Restrain not normal effect, Vitamin E is used for QT interval prolongation and phase after preparation preventing and treating heart ischemia reperfusion
Close ARR medicine, this kind of medicine is that action target spot is clear and definite, and new ischemia resisting known to molecular structure is again
The medicine of QT interval prolongation after perfusion.Prove that this kind of medicine can subtract by isolated heart ischemia-reperfusion injury model
The QT interval prolongation that few ischemia-reperfusion causes, you can to reduce the risk that related arrhythmia occurs.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to
This.
Cause the effect examination of QT interval prolongation after embodiment 1 Vitamin E anti-isolated guinea pig heart ischemia-reperfusion
Test
Method：In pre-operative preparation operating theater instruments, alcohol-pickled overnight with 75% (v/v).Prepare K-H
After solution, take and pour in glass culture dish in right amount, and glass culture dish is placed on (4 DEG C about) on ice, fill
Oxygen.Give 0.5mL 1% (m/v) heparin, after 20～30min, lumbar injection using lumbar injection mode
5% (m/v) pentobarbital sodium (0.2mL/100g) anaesthetizes, after deep anaesthesia, by Cavia porcelluss (Guinea pig)
(adult regular grade hartly Cavia porcelluss, purchased from Traditional Chinese Medicine University Of Guangzhou's Experimental Animal Center) facing upward is placed in operating-table
On, use medical adhesive tape fixing limbs, cut off skin to xiphoid-process along front wall center, with the steady xiphoid-process of clamp that stops blooding,
Quickly open breast and expose heart and blood vessel, clamp heart root with tweezers, cut off superior and inferior vena cava, pulmonary artery, master
Tremulous pulse and heartsurroundings, take out heart, aortic root stay 0.5cm about length in case intubation use.
Heart is immediately placed in the cold K-H liquid that oxygen saturation in advance was processed after taking out, and gently presses ventricle with profit with finger
In the discharge wherein lefting in blood.Inject the cold K-H liquid that oxygen saturation was processed with syringe from aortic root,
On the one hand cardiac arrest can be made thus reducing energy expenditure, on the other hand can be by rinsing coronary vasodilator, clearly
Except residual flow blood thus avoiding the formation of little sludged blood blocking blood vessel.Heart is shifted rapidly, drives in the wrong direction through aorta and insert
Pipe, is clamped with bulldog clamp, is ligatured and be fixed on power Lab heart Langendorff with 3-0 operation silk thread
On perfusion device (Australian AD company, model ML176-220), carry out conventional constant speed (10 with K-H liquid
ML/min) perfusion, keeps perfusate temperature constant to be 37 DEG C, and fills 95% (v/v) O2+ 5% (v/v)
CO2Saturation.Electrocardiogram recording device is connected, according to the isolated heart electrocardiographic recorder method of document description,
It is attached to heart surface using three filamentary silvers, in the apex of the heart, in right auricle, ground wire is at aortic root for negative pole for positive pole.
Cardiac perfusion first stablizes 20min after starting, and then stop perfusion making heart cause global ischemia, after 30min again
Perfusion, normal group Reperfu- sion 30min.Vitamin E group irrigates containing 200 μM of dimension lifes after Reperfu- sion 15min
The K-H liquid perfusion of plain E.All recorded heart rate and electrocardiogram in whole process.Power Lab is passed through in the collection of signal
Carry windows collection in software Labchart, between QT, the phase adopts ECG Analysis to analyze and process.QTc
Be through heart rate calibration QT between the phase.
Before result shows compared to ischemia, after Reperfu- sion, between QT, the phase substantially increases, and gives 200 μM during Reperfu- sion
After Vitamin E, between QT, the phase returns to state before ischemia.Between QT, the phase is 361.10 ± 5.90ms before ischemia,
400.11 ± 7.92ms after Reperfu- sion, gives 368.69 ± 5.99ms after 200 μM of Vitamin E during Reperfu- sion.
Specifically it is shown in Table 1.
Table 1 after ischemia-reperfusion between QT the phase impact
Compared with normal group,**P<0.01；Compared with ischemia-reperfusion group,#p<0.05.
Note：It is same heart own control in table, 6 guinea pig hearts altogether.
Embodiment 2 Vitamin E reduces ischemia-reperfusion to IKrThe suppression of electric current (hERG correlated current) is made
With test
Myocardial cell separation method：Take out cardiac component and see embodiment 1, after taking out heart, find aorta,
Aorta is enclosed within sleeve bottom, is careful not to be inserted through aortic valve, and is tightened with stitching thread.With no calcium Tai Shi
Liquid perfusion 4～5min, pumps out blood stains, so that the blood of heart is completely exhausted out.Then with 95% (v/v) O2+ 5%
(v/v)CO2Oxygen-saturated 15mL 0.4mg/mL II Collagenase Type (worthington) enzyme liquid circulates perfusion.
Check continually on cardiac stiffness, drip a small amount of 0.4mg/mL II Collagenase Type enzyme liquid after heart deliquescing in inverted microscope
Under seen whether myocardial cell, have in the visual field and cut ventricular section at once during several myocardial cell, fresh
In 10mL 0.4mg/mL II Collagenase Type (worthington), heart is shredded, and in 37 DEG C of water-baths gently
Piping and druming, makes cell accelerate to separate, and is filtered with 250 μm of cell sieve, inhaled filtrate with suction pipe after piping and druming 5min
To 15mL round bottom centrifuge tube, it is centrifuged (500rpm, 1min), gives up supernatant.Add and contain 50 μM of calcium
Tyrode's solution re-suspended cell, treats cell natural subsidence, is added sequentially to containing 200 μM of Ca2+, 500 μM of Ca2+With
1mM Ca2+Tyrode's solution in multiple calcium, obtain the myocardial cell of resistance to calcium；Finally cell is resuspended in M199 culture medium
In and in CO2In incubator, culture treats that cell attachment (adds laminin (sigma) to promote cell patch in culture dish
Wall) cell attachment can be used for patch clamp experiments after 1h.Adherent stand-by myocardial cell is placed in 35mm's
In culture dish, add 2mL ischemia liquid simulated ischemia process, in ischemia liquid, be separately added into 1,5-anhydroglucitol (sugar
Zymolysis inhibitor, sigma), lactic acid (simulation lactic acid is piled up, Aladdin), pH is adjusted to 6.5 simulation acid
Poisoning, adds 1mM sodium dithionite (sigma) and causes anoxia with ParafilmTM culture dish, put
In 37 DEG C of incubators, ischemia, after 1 hour, is washed 2 times with normal tyrode's solution, adds 2mL tyrode's solution to fill again
Note 15min, Patch-clamp experiments to be done.Using whole-cell patch-clamp voltage-clamp mode record Cardiac myocytesKrElectricity
Stream, result shows, ischemia-reperfusion is to IKrElectric current has significant inhibitory action.I before ischemiaKrTail current is close
Spend for 1.44 ± 0.06pA pF-1, I after ischemia-reperfusionKrTail current density is 0.52 ± 0.04pA pF-1, then
After adding 100 μM of Vitamin E during perfusion, IKrElectric current density is 0.94 ± 0.09pA pF-1.Filling again simultaneously
After note gives 10 μM of comparison medicines mitochondrion ROS scavenger Mito-tempo (sigma), IKrElectric current also increases,
Its electric current density is 0.97 ± 0.08pA pF-1；Specifically it is shown in Table 2.Add exogeneous reactivity oxygen (reactive
Oxygen species, ROS) composition hydrogen peroxide carries out pretreatment 10min to myocardial cell, recycles entirely thin
Born of the same parents' patch-clamp voltage-clamp mode record Cardiac myocytesKrElectric current, finds IKrElectric current is also suppressed, and inhibition level
Suitable with ischemia-reperfusion inhibition level；Specifically it is shown in Table 3.
Table 2 is to I after ischemia-reperfusionKrThe impact of electric current
Compared with normal group,**P<0.01；Compared with ischemia-reperfusion group,#p<0.05.
Table 3 hydrogen peroxide pretreatment is to IKrThe impact of electric current
Compared with normal group,**P<0.01.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not subject to above-mentioned reality
Apply the restriction of example, the change made under other any spirit without departing from the present invention and principle, modification,
Substitute, combine, simplify, all should be equivalent substitute mode, be included within protection scope of the present invention.
Claims (8)
1. Vitamin E answering in the antiarrhythmic medicament of preparation prevention and/or treatment ischemia-reperfusion induction
With.
2. according to claim 1 application it is characterised in that：Described arrhythmia is room property, room
Property or sinus arrhythmia.
3. according to claim 1 application it is characterised in that：Described arrhythmia is with QT
The arrhythmia of interval prolongation.
4. according to claim 1 application it is characterised in that：Described arrhythmia be diabetes,
The arrhythmia that myocardial hypertrophy or hypertension cause.
5. according to claim 1 application it is characterised in that：Described Vitamin E is lived by minimizing
Property oxygen the suppression of hERG electric current is risen with prevention and/or therapeutical effect.
6. according to claim 1 application it is characterised in that：Described Vitamin E make tablet,
Injection or suction preparation.
7. according to claim 1 application it is characterised in that：Described Vitamin E be administered orally, quiet
Arteries and veins injection, intramuscular injection or transpulmonary inhalation mode.
8. a kind of composition of medicine or food are it is characterised in that comprise Vitamin E.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510508034.6A CN106466312A (en) | 2015-08-18 | 2015-08-18 | Application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for the Vitamin E |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510508034.6A CN106466312A (en) | 2015-08-18 | 2015-08-18 | Application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for the Vitamin E |
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| Publication Number | Publication Date |
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| CN106466312A true CN106466312A (en) | 2017-03-01 |
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| CN201510508034.6A Pending CN106466312A (en) | 2015-08-18 | 2015-08-18 | Application in the antiarrhythmic medicament of preparation preventing and treating ischemia-reperfusion induction for the Vitamin E |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115364115A (en) * | 2022-06-24 | 2022-11-22 | 新乡医学院第一附属医院 | Application of salidroside in preparation of medicine for intervening ischemia reperfusion arrhythmia |
-
2015
- 2015-08-18 CN CN201510508034.6A patent/CN106466312A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 刘岐山等: "维生素E对再灌注心律失常的预防作用", 《中国高血压杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115364115A (en) * | 2022-06-24 | 2022-11-22 | 新乡医学院第一附属医院 | Application of salidroside in preparation of medicine for intervening ischemia reperfusion arrhythmia |
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Application publication date: 20170301 |
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