CN103156842B - Novel application of Arctigenin in preparation of anti-arrhythmia medicine - Google Patents
Novel application of Arctigenin in preparation of anti-arrhythmia medicine Download PDFInfo
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- CN103156842B CN103156842B CN201310073395.3A CN201310073395A CN103156842B CN 103156842 B CN103156842 B CN 103156842B CN 201310073395 A CN201310073395 A CN 201310073395A CN 103156842 B CN103156842 B CN 103156842B
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Abstract
The invention discloses a novel application of a traditional Chinese medicine extract product-Arctigenin in preparation of anti-arrhythmia medicines. A research found that the Arctigenin has bidirectional anti-arrhythmia effect and can adjust arrhythmia caused by aconitine and ouabain. Arctigenin has an effect for reducing ventricular muscle contraction force. A pharmacological effect of the Arctigenin is bidirectional adjusted cardiac muscle cell inner calcium current, the cardiac muscle cell inner potassium current is increased, and the sodium current is inhibited. The invention shows that the Arctigenin has anti-arrhythmia effect, and especially has bidirectional adjusting on arrhythmia, the side-effect is smaller, the Arctigenin has application prospect for treating toxic arrhythmia and ischemic-reperfusion arrhythmia in aconitine and ouabain; and the Arctigenin with myocardial contractility reduction effect can be taken as an auxiliary treatment measurement for hypertensive disease.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract and uses thereof, particularly a kind of known Chinese medicine extract---arctigenin antiarrhythmic purposes.
Background technology
Arrhythmia is commonly encountered diseases, the frequently-occurring disease in cardiovascular disease field, and its mechanism can be summarized as that impulsion forms abnormal, conduction abnormalities or impulsion forms and conduction abnormalities exists simultaneously.
Bibliographical informations such as " arrhythmia Pathogenesis ", in cardiovascular system diseases, arrhythmia is one of the most serious disease.ARR harm is that it not only can increase the weight of original heart disease, as accelerated the progress of heart failure, but also can cause patient's sudden death, serious threat human health.Ischemic heart desease is to bring out chamber speed, the chamber main cause of malignant arrhythmia such as quiver; Heart failure is also the major reason that malignant arrhythmia occurs; Atrial fibrillation is modal chronic sustained arrhythmia, can cause thrombotic disease, increases patient's mortality rate.
The basis of cardiac electric signals conduction is myocardial cell cross-film ion channel current.Myocardial cell sodium, potassium, calcium plasma channel order are opened and kept dynamic equilibrium is the basis of the normal work of heart.Some arrhythmia predisposing factors can, by affecting sodium, potassium, calcium plasma channel function, cause dysequilibrium between ion channel, and myocardial electrical signals conduction disturbance, brings out ARR generation.The ion channel that cardiac muscle is played a major role is the particularly target spots of antiarrhythmic drug effect of most of cardiac drugs.
On myocardial cell membrane, have different kinds of ions passage, these passages are expressed and balancing each other of function is the basis of heart normal function.In the time of the function of certain passage or abnormal expression, interchannel balance is broken, and will occur arrhythmia.
Slow Na
+it is lower that passage activates needed voltage, and the speed of inactivation is slow, participates in maintaining 2 phase platforms of myocardial action potential.This Na+ passage exists in people's ventricular muscle cell, in the time of heart failure, can upwards be regulated.Instantaneous Outward Ito is the main membrane current that participates in heart action potential repolarization, forms the multipole phase of action potential.K
aTPpassage is under normal circumstances in closed condition, once ATP declines in cell, and K
aTPchannel opener, makes cell be tending towards repolarization or hyperpolarization, protecting myocardial cell.Be present in the L-type Ca on myocardial cell membrane
2+passage is initial for the electric reconstruct of cardiac muscle, and in action potential development process, has played vital effect.
The antiarrhythmic drug using clinically at present has with Types Below:
I class medicine---sodium channel blockers
II class medicine---beta-2 adrenoceptor blocker
III class medicine---over reach current potential time-histories medicine
IV class medicine---calcium channel blocker
Aspect arrhythmia, there is obvious individual variation in the sensitivity of medicine, the side effect that some generations are bad, and the medicine of unidirectional therapeutical effect may produce " causing " Arrhythmia.Therefore, be necessary to develop new more effective, the less antiarrhythmic drug of side effect, or even Arrhythmia had to the medicine of two-ways regulation.But, up to now, can affect ion channel, particularly there is the ARR medicine of two-ways regulation also rarely found.
Summary of the invention
The object of the present invention is to provide a kind of known compound---arctigenin is in the new purposes of preparing in antiarrhythmic drug.
Arctigenin
Belong to lignin compound.
Chinese another name: aretigenin
Chemical name: (3R, 4R)-4-[(3,4-Dimethoxyphenyl) methyl] dihydro-3-[(4-hydroxy 3-methoxybenzene base) methyl]-2 (3H)-furanones
English name: Arctigenin (ARC-G)
Molecular formula: C
21h
24o
6
Molecular weight: 372.4117
Chemical constitution:
Known action: the effect such as antiinflammatory and immunomodulating, antiviral, antitumor, antioxidation, blood sugar lowering, protection chemical liver injury, treatment of kidney disease, inhibition heat shock response, neuroprotective, blood vessel dilating, antiplatelet aggregation etc.
Pharmacokinetics: pharmacokinetic characteristic and arctigenin to the absorption of arctigenin mouse GI tract, rabbit vein injection, gavage arctigenin distribute and done research in rat body, experimental result shows that arctigenin is comparatively stable in gastrointestinal tract, transforms, destroys less.The gastrointestinal absorption of arctigenin is first order kinetics process, and the elimination of arctigenin is linear kinetics, rabbit vein injection arctigenin, and its pharmacokinetics behavior meets one compartment model.Within after rat oral gavage arctigenin 24 hours, from urine, discharge original shape thing cumulant and be equivalent to 0.423% of dosage, and mostly in 18h, discharge.Arctigenin is widely distributed in rat body, and in liver, lung, distributed density is higher, is secondly the heart, spleen, kidney etc.Plasma protein binding rate is tested and is shown, arctigenin and the average combination rate of rat plasma albumen are: 78.3%.
Applicant finds in to the further research of arctigenin, arctigenin can reduce the contractility of ventricular muscle cell, decreased heart rate and adjusting intracellular Ca2+ level, suppress myocardial cell sodium current, reduce myocardial cell calcium current, increase myocardial cell transient outward potassium, can reduce that quiver in chamber and the generation of chamber speed, reduce incidence of arrhythmia, therefore, there is antiarrhythmic effect.
So the present invention proposes the new purposes of Chinese medicine extract arctigenin known described in more than one in preparation prevention and treatment antiarrhythmic medicament.
Meanwhile, the present invention gives described known Chinese medicine extract arctigenin in the new purposes of preparing in the alkalotic antidote of Aconitum carmichjaelii Debx.;
Described known Chinese medicine extract arctigenin is in the new purposes of preparing in the poisoning antidote of ouabain.
And, the new purposes of described known Chinese medicine extract arctigenin in the adjuvant therapy medicaments of preparation hypertension.
Advantage of the present invention and beneficial effect:
From applicant's research prompting, arctigenin reduces the contractility of ventricular muscle cell, decreased heart rate effect and intracellular Ca2+ level, suppress myocardial cell sodium current, reduce myocardial cell calcium current, increase myocardial cell transient outward potassium, therefore, arctigenin have antiarrhythmic drug effect its act on similar calcium antagonists, reaching a kind of medicine can affect the effect of different kinds of ions passage simultaneously.This feature of arctigenin is that four class antiarrhythmic medicines of current clinical use are not available.
Arctigenin can be alleviated the ANOMALOUS VARIATIONS of the ion channel of ouabain induction, and the calcium current declining is raised, and recovers the activity of cross-film ion channel, reverses some reconstruct, thus arrhythmia.The ARR mechanism that arctigenin reverses ouabain induction is still not clear, and supposition may be relevant with the multiple effect of arctigenin, comprises and improve inner skin cell function, antiinflammatory antioxidation etc.These effects can damage by reducing upstream, thereby change the characteristic of transmembrane signal transduction path and ion channel, improve the electric physiological stability of myocardial cell.Therefore, we can infer that the antiarrhythmic effect of arctigenin is to realize by the overall manifold effect of heart thus.
Antiarrhythmic drug is mainly limited to the directly blocker to ion channel at present, likely makes myocardial cell ion current occur new imbalance.Arctigenin is that to reduce ion channel damage be point of penetration, the short ARR side effect that does not have traditional antiarrhythmic drug to occur.So the formation of blocking-up and the reconstruct of reverse abnormal electrical, may be used for the treatment of an ARR new compound.
Accompanying drawing explanation
Fig. 1 is the impact that arctigenin shrinks rat myocardial cell, and arctigenin can reduce the contractility of myocardial cell.
Fig. 2 is that the anti-aconitine of arctigenin causes myocardium calcium current increase schematic diagram, and A is normal control; B adds aconitine (1uM) in the perfusate of extracellular; C adds arctigenin (0.1mM) after the outer liquid of cell perfusion adds aconitine again; D is scale.
Fig. 3 is that arctigenin anti-ouabain causes myocardium calcium current reduction schematic diagram, and A is normal control; B adds ouabain (5uM) in the perfusate of extracellular; C adds arctigenin (0.1mM) after the outer liquid of cell perfusion adds ouabain again; D is scale.
Fig. 4 is that arctigenin suppresses myocardial cell sodium current schematic diagram; A is normal control; B adds in the perfusate of extracellular after recording result: C and be eluting arctigenin after arctigenin (0.1mM) 2min; D is scale.
Fig. 5 is that arctigenin increases myocardial cell potassium current schematic diagram; A is normal control; B is transient outward potassium real time record result; C is scale; D is the current-voltage relation figure of transient outward potassium.
Five, the specific embodiment
Below in conjunction with accompanying drawing, the present invention is described in further detail.
Embodiment 1
Applicant patch-clamp measure aretigenin to the experiment of rat myocardial cell ion channel effect in, find arctigenin except known effect, have following effect:
(1) reduce myocardial cell calcium current;
(2) the myocardial cell calcium current reducing due to aconitine increases, the Arrhythmia due to anti-aconitine;
(3) Arrhythmia due to anti-ouabain;
(4) increase myocardial cell transient outward potassium;
(5) suppress myocardial cell sodium current;
(6) weaken contractility and the decreased heart rate of heart;
Therefore, arctigenin is the medicine that will have clinical value a kind of future.
1. the impact of the contractility of the rat myocardial cell of arctigenin on aconitine induction.
Isolated working heart preparation method list of references " aconitine and potassium-channel agonist share the positive inotropic action research to isolated rat heart ", tunk rat headrest portion and cause the dizzy breast taking-up heart of opening immediately, be placed in the plate that fills cold tyrode's solution, find out aorta section, insert aorta sleeve pipe, open infusion pump and start perfusion, perfusate is oxygen-saturated tyrode's solution, perfusate temperature remains on 37 ℃, and perfusion flow is 8-10ml/min.Pacing stimulation electrode is placed in right ventricle, and frequency is 200 times/min.Perfusion l min is by after in ventricle, congestion is rinsed well, one latex water pocket is inserted in left ventricle through left atrium, in water pocket, be full of normal saline, the water balloon catheter other end is connected through pressure transducer Yu Ba road physiograph, in the time of heart contraction, the variation of left indoor pressure can be recorded and measure through eight trace record instrument by the sensing of pressure transducer, sees Fig. 1.0.1mM arctigenin can make the left chamber contractility of Isolated Perfused Rat Hearts weaken.
2. arctigenin is on ARR impact.
36 of SD rats, 20 grams of body weight 200 scholars, male and female half and half, are divided into 3 groups at random, Normal group, aconitine group, arctiin tuple.25% urethane (4ml/kg) is through intraperitoneal injection of anesthesia, and after anesthesia in about 5-7 minute, back of the body position is fixed on operating-table, monitoring standard limbs II lead electrocardiogram.Aconitine (12mg/L) is with intravenous administration under 30g/kg Rat Tongue, and 1min gives, and copies the arrhythmia model of aconitine induction.Arctiin tuple is being given after aconitine according to arctigenin (6mg/kg) tail intravenously administrable.Observe and calculate each group of ARR incidence rate.Data are in table 1, and arctigenin can reduce that quiver in chamber and the generation of chamber speed, reduces incidence of arrhythmia.
The impact of table 1. arctigenin on rat ventricular
N=12,
compared with Normal group
3. the impact of arctigenin on myocardial cell calcium current.
The separation of rat ventricular myocytes: with 25% urethane by rat anesthesia, dorsal position is fixed on Mus platform, from xiphoid-process, open rapidly breast chamber, cut off pericardium and fully expose heart and ascending aorta, open breast and take out heart, being placed in immediately 0 ℃ oxygen-saturatedly has calcium tyrode's solution to prune, retain the aorta of heart the long 0.5-1.0cm that dissociates, after treating that intracardiac blood pumps completely, insert the aorta sleeve pipe of Langendorff perfusion device, and fix with fine rule, under 9-10kPa perfusion pressure, with saturated 37 ℃ of 95%O2+5%CO2 without the continuous perfusion 5min of calcium tyrode's solution 8mL/min, wash away use instead after the residual blood of heart 50mL containing 15mg collagenase II without the calcium tyrode's solution perfusion that circulates.Along with the carrying out of perfusion, it is sticky that effluent becomes, cardiac muscle color shoal gradually, bright, it is large, soft that heart size becomes gradually.Now divide and cut for several times the KB liquid that a small amount of cardiac muscular tissue is placed in 37 ℃ and shred, with the piping and druming repeatedly gently of thick mouthful suction pipe, then use after 100 object screen filtrations, directly put at 4 ℃, refrigerator cold preservation 2h for subsequent use.
Apply full cell patch tongs technology and record rat Cardiomyocytes ion current.Record current under voltage clamp pattern.By be fixed on-50mV of maintenance voltage, command voltage is from-40mV take 10mV as step to+50mV, measures steady-state current value poor of depolarization current peak value and pulse ending place under each command voltage.The size of membrane current is with electric current density, and the membrane current of unit membrane electric capacity represents.Arctigenin can cause myocardium calcium current increase by anti-aconitine, as shown in Figure 2, A is normal control, and B adds aconitine (1uM) in the perfusate of extracellular, C adds arctigenin (0.1mM), scale shown in D after the outer liquid of cell perfusion adds aconitine again; Add aconitine (1uM) intracellular Ca2+ electric current is increased, and continue to add arctigenin (0.1mM), intracellular Ca2+ electric current is declined.Arctigenin can cause myocardium calcium current minimizing by anti-ouabain, as shown in Figure 3, A is normal control, and B adds ouabain (5uM) in the perfusate of extracellular, C adds arctigenin (0.1mM), scale shown in D after the outer liquid of cell perfusion adds ouabain again; Add ouabain (5uM) intracellular Ca2+ electric current is declined, make intracellular Ca2+ electric current no longer continue to decline and continue to add arctigenin (0.1mM).
4. arctigenin suppresses the impact of myocardial cell sodium current.
By the sodium current of whole cell voltage clamp recording rat Ventricular Myocytes.Keep current potential be-90mV, command voltage from-140mV take 10mV as step extremely+50mV.A. normal control; B. in the perfusate of extracellular, add the result that records after arctigenin (0.1mM) 2min: after C. eluting arctigenin; Scale shown in D.Visible when adding after arctigenin in extracellular perfusate in figure, can significantly reduce sodium current.
5. arctigenin increases the impact of myocardial cell potassium current.
With the transient outward potassium of whole cell voltage clamp recording rat Ventricular Myocytes.Form after whole-cell configuration record current under voltage clamp pattern.Extracellular fluid is with 0.3mM CdCl2 blocking-up I
ca-Ldisturb, by be fixed on-70mV of maintenances voltage, experimental voltage jumps take 10mV as step to+60mV from-50mV, pulse persistance 300ms, stimulus intervals time 10s, measure Ito since 0 o'clock the 300ms electric current steady-state value when stimulating end.Electric current electric current density (pA/pF) expression of carrying out standardization according to cell membrane electric capacity.A is normal control; B is transient outward potassium real time record result; C is the current-voltage relation figure of transient outward potassium; Scale shown in D.Visible when adding after arctigenin in extracellular perfusate in B figure, increase potassium current amplitude.
Show from applicant's research, arctigenin can have following potential applicability in clinical practice:
(1) treatment arrhythmia: can be used for treating the arrhythmia that coronary heart disease, heart failure, heart infarction, cardiomyopathy, myocarditis, rheumatic heart disease, endocrine disturbance, anesthesia, low temperature, thoracic cavity or operation on heart, drug effect and central nervous system's disease cause: have different kinds of ions passage on myocardial cell membrane, these passages are expressed and balancing each other of function is the basis of heart normal function.In the time of the function of certain passage or abnormal expression, interchannel balance is broken, and will occur arrhythmia.Arctigenin is by regulating the variation, the particularly two-ways regulation to calcium current of intracellular calcium in rat ventricular myocytes, potassium, sodium ion electric current, and prompting arctigenin has antiarrhythmic effect, but without short Arrhythmia.
(2) treatment aconitine is poisoning: Aconitum carmichjaelii Debx. is one of conventional Chinese herbal medicine, has heart tonifying analgesic effect.In clinical use procedure, often have the alkalotic Case report of Aconitum carmichjaelii Debx., therefore, it is poisoning that arctigenin can be used for the treatment of aconitine in the future.
(3) treatment cardenolide class drug intoxication: ouabain (Ouabain) belongs to cardenolide class material, at Na
+-K
+the alpha subunit of-ATPase is positioned at cell membrane outside 1 Ouabain specific bond site, makes intracellular Na
+and Ca
2+concentration increases, and finally causes calcium overload and after-depolarization, thereby brings out tachyarrhythmia, mainly comprises ventricular tachycardia and ventricular fibrillation.
Claims (1)
1. a known Chinese medicine extract arctigenin prevents and treats the purposes in antiarrhythmic medicament in preparation, described arctigenin Chinese another name is aretigenin, chemistry (3R by name, 4R)-4-[(3,4-Dimethoxyphenyl) methyl] dihydro-3-[(4-hydroxy 3-methoxybenzene base) methyl]-2 (3H)-furanones, molecular formula: C
21h
24o
6, molecular weight: 372.4117, chemical constitution:
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| CN104529810A (en) * | 2014-09-02 | 2015-04-22 | 辽宁中医药大学 | Preparation method and application of arctigenin derivatives |
| CN108210487A (en) * | 2018-03-02 | 2018-06-29 | 武汉科技大学 | Application of the Sodium Houttuyfonate in treatment heart failure and/or antiarrhythmic medicament is prepared |
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| CN101278940A (en) * | 2008-04-29 | 2008-10-08 | 中国人民解放军第三军医大学第二附属医院 | Medicament composition for curing diabetic cardiovascular pathological changes and method of preparing the same |
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Non-Patent Citations (4)
| Title |
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| Arctigenin Efficiently Enhanced Sedentary Mice Treadmill Endurance;Xuan Tang;《PloS ONE》;www.plosone.org;20110831;第6卷(第8期);第1-13页 * |
| Herb–drug interactions: an overview of systematic reviews;Paul Posadzki;《British Journal of Clinical Pharmacology》;20120601;第75卷(第3期);第603–618页 * |
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| Xuan Tang.Arctigenin Efficiently Enhanced Sedentary Mice Treadmill Endurance.《PloS ONE》.www.plosone.org,2011,第6卷(第8期),第1-13页. |
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