CN106581003A - Application of rutaecarpine - Google Patents
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- CN106581003A CN106581003A CN201611043941.9A CN201611043941A CN106581003A CN 106581003 A CN106581003 A CN 106581003A CN 201611043941 A CN201611043941 A CN 201611043941A CN 106581003 A CN106581003 A CN 106581003A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
The invention discloses application of rutaecarpine to preparation of drugs used for preventing or treating myocardial hypertrophy and/or cardiac hypertrophy. Rutaecarpine can obviously inhibit cardiomyocyte hypertrophy induced by AngII and cardiac hypertrophy caused by coarctation of the aorta abdominalis. Through application of rutaecarpine, the diameters of myocardial cells treated by AngII can be obviously decreased; the protein contents of the myocardial cells are reduced; the expression of ANF mRNA is substantially decreased; and the content of NO and the activity of NOS obviously rise. The rutaecarpine allows the cardiac hypertrophy index of the ventriculus sinister to be obviously decreased, has similar effect like L-arg, obviously improves the morphological changes of cardiac muscle tissue and enables the expression of ANF mRNA to be obviously decreased.
Description
Technical field
The present invention relates to a kind of application of Rutaecarpine, particularly belongs to pharmaceutical technology field.
Background technology
It is a more complicated pathologic process that myocardial hypertrophy is formed, and myocardial hypertrophy is referred in organ and tissue horizocardia myoplasm
Amount (weight) increases, in the increase of cellular level cardiac muscle cell's volume, weight and surface area, referred to as cardiac myocyte hypertrophy
(cardiomyocyte hypertrophy).Due to cardiac muscle cell people, after birth soon cardiac muscle cell just loses splitting ability,
Therefore cardiac muscle is in the case where long-term load increases after being born, long-term to continue with loose compensatory mechanism to adapt to the needs of body
Myocardial hypertrophy do not only result in cardiac muscle cell and change, non-myocardial infarction (fibroblast, VSMC and endothelium
Cell) and extracellular matrix (mainly collagenous fibres) also change, it is final to cause the function and structure of ventricle all to experienced one
Individual process of reconstruction, claims remodeling ventricle or myocardial remodelling.Although the initial stage of myocardial hypertrophy is the one kind for maintaining normal cardiac output having
The adaptation reaction of benefit, but long-term lasting pressure load or volume load will cause decompensation and occur DCM,
Heart failure and sudden death, are one of dead major reasons of cardiovascular patient.At present myocardial hypertrophy oneself be listed in cardiovascular morbidity
With the independent hazard factor of the death rate.It is clinically used for preventing and treating the medicine of myocardial hypertrophy based on antihypertensive drugs, such as angiotensins
Converting enzyme inhibitor, angiotensin ii receptor blocker, calcium antagonist and nitric oxide (NO) donor etc..But there is its bad
React and apply limited, therefore, the anti-myocardial hypertrophy medicine for continually looking for high-efficiency low-toxicity is significant.
Rutaecarpine (rutaecarpine, Rut) is a kind of indole quinazoline Alkaloid extracted in evodia rutaecarpa, right
Heart has positive inotropic, positive chronotropic action and cardioprotection, and this promotes CGRP release relevant with it.
Research shows that Rutaecarpine has extensive cardioprotection, but not yet has Rutaecarpine for preparing prevention or controlling
Treat myocardial hypertrophy and/or the relevant report in myocardial hypertrophy medicine.
The content of the invention
To solve the deficiencies in the prior art, it is an object of the invention to provide a kind of application of Rutaecarpine, will Wu
The fruit of medicinal cornel time alkali is used to prepare prevention or treats in myocardial hypertrophy and/or myocardial hypertrophy medicine.
In order to realize above-mentioned target, the present invention is adopted the following technical scheme that：
Rutaecarpine is preparing prevention or is treating myocardial hypertrophy and/or the application in myocardial hypertrophy medicine.
In the application of aforementioned Rutaecarpine, the medicine adds medicinal load to take Rutaecarpine as active component
Tablet, capsule, granule, soft capsule, pill, syrup, sublingual lozenge or injection made by body or excipient.
In the application of aforementioned Rutaecarpine, tablet is prepared by following steps：Using wet granule compression tablet, according to weight
Number meter, by the 3 parts of mixings of 1 part of Rutaecarpine xeraphium and starch, adds the starch slurry softwood that mass fraction is 10%, forms sediment
Containing the citric acid that mass fraction is 1% in slurry, it is allowed to gently to hold agglomerating, light pressure and dissipates, the granulation of 16 mesh sieves is crossed, by wet grain in 40
DEG C～60 DEG C of dryings, with 16 mesh sieve whole grains, and add quality to be to be obtained after the talcum powder of granular mass 5% mixes, direct tablet compressing
Obtain final product.
In the application of aforementioned Rutaecarpine, capsule is prepared by following steps：Take Rutaecarpine dried powder and
Quality is mixed for the soluble starch of 5 times of dry powder quality, after crossing 100 mesh sieves, is filled by hand to No. 5 capsules and is obtained final product.
In the application of aforementioned Rutaecarpine, granule is prepared by following steps：In parts by weight, evodia rutaecarpa is taken
1 part of secondary alkali xeraphium, the 1.25 parts of mixings of 3 parts of cane sugar powder and dextrin, add 60% ethanol softwood, are allowed to gently hold agglomerating, light pressure
Dissipate, cross 16 mesh sieves and pelletize, 60 DEG C～80 DEG C dryings, with 16 mesh sieve whole grains, sealing is obtained final product.
In the application of aforementioned Rutaecarpine, Rutaecarpine is through the following steps that prepare：Take evodia rutaecarpa pulverizing medicinal materials
To meal, plus after ethanol immersion, then extracted with 95% alcohol heat reflux, repeat refluxing extraction 2～4 times；Medicinal extract is concentrated to give, salt is used
Acid solution fully dissolves medicinal extract, filters, and filtrate adjusts pH with ammoniacal liquor, and filtrate is crossed cationic ion-exchange resin, eluted with DDW
It is extremely colourless, then eluted with acidic ethanol, eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, i.e.,
.
Further, in the application of aforementioned Rutaecarpine, Rutaecarpine is through the following steps that prepare：Take evodia rutaecarpa
Pulverizing medicinal materials add ethanol to soak 3～5h to meal by 1～3g, 10～45mL of ︰ of solid-to-liquid ratio, then are carried with 95% alcohol heat reflux
Take, repeat refluxing extraction 2～4 times；Medicinal extract is concentrated to give, with the hydrochloric acid solution that mass concentration is 3.5% medicinal extract, mistake are fully dissolved
Filter, filtrate adjusts pH to 9～11 with ammoniacal liquor, and filtrate crosses cationic ion-exchange resin, be eluted to DDW it is colourless, then with acidity
Ethanol elution, eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, is obtained final product.
Preferably, in the application of aforementioned Rutaecarpine, Rutaecarpine is through the following steps that prepare：Take evodia rutaecarpa medicine
Material is crushed to meal, adds ethanol to soak 3h by 1g ︰ 10mL of solid-to-liquid ratio, then is extracted with 95% alcohol heat reflux, repeats backflow and carries
Take 3 times；Medicinal extract is concentrated to give, with the hydrochloric acid solution that mass concentration is 3.5% medicinal extract is fully dissolved, filtered, filtrate is adjusted with ammoniacal liquor
PH to 10, filtrate crosses cationic ion-exchange resin, be eluted to DDW it is colourless, then with acidic ethanol elute, eluent concentration
Extremely without alcohol taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, obtain final product.
In the application of aforementioned Rutaecarpine, myocardial hypertrophy is the cardiac myocyte hypertrophy of hypertensinⅡinduction.
In the application of aforementioned Rutaecarpine, ventricular hypertrophy is myocardial hypertrophy caused by abdominal aorta constriction.
In order to ensure the science, effectively of technical solution of the present invention, inventor has carried out series of experiments.
First, inhibitory action of the Rutaecarpine to cardiac myocyte hypertrophy caused by angiotensinⅡ (Ang II)
1st, experiment material
1.1st, animal used as test
Sprague Dawley rat kinds mouse 150, cleaning grade, provided by Third Military Medical University's Experimental Animal Center.Close
Lattice certificate number SCXK2002008.The relevant criterion of management of laboratory animal and protection is observed in raising and experimentation.
1.2, primary drug and reagent
Rutaecarpine (Basic pharmacology key lab extracts, and HPLC >=98%)；(TaKaRa gives birth to RNA extracts kits
Thing engineering company)；Purification kit (Shanghai Hua Shun bioengineering Co., Ltd)；Reverse transcription reaction system reagent box (TaKaRa
Bio-engineering corporation)；GREEN PCRMaster Mix (Applied Biosystems, Cheshire, UK).Other
Reagent is domestic pure analysis pure.
1.3rd, key instrument and equipment
A2-100 inverted microscopes (Japanese Nikon)；KDC-2044 low speed refrigerated centrifuges (the limited public affairs of University of Science and Technology's Innovations
Si Zhongjia branch companies)；5417R- high speed freezing centrifuges (German Eppendor companies)；ST-TC- ELIASAs (the U.S.
SUNRISE), TU-1810- ultraviolet-uisible spectrophotometers (Beijing Puxi General Instrument Co., Ltd)；4000B- is thin
Born of the same parents' image analysis system (German Leica)；SL-SHELNB CO2 incubators are U.S.'s product；(Suzhou purification sets superclean bench
Standby company).2nd, experimental technique
2.1st, neonatal rat cardiomyocytes culture
Take out 1～3d age SD rats after life and aseptically take out heart, put 4 DEG C in D-Hank ' s liquid, cut off the heart
Ventricular muscles are cut into 1～3mm by dirty big blood vessel and atrial tissue3Small tissue blocks.Using 0.125% trypsase, 37 DEG C of constant temperature shake
20min is digested in bed, individual cells suspension is digested to by several times.Jing after differential velocity adherent is separated, by not adherent cardiac muscle cell with containing
The DMEM of 20% calf serum and penicillin and streptomycin is diluted to 3 × 109Cells/L, needs to be inoculated in 6 orifice plates respectively according to experiment
Or 25mL blake bottles in or and 24 orifice plates, be placed in 5%CO2, cultivate in 37 DEG C of cell culture incubators, initial 48h adds 0.1mmol/
L5 '-BrdU suppress non-myocardial infarction propagation.Then change nutrient solution to continue to cultivate 24h, serum-free medium is changed during to 72h simultaneously
Corresponding reagent is added, continues to be incubated after 48h for detecting.During cell is inoculated in into blake bottle or culture plate.Be placed in 37 DEG C, 5%
CO248h is cultivated in incubator, serum-free medium is then placed in.
2.2nd, experiment packet
Above-mentioned cell adds corresponding reagent and is grouped when changing serum-free medium after 72 hours, experiment is divided into normal group i.e.
Control groups (adding equal-volume PBS liquid), model group are that II group of Ang (adds 0.1 μm of olL- 1Ang II) and 3 administration
Group is that 0.03 group of II+Rut of Ang, II+Rut of Ang, 0.3 group and Ang 3.0 groups of II+Rut (are adding 0.1 μm of olL- 1Ang
II simultaneously, is separately added into 0.03 μm of olL of Rut- 1、0.3μmol·L- 1、3.0μmol·L- 1), after effect 48h, for index
Detection.Wherein, concentrations above is the final concentration of medicament contg in dosing wild Oryza species.
2.3rd, observation index
2.3.1 cardiac muscle cell's morphological observation.
2.3.2 diameter of myocytes measurement and the detection of cardiac muscle cell's protein content.
2.3.3 RT-PCR detects the expression of myocardial hypertrophy related gene
2.3.4 nitric oxide (NO) content and nitricoxide synthase (NOS) determination of activity
(1) carry out by the operation of NO detection kits specification.
(2) total NOS vigor of each sample is calculated according to serum NO level S vigor computing formula.
3rd, experimental result
3.1st, cardiac muscle cell's morphological observation
HE dyeing is visible, and normal group cellular morphology is in irregular polygon, there is pseudopodium, and kytoplasm pinkiness, karyon understands,
There is 1～2 hepatic core；And add II 0.1 μm of olL of Ang-1Afterwards, cardiac muscle cell's volume is significantly increased, cellular swelling, carefully
Born of the same parents' blur margin is clear；And add after various dose Rut, cell is shown in and is obviously reduced, and swelling mitigates, and as a result sees Fig. 1.
The impact of diameter of myocytes and protein content that the 3.2, Rut is induced Ang II
As a result show, compare with normal group, model group diameter of myocytes significantly increases (increase about 2 times of (P ﹤ of diameter
0.05), protein content increases, and three administration groups are caused because Ang II causes the diameter of myocytes for increasing to be obviously reduced,
Substantially suppress the increase of the protein content of the inductions of Ang II simultaneously.The results are shown in Table 1.
The impact of diameter of myocytes and protein content sum that the Rut of table 1 is induced Ang II
Compare with normal group, * P<0.05, * * P<0.01；Compare with model group,#P<0.05,##P<0.01。
The impact of the hypertrophic cardiomyocytes ANF mRNA expression that the 3.3rd, Rut is induced Ang II
As a result show, normal group cardiac muscle cell ANF expression is relatively low, compares with normal group, II group of inducing cardiomyocytes of Ang
ANF (atrionatriuretic factor) relative expression quantity increases nearly 2 times of (P<0.05), and administration group then causes to increase because Ang II is added
Plus ANF expression significantly reduce, as shown in table 2.
The impact of the hypertrophic cardiomyocytes ANF mRNA expression that the Rut of table 2 is induced Ang II
Compared with normal group,*P<0.05；Compared with model group,#P<0.05,##P<0.01。
3.4th, impact NO contents and NOS active in the hypertrophic cardiomyocytes that Rut is induced Ang II
Compare with normal group, the content of II group of NO of Ang and NOS activity reduce respectively 73.9%, 66.7% (P ﹤ 0.05).
II group is compared with Ang, and administration group These parameters are dramatically increased.As shown in table 3.
The impact of cardiac muscle cell NO contents and NOS activity that the Rut of table 3 is induced Ang II
Compared with Control groups,*P<0.05,**P<0.01；Compared with model group,#P<0.05。
2nd, Rutaecarpine causes the impact of rat cardiac hypertrophy model to part abdominal aorta constriction
Experiment main research Rutaecarpine in this part is acted on the prevention administration of AAC rats.
1st, experiment material：
1.1st, animal used as test
Male SD (Spragye-Dawley) rat, 2～3 months monthly ages, 220～250g of body weight, by the medical officer of Chongqing the 3rd
The adult rat cleaning grade (quality certification number SCXK (Chongqing) 20070005) that great Ping hospitals of university Experimental Animal Center is provided, rat
Grain forage feed, illumination/dark time was circulated for 12/12 hour, 22～25 DEG C of room temperature.
1.2nd, medicine and reagent
Rutaecarpine (by Basic pharmacology, key lab extracts, and HPLC >=98%)；RNA extracts kit (TaKaRa
Bio-engineering corporation)；Purification kit (Shanghai Hua Shun bioengineering Co., Ltd)；Reverse transcription reaction system reagent box
(TaKaRa bio-engineering corporations)；GREEN PCRMaster Mix (Applied Biosystems, Cheshire,
UK)；Yellow Jackets (Beijing chemical reagent factory, lot number：060222)；Other reagents are domestic pure analysis pure.
1.3rd, key instrument
TU1810 ultraviolet specrophotometers (the public production of the general analysis general finite in Beijing)；Eppend of Mastercycler
Gradient PCR instruments (German Eppendorf companies production)；Eppendorf 5417R refrigerated centrifuges (German Eppendorf
Company produces)；X-15R refrigerated centrifuges (German Eppendorf companies production)；Centrifuge 5415D centrifuges (Germany
Eppendorf companies produce)；Icycler IQ real-time fluorescence quantitative PCR instrument (BIO-RAD companies of the U.S.)；BS10S types electronics point
Analysis balance (Beijing Sai Duolisi Electronics Co., Ltd.s)；Cell image analysis system (German Leica).
2nd, experimental technique
2.1st, animal used as test packet：
Myocardial hypertrophy model is set up using part abdominal aorta constriction：Cleaning grade male SD rat 50, body weight 220-
250g, is randomly divided into 5 groups：
1. sham-operation group (sham)；Molding 1w, 2w start to give etc. and hold distilled water, continuous 3w；
2. model control group (Model)；Molding 1w, 2w start to give etc. and hold distilled water, continuous 3w；
3. positive controls (L-arg, L-arginine, 200mg/kg)；Molding 1w, 2w start to give 200mg/kg, often
Day oral gastric infusion, once a day (i.g, qd), continuous 3w；
4. Rutaecarpine low dose group (Rut-L, 10mg/kg)；Molding 1w, 2w start to give 10mg/kg, i.g,
Qd, continuous 3w；
5. Rutaecarpine high dose group (Rut-H, 20mg/kg).Molding 1w, 2w start to give 20mg/kg, i.g,
Qd, continuous 3w；
2.2nd, the preparation of Left Ventricular Hypertrophy in Rats model
SD rats, claim its heavy, to press method system of the prior art after yellow Jackets (30mg/kg) intraperitoneal injection of anesthesia
Standby myocardial hypertrophy model：Abdominal aorta is separated above double arteria renalis, No. 7 syringe needles for removing point are tied in the lump together with abdominal aorta
Prick, extract syringe needle out immediately after, that is, cause the Partial Coarctation of abdominal aorta, then abdominal cavity is closed after internal organ are resetted, with 50,000 U/ only
Penicillin anti-inflammatory 3 days, rearmounted cage of regaining consciousness is fed, postoperative all animal drinking public water supplies.Model 3～4 days rat heart muscles after surgery
Start plumpness, 2w～3w reaches and stablizes peak.Each group mouse starts gastric infusion respectively in 2w, after 4w week administrations terminate
Put to death.
2.3rd, the measure of left ventricular hypertrophy index
Yellow Jackets (40mg.kg is adopted to rat-1, intraperitoneal injection of anesthesia and fixation of lying on the back, while open chest rapidly coring
It is dirty to cut off atrium, big blood vessel and pericardial tissue, rinsed well with the physiological saline of precooling, and moisture is inhaled with cleaning filter paper
It is dry, weigh immediately, weigh left ventricle (containing interventricular septum) weight in wet base (Left ventricular weigh, LVW), right ventricle weight in wet base
(Right ventricular weigh, RVW), calculates left ventricular hypertrophy index (Left ventricular hypertrophy
index):
LVHI=LVW/weigh or LVHI=LVW/BW or LVHI=LVW/RVW
Wherein, LVHI- myocardium of left ventricle plumpness index, weigh- whole-heartedly weight/g, LVW- left ventricular mass/g, BW- is big
Mouse body weight/g, RVW- right ventricle weight/g.
2.4th, Pathomorphologic observation
Its heart is after death taken at rat, left ventricle is separated, with 4% paraformaldehyde 24 hours are fixed, FFPE, section,
Its myocardial morphology change is observed in HE dyeing.
2.5th, RT-PCR methods detect the expression of ANF, CaN mRNA in cardiac muscle cell
2.5.1, the extraction of total serum IgE：Carry out in accordance with the following steps：
Take 50～100mg tissues and add 500 μ L Trizol liquid, stand after 5min under room temperature, plus 500 μ L chloroforms, shaking
15sec, with 12000rpm centrifugation 15min at 4 DEG C, obtains supernatant, 300 μ L of supernatant liquid plus 300 μ L isopropanols is taken, at 4 DEG C
With 12000rpm centrifugation 10min, supernatant is abandoned, then add 75% ethanol, with 12000rpm centrifugation 5min at 4 DEG C, clearly
Wash 2 times, remove ethanol, be air-dried RNA 3min, plus the μ L of 0.1%DEPC water 100 are obtained final product.
2.5.2, RNA purifying：Carry out in accordance with the following steps：
1. in the EP for slightly carrying RNA is managed, the μ L of RP350 μ L+75% alcohol 250 are added；
2. upper prop：By liquid mixed above suction RNA purification column centrifugation 10000rpm, 1min；
3. rinse：The μ L of 75% alcohol 500 are added in post, 10000rpm centrifugation 1min, are repeated 1 times.
4. elute and collect purifying RNA liquid：Purification column is moved in new EP pipes, adds the μ L of DEPC water 100 to be eluted,
10000rpm is centrifuged 1min.The RNA liquid testing samples that the 100 μ L aqueous solution being contained in EP pipes are purified.
2.5.3, the Purity of RNA sample
20 μ LRNA samples and 980 μ L DEPC water are taken in quartz cuvette, is mixed.With the zeroing of DEPC water, at ultraviolet point
Determine the OD values of its 260nm and 280nm on light photometer respectively.OD260/OD280>1.80 think that purity meets the requirements, RNA concentration
=OD260× 40 × extension rate.
2.5.4, two-step method reverse transcription polymerase chain reaction (Two steps RT-PCR)
Reverse transcription reaction system：
The μ L of cumulative volume 20.
Reaction condition：
First stage (reverse transcription reaction)：37℃×15min
Second stage (inactivation reaction of reverse transcriptase)：85 DEG C × 5sec, 4 DEG C of holdings.PCR primer dilutes 3.25 times；
Reaction system：
Reaction condition：The first step, 95 DEG C × 8min；Second step, 95 DEG C × 15sec, annealing temperature × 1min.Second step is followed
Ring 45 times.Primer：
Relevant primer sequence is found from gene GeneBank, is synthesized by TaKaRa bio-engineering corporations, as shown in table 4.
Table 4 is used for the primer pair of Real time PCR
2.6th, statistical procedures
All data are with mean ± standard deviationRepresent, checked by t, P<0.05 thinks statistically significant.
3rd, experimental result
3.1st, impacts of the Rut to left ventricular hypertrophy rat blood pressure
Compare with sham-operation group, model group rats systolic pressure (SAP) and diastolic pressure (DAP) substantially rise (P ＜ 0.05)；With
Model group is compared, and Rut is low, high dose group, the systolic pressure of positive drug group and diastolic pressure are reduced (P ＜ 0.05).The results are shown in Table 5.
Impacts of the Rut of table 5 to Hypertrophic Heart rat cardiac hypertrophy blood pressure
Compared with Sham groups, * P<0.05；Compared with Model groups,#P<0.05。
3.2nd, Rut is on hemodynamic impact
As a result as shown in table 6, model control group LVSP, LVEDP is all remarkably higher than Sham-operated control group (P<0.05), Rut
These parameters substantially reduce (P after administration<0.05), but still slightly above sham-operation group.Compare with sham-operation group, model control group
Rat ± dp/dtmax is reduced, but to be given and can obviously improve (P after L-arg and Rut<0.05).
The Rut of table 6 is on the hemodynamic impact of SHR rats
Compared with Sham groups, * P<0.05, * * P<0.01；Compared with Model groups,#P<0.05,##P<0.01。
3.3rd, impact of the Rutaecarpine to left ventricular hypertrophy index
As a result show, compare with sham-operation group, model group left ventricular hypertrophy index (LVHI) increases；Compare with model group,
Rutaecarpine high and low dose left ventricular hypertrophy index significantly reduces (P<0.05) 7, be the results are shown in Table.
Impacts of the Rut of table 7 to Hypertrophic Heart myocardial hypertrophy index
Compared with Sham groups, * P<0.05；Compared with Model groups,#P<0.05。
3.4th, Rutaecarpine is on the morphologic impact of AAC rat left chamber cardiac muscle cell
Normal in light Microscopic observation sham-operation group (A) cardiac muscle cell arrangement, cardiac muscle fibre traveling is neat, and cardiac cell nucleus are in
Circular or oval, occupies cell central authorities, and, without obvious hyperplasia, microvessel structure is normal, without expansion and vessel wall thickening for cardiac interstitium
Deng performance.Model group (B) cardiac muscle cell's denaturation, part cardiac muscle cell dissolving, surrounding structure is unclear；Cardiac muscle fibre arrangement disorder,
Gap is broadening；The obvious oedema of cardiac interstitium, fibroplasia is loose, fracture, there is inflammatory cell infiltration in interstitial.Rutaecarpine is given
Medicine is low, high dose group (D, E), compares with model group, and myocardial ultramicrostructure is more clear, and the traveling of cardiac muscle fibre is more neat, but
Henle's fissures is still broadening；Cardiac interstitium oedema substantially mitigates, as shown in Figure 2.
3.5th, impact of the Rutaecarpine to rat left chamber's cardiac muscle ANF, CaN mRNA expression
Compare with sham-operation group, model group ANF, CaN mRNA expression is shown in significantly raised；After Rutaecarpine is administered 3 weeks
ANF, CaN mRNA expression is then significantly reduced.
3rd, therapeutic action of the Rutaecarpine to myocardial hypertrophy caused by rat aorta constriction
Experiment main research Rutaecarpine in this part is acted on the therapeutic administratp of AAC rats.
1st, experiment material：It is same with Section 2.
2nd, experimental technique
2.1st, animal packet and administration
By rat sub-cage rearing, free water, environment is adapted to 1 week, Jing after many non-invasive arteria caudalis blood pressure measurements, by blood
Pressure is not up to hypertension (150mmHg) standard person and is grouped at random, every group of n=10.Specifically it is grouped as follows：
(1) sham-operation group：In addition to not constriction abdominal aorta, the same model group of remaining operation technique, molding 3w, 4w start to
Give etc. and to hold distilled water 30d；
(2) model group：Abdominal aorta constriction model, molding 3w, 4w starts to give etc. and holds distilled water 30d；
(3) Rutaecarpine low dose group (Rut-L, 10mg/kg)：Abdominal aorta constriction model, molding 3w, 4w starts
10mg/kg is given, daily oral gastric infusion, once a day (i.g, qd), continuous 30d；
(4) Rutaecarpine high dose group (Rut-H, 20mg/kg)：Abdominal aorta constriction model, molding 3w, 4w starts
Give 20mg/kg, i.g, qd, continuous 30d；
(5) positive drug group (Valsartan, 10mg/kg)：Molding 3w, 4w start to give 10mg/kg, i.g, qd, continuously
30d。
2.2nd, the preparation of rat left chamber's hypertrophy model
7% chloraldurate lumbar injection is by rat anesthesia.Postanesthetic rat lies on the back and is fixed on mouse plate, shaves belly
Hair, with iodophor disinfection, 1-1.5cm exposes abdominal cavity along rat hunter's line otch (about 1.5-2cm) under manubrium, isolates
Abdominal aorta, by the ligation parallel with abdominal aorta of the syringe needle of No. 7, extraction syringe needle, and injects the penicillin anti-inflammatory of 0.5mL, layering
Rat abdominal cavity is sutured.Place mouse cage after clear-headed to feed, the free drinking public water supply of postoperative rat.Rat 3～4 days after surgery
Cardiac muscle starts hypertrophy, and 2w～3w reaches and stablizes peak.
2.3rd, rat tail artery non-invasive blood pressure measurement
Non-invasive blood pressure measuring instrument is preheated into about 20 minutes and calibrating (base measuring) pressure signal, the SD rats of test are loaded into fixed box
In son, rat fixed mount is then placed in, rat tailses pressure cuffs are inserted in into rat-tail root.Rat tailses are made to be located exactly at pulse letter
The top of number vane, and correct the position of the pressure film of rat tailses.Vane is close to the tail below rat tailses to move
Arteries and veins.Deng rat pulse wave it is stable after carry out the measurement of rat blood pressure again.Require to be kept as far as possible during measurement rat blood pressure every time
It is outer consistent.
2.4th, the preparation of tissue specimen
Measurement blood pressure terminates, and with chest is opened after 7% chloraldurate (350mg/kg) lumbar injection rat anesthesia, takes out immediately
Heart, is rinsed with pre-prepd cold saline, goes to atrium and big vascular tissue, and left ventricle (left is cut respectively
Ventricle, LV) and right ventricle (right ventricle, RV), dipped in clean filter paper after doing, weigh, calculated according to formula
(left ventricular hypertrophy index, LVHI=LVW/BW, LVW refer to left ventricle to left heart plumpness index LVHI
Weight/g, BW refer to rat body weight/g).Packing sample, be positioned over rapidly -80 DEG C it is frozen standby.
2.5th, the content that method of exempting from determines cardiac muscular tissue's angiotensinⅡ (Ang II) is put
Radiation exempts to send out the content for determining cardiac muscular tissue's angiotensin I (Ang II) by kit operational manual behaviour
Make.
2.6th, cardiac muscular tissue CaN determinations of activity
Bioengineering Research Institute's kit specification operation is built up in strict accordance with Nanjing.CaN activity is with per milligram per hour
The CaN of total protein decompose the amount of the Pi that substrate PNPP is produced represent (i.e. μm ol Pi/ (h.mg pro)].
2.7th, ANF, CaNmRNA expression in real-time fluorescence RT-PCR detection cardiac muscular tissue
Experimental technique is identical with 2.5 projects in Section 2.
3rd, experimental result
3.1st, impacts of the Rut to left room myocardial hypertrophy index
As a result show, compare with sham-operation group, the left heart plumpness index of model group is more than sham-operation group (P<0.05), there is system
Meter learns meaning；Compare with model group, the left heart plumpness index of Rut high dose groups and low dose group all substantially reduces (P compared with model group
<0.05)。
3.2nd, pathological observation under cardiac muscular tissue HE dyeing mirror
HE is dyeed, spectroscopy basis of microscopic observation, and model group cardiac muscle cell increases compared with sham-operation group cardiac muscle cell, myocardium group
Textured fiber arrangement is more disorderly, it is seen that fracture.Zhu alkali of Wu is low, the above-mentioned pathological change of high dose group substantially mitigates compared with model group.
3.3rd, impacts of the Rut to the content and CaN activity of cardiac muscular tissue's angiotensinⅡ (Ang II)
As a result show, compare with sham-operation group, model group cardiac muscle cardiac muscular tissue angiotensinⅡ content, cardiac muscle CaN live
Property increases (P<0.05)；The content of cardiac muscle Ang II is decreased obviously (P with CaN activity Jing after Rutaecarpine treatment<0.05).
As shown in table 8.
The Rut of table 8 is to the content of rat angiotensin II (Ang II) and the active impact of CaN
Note：Sham-operation group ratio,#P<0.05；The * P compared with model group<0.05.
3.4th, impacts of the Rut to the expression of ANF, CaNmRNA in cardiac muscular tissue
As a result show, model group atrionatriuretic factor (ANF) increases (P with the expression of calcineurin (CaN) mRNA
<0.05)；Atrionatriuretic factor (ANF) and calcineurin (CaN) mRNA in Jing Rutaecarpines treatment rear myocardium tissue
Expression be subject to significantly to suppress (P<0.05).As shown in table 9.
The expression of protein kinase (CaN) mRNA of detection atrionatriuretic factor (ANF) calmodulin-dependent of table 9
Note：Sham-operation group ratio,#P<0.05；The * p compared with model group<0.05.
The invention has benefit that：A kind of application of Rutaecarpine that the present invention is provided, will Rutaecarpine
For preparing prevention or treating in myocardial hypertrophy and/or myocardial hypertrophy medicine.Rutaecarpine can substantially suppress Ang II to lure
The cardiac myocyte hypertrophy led and abdominal aorta constriction cause myocardial hypertrophy.
(1) for the cardiac myocyte hypertrophy of the inductions of Ang II, Ang II significantly increase cardiac muscle cell's cell dia, albumen contains
Amount substantially increases, and ANF mRNA expression is substantially raised, then NO contents and NOS activity is substantially reduced.And Rutaecarpine
Administration is obviously reduced can the diameter of myocytes that Jing Ang II are processed；Cardiac muscle cell's protein content is reduced；The table of ANF mRNA
Up to significantly reducing；NO contents and NOS activity are significantly raised.
(2) for part abdominal aorta constriction causes myocardial hypertrophy, compare with sham-operation group, model group left ventricular hypertrophy parameter
LVHI is dramatically increased with LVW/RVW, and left room cardiac muscle is substantially impaired, and makes ANF mRNA expression significantly raised.Compare with model group,
Rutaecarpine high and low dose group LVHI, LVW/RVW substantially reduces (P<0.05), play the role of to L-arg it is similar, myocardium group
Knit morphological change to be obviously improved, and ANF mRNA expression is substantially reduced；The left room cardiac muscle CaN mRNA expression of model control group
It is significantly raised compared with Sham-operated control group, show that Rutaecarpine high and low dose group can suppress the expression of CaN mRNA.
(3) for point abdominal aorta constriction causes myocardial hypertrophy to compare with sham-operation group, the blood pressure of model group control rats,
Left heart plumpness index LVHI (left room weight/body weight) and LVW/RVW (left room weight/right ventricle weight) significantly increase, left room cardiac morphology
Learn substantially impaired, ANF and CaNmRNA expression is increased, the content of myocardium Ang II and CaN activity are raised；With model group control group ratio
Compared with, model group rats blood pressure, LVHI, LVW/RVW can be reduced after Rutaecarpine high and low dose therapeutic administratp, reduce cardiac muscle Ang
CaN is active for II content, suppression.Myocardial pathological structure has preferably improvement, and makes the mRNA expression of ANF and CaN notable
Reduce.
Description of the drawings
Fig. 1 is the HE colored graphs (400 ×) that the Rutaecarpine of the present invention induces Ang II hypertrophic cardiomyocytes to affect；
Fig. 2 is HE colored graph of the Rutaecarpine to myocardium of left ventricle Morphology Effects；
The implication of reference in figure：Fig. 1：A- normal groups (equal-volume PBS), (the 0.1 μm of olL of b-Ang II- 1), c-
AngⅡ(0.1μmol·L- 1)+Rut(0.03μmol·L- 1), (the 0.1 μm of olL of d-Ang II- 1)+Rut(0.3μmol·L- 1), (the 0.1 μm of olL of e-Ang II- 1)+Rut(3.0μmol·L- 1)；Fig. 2：A:Sham-operation group (10X20)；B:Model group
(10X20)；C:Positive controls (10X20)；D:Rut low dose groups (10X20)；E:Rut high dose groups (10X20).
Specific embodiment
The present invention is further introduced below in conjunction with specific embodiment.
Embodiment 1
Application of the Rutaecarpine in prevention or treatment myocardial hypertrophy medicine is prepared.The medicine is to take Rutaecarpine
As active component, pharmaceutical carrier or tablet made by excipient are added.The tablet is prepared by following steps：Using wet method
Pelletizing press sheet, in parts by weight, by the 3 parts of mixings of 1 part of Rutaecarpine xeraphium and starch, adds mass fraction to be 10%
Starch slurry softwood, containing the citric acid that mass fraction is 1% in starch slurry, be allowed to gently to hold agglomerating, light pressure and dissipate, cross 16 mesh
Sieve series grain, by wet grain in 40 DEG C～60 DEG C dryings, with 16 mesh sieve whole grains, and adds quality to be the talcum that granular mass 5% is obtained
After powder is mixed, direct tablet compressing is obtained final product.Wherein, Rutaecarpine is through the following steps that prepare：Evodia rutaecarpa pulverizing medicinal materials are taken to thick
Powder, adds ethanol to soak 3h by 1g ︰ 10mL of solid-to-liquid ratio, then is extracted with 95% alcohol heat reflux, is repeated 3 times；Medicinal extract is concentrated to give, is used
Volumetric concentration is that 3.5% hydrochloric acid solution fully dissolves medicinal extract, is filtered, and filtrate adjusts pH to 10 with ammoniacal liquor, and filtrate crosses cation
Exchanger resin, is eluted to colourless with DDW, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol taste, plus alkali neutralization, then
Jing desalting processings, freeze-drying is obtained final product.The usage and consumption of tablet be：Gastric infusion, in terms of Rutaecarpine, low dosage
10mg/kg, high dose 20mg/kg.
Embodiment 2
Application of the Rutaecarpine in prevention or treatment myocardial hypertrophy medicine is prepared.The medicine is to take Rutaecarpine
As active component, pharmaceutical carrier or capsule made by excipient are added.The capsule is prepared by following steps：Take Wu
The fruit of medicinal cornel time alkali dried powder and quality are mixed for the soluble starch of 5 times of dry powder quality, after crossing 100 mesh sieves, are filled by hand to No. 5
Obtain final product in capsule.
Wherein, Rutaecarpine is through the following steps that prepare：Evodia rutaecarpa pulverizing medicinal materials are taken to meal, is with solid-to-liquid ratio
3g ︰ 45mL add ethanol to soak 5h, then are extracted with 95% alcohol heat reflux, are repeated 2 times；Medicinal extract is concentrated to give, is with mass concentration
3.5% hydrochloric acid solution fully dissolves medicinal extract, filters, and filtrate adjusts pH to 9 with ammoniacal liquor, and filtrate crosses cationic ion-exchange resin, uses
DDW is eluted to colourless, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings,
Freeze-drying, obtains final product.The usage and consumption of capsule be：Gastric infusion, in terms of Rutaecarpine, consumption be 10mg/kg～
20mg/kg。
Embodiment 3
Rutaecarpine is preparing prevention or is treating myocardial hypertrophy and the application in myocardial hypertrophy medicine.Myocardial hypertrophy is blood
The cardiac myocyte hypertrophy of the induction of angiotensin II.Myocardial hypertrophy is myocardial hypertrophy caused by abdominal aorta constriction.The medicine is
Rutaecarpine is taken as active component, pharmaceutical carrier or granule made by excipient is added.The granule is by following
It is prepared by step：In parts by weight, 1 part of Rutaecarpine xeraphium, the 1.25 parts of mixings of 3 parts of cane sugar powder and dextrin are taken, is added
60% ethanol softwood, is allowed to gently to hold agglomerating, light pressure and dissipates, and crosses the granulation of 16 mesh sieves, and 60 DEG C～80 DEG C dryings are whole with 16 mesh sieves
Grain, sealing is obtained final product.
Wherein, Rutaecarpine is through the following steps that prepare：Evodia rutaecarpa pulverizing medicinal materials are taken to meal, is with solid-to-liquid ratio
2g ︰ 25mL add ethanol to soak 4h, then are extracted with 95% alcohol heat reflux, are repeated 4 times；Medicinal extract is concentrated to give, is with mass concentration
3.5% hydrochloric acid solution fully dissolves medicinal extract, filters, and filtrate adjusts pH to 11 with ammoniacal liquor, and filtrate crosses cationic ion-exchange resin, uses
DDW is eluted to colourless, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings,
Freeze-drying, obtains final product.The usage and consumption of granule be：Gastric infusion, in terms of Rutaecarpine, low dosage 10mg/kg, high agent
Amount 20mg/kg.
Embodiment 4
Application of the Rutaecarpine in prevention or treatment myocardial hypertrophy medicine is prepared.Myocardial hypertrophy is angiotensinⅡ
The cardiac myocyte hypertrophy of induction.The medicine adds pharmaceutical carrier or excipient system to take Rutaecarpine as active component
Into soft capsule.Soft capsule is prepared using conventional method.Wherein, Rutaecarpine is through the following steps that prepare：Take evodia rutaecarpa
Pulverizing medicinal materials add ethanol to soak 3.5h to meal by 1.5g ︰ 20mL of solid-to-liquid ratio, then are extracted with 95% alcohol heat reflux, repeat 2
It is secondary；Medicinal extract is concentrated to give, with the hydrochloric acid solution that mass concentration is 3.5% medicinal extract is fully dissolved, filtered, filtrate adjusts pH and arrives with ammoniacal liquor
9, filtrate crosses cationic ion-exchange resin, is eluted to DDW colourless, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol
Taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, obtain final product.The usage and consumption of soft capsule be：Gastric infusion, with evodia rutaecarpa
Secondary alkali meter, consumption is 10mg/kg～20mg/kg.
Embodiment 5
Application of the Rutaecarpine in prevention or treatment myocardial hypertrophy medicine is prepared.Myocardium fertilizer is led for abdominal aorta constriction
The myocardial hypertrophy of cause.The medicine added and dripped made by pharmaceutical carrier or excipient to take Rutaecarpine as active component
Pill.Pill is prepared using conventional method.Wherein, Rutaecarpine is through the following steps that prepare：Take evodia rutaecarpa medicinal material powder
Meal is broken to, adds ethanol to soak 4.5h by 2.5g ︰ 35mL of solid-to-liquid ratio, then extracted with 95% alcohol heat reflux, be repeated 3 times；It is dense
Contract to obtain medicinal extract, and with the hydrochloric acid solution that mass concentration is 3.5% medicinal extract is fully dissolved, and filters, and filtrate adjusts pH to 10, filter with ammoniacal liquor
Liquid crosses cationic ion-exchange resin, is eluted to DDW colourless, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol taste,
Plus alkali neutralization, then Jing desalting processings, freeze-drying, obtain final product.The usage and consumption of pill be：Gastric infusion, with evodia rutaecarpa time
Alkali meter, low dosage 10mg/kg, high dose 20mg/kg.
Rutaecarpine answering in preparing prevention or treating myocardial hypertrophy and/or myocardial hypertrophy medicine in embodiment 1～5
With the medicine can also be to take Rutaecarpine as active component, add pharmaceutical carrier or syrup, tongue made by excipient
Lower lozenge or injection.
Claims (10)
1. Rutaecarpine is preparing prevention or is treating myocardial hypertrophy and/or the application in myocardial hypertrophy medicine.
2. the application of Rutaecarpine according to claim 1, it is characterised in that：The medicine is made to take Rutaecarpine
For active component, add pharmaceutical carrier or tablet made by excipient, capsule, granule, soft capsule, pill, syrup,
Sublingual lozenge or injection.
3. the application of Rutaecarpine according to claim 2, it is characterised in that：The tablet passes through following steps system
It is standby：Using wet granule compression tablet, in parts by weight, by the 3 parts of mixings of 1 part of Rutaecarpine xeraphium and starch, matter is added
Amount fraction is 10% starch slurry softwood, containing the citric acid that mass fraction is 1% in starch slurry, is allowed to gently hold agglomerating, light
Pressure dissipates, and crosses the granulation of 16 mesh sieves, by wet grain in 40 DEG C～60 DEG C dryings, with 16 mesh sieve whole grains, and adds quality for particle is obtained
After the talcum powder of quality 5% is mixed, direct tablet compressing is obtained final product.
4. the application of Rutaecarpine according to claim 2, it is characterised in that：The capsule passes through following steps system
It is standby：Take Rutaecarpine dried powder and quality and mix for the soluble starch of 5 times of dry powder quality, after crossing 100 mesh sieves, fill out by hand
It is charged in No. 5 capsules and obtains final product.
5. the application of Rutaecarpine according to claim 2, it is characterised in that：The granule passes through following steps system
It is standby：In parts by weight, 1 part of Rutaecarpine xeraphium, the 1.25 parts of mixings of 3 parts of cane sugar powder and dextrin are taken, 60% second is added
Alcohol softwood, is allowed to gently to hold agglomerating, light pressure and dissipates, and crosses the granulation of 16 mesh sieves, 60 DEG C～80 DEG C dryings, with 16 mesh sieve whole grains, sealing
Obtain final product.
6. the application of Rutaecarpine according to claim 1, it is characterised in that：The Rutaecarpine is by following
It is prepared by step：Evodia rutaecarpa pulverizing medicinal materials are taken to meal, plus after ethanol immersion, then extracted with 95% alcohol heat reflux, repeat to flow back
Extract 2～4 times；Be concentrated to give medicinal extract, with hydrochloric acid solution medicinal extract fully dissolved, filter, filtrate with ammoniacal liquor adjust pH, filtrate excessively sun from
Sub-exchange resin, is eluted to colourless with DDW, then is eluted with acidic ethanol, and eluent is concentrated into without alcohol taste, plus alkali neutralization,
Again Jing desalting processings, freeze-drying, obtain final product.
7. the application of Rutaecarpine according to claim 6, it is characterised in that：The Rutaecarpine is by following
It is prepared by step：Evodia rutaecarpa pulverizing medicinal materials are taken to meal, adds ethanol to soak 3～5h by 1～3g, 10～45mL of ︰ of solid-to-liquid ratio, then used
95% alcohol heat reflux is extracted, and repeats refluxing extraction 2～4 times；Medicinal extract is concentrated to give, with the hydrochloric acid solution that mass concentration is 3.5%
Fully dissolving medicinal extract, filters, and filtrate adjusts pH to 9～11 with ammoniacal liquor, and filtrate crosses cationic ion-exchange resin, is eluted with DDW
It is extremely colourless, then eluted with acidic ethanol, eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, i.e.,
.
8. the application of Rutaecarpine according to claim 7, it is characterised in that：The Rutaecarpine is by following
It is prepared by step：Evodia rutaecarpa pulverizing medicinal materials are taken to meal, adds ethanol to soak 3h by 1g ︰ 10mL of solid-to-liquid ratio, then it is hot with 95% ethanol
Refluxing extraction, repeats refluxing extraction 3 times；Medicinal extract is concentrated to give, with the hydrochloric acid solution that mass concentration is 3.5% medicinal extract is fully dissolved,
Filter, filtrate adjusts pH to 10 with ammoniacal liquor, and filtrate crosses cationic ion-exchange resin, be eluted to DDW it is colourless, then with acidity
Ethanol elution, eluent is concentrated into without alcohol taste, plus alkali neutralization, then Jing desalting processings, freeze-drying, is obtained final product.
9. the application of Rutaecarpine according to claim 1, it is characterised in that：The myocardial hypertrophy is angiotensins
The cardiac myocyte hypertrophy of II induction.
10. the application of Rutaecarpine according to claim 1, it is characterised in that：The ventricular hypertrophy is abdominal aorta
Myocardial hypertrophy caused by constriction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107375295A (en) * | 2017-08-04 | 2017-11-24 | 上海华堇生物技术有限责任公司 | The medicinal usage of Rutaecarpine |
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| CN105213580A (en) * | 2015-10-19 | 2016-01-06 | 遵义医学院 | Pharmaceutical composition of a kind of resisting cardiac hypertrophy and preparation method thereof |
| CN105859715A (en) * | 2016-04-27 | 2016-08-17 | 聊城大学 | Critical fluid chromatographic method for separating and purifying evodiamine and rutaecarpine from fructus evodiae |
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2016
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| CN105213580A (en) * | 2015-10-19 | 2016-01-06 | 遵义医学院 | Pharmaceutical composition of a kind of resisting cardiac hypertrophy and preparation method thereof |
| CN105859715A (en) * | 2016-04-27 | 2016-08-17 | 聊城大学 | Critical fluid chromatographic method for separating and purifying evodiamine and rutaecarpine from fructus evodiae |
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