CN101269151B - Application of radix scrophulariae in preparing medicament for preventing and controlling myocardial hypertrophy, hypertrophic cardiomyopathy and chronic heart failure - Google Patents
Application of radix scrophulariae in preparing medicament for preventing and controlling myocardial hypertrophy, hypertrophic cardiomyopathy and chronic heart failure Download PDFInfo
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Abstract
The invention belongs to the traditional Chinese pharmaceutics field, and relates to an application of traditional Chinese medicine radix scrophulariae to the preparation of a drug for preventing and curing cardiac hypertrophy, hypertrophic cardiomyopathy and chronic heart failure. The invention researches the effect of the cardiac hypertrophy and ventricle reconstruction model of a plurality of mice and rats on the traditional Chinese medicine radix scrophulariae. The experimental results show that the radix scrophulariae water or the alcohol abstracts has evident function for preventing thecardiac hypertrophy, the ventricular remodeling and the chronic heart failure caused by various reasons, the mechanism is obviously related with the excessive activation of the neuroendocrine system such as a suppressing renin-angiotensin-aldosterone system and is related with the functions of blood pressure reduction, heart beat slowing and hemodynamics improvement. The figwort can be used for preparing the drug for preventing the diseases of cardiac hypertrophy, hypertrophic cardiomyopathy and chronic heart failure and for reducing the possibility of the incidence rate of arrhythmia and the sudden death of patients with cardiac hypertrophy, hypertrophic cardiomyopathy and chronic heart failure.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to the purposes of Chinese medicine Radix Scrophulariae in preparation control remodeling ventricle medicine, be specifically related to the Chinese medicine Radix Scrophulariae and prevent and treat purposes in myocardial hypertrophy (myocardial hypertrophy), hypertrophic neuropathy (hypertrophic cardiomyopathy) and chronic heart failure (the chronic heart failure) medicine in preparation.
Background technology
Chronic cardiac insufficiency claims congestive heart failure (Congestive heart failure again, CHF), be that cardiac pumping function reduces due to the Different types of etiopathogenises, can not discharge enough blood to satisfy a kind of clinical syndrome of body tissue's organ metabolism needs, clinical case fatality rate is very high.
The clinical in the past treatment emphasis to CHF is to use heart tonifying glycoside positive inotropic action medicine and diuretic.After the seventies CHF is also advocated the novel non-Folium Digitalis Purpureae class positive inotropic action medicine of use, mainly contain phosphodiesterase inhibitor and beta-receptor agonist.At present 1. the long-term base therapy medicine of the chronic heart failure of treatment has diuretic, 2. digitaloid drugs such as digoxin, 3. angiotensin converting enzyme inhibitor, represent medicine: captopril and angiotensin receptor antagonist such as losartan, 4. four class medicines such as beta-blocker such as Propranolol, metoprolol are formed.Wherein diuretic is mainly used in the elimination edema, alleviates the heart burden; Digitaloid drugs is mainly used in and improves the hemodynamics symptom.
In recent years a large amount of clinical data is summed up and finds, though but all strengthen myocardial contractions, improve hemodynamics class medicine short-term and receive certain effect of improving symptom, all can not prevent and treat ventricular hypertrophy, can not reduce patient's case fatality rate.Life-time service phosphodiesterase inhibitor and beta-receptor agonist though can short-term improve hemodynamics and symptoms of heart failure, can increase the ARR incidence rate of patients with heart failure, sudden death rate and late mortality rate on the contrary.The cardiac glycoside medicine still is used for the treatment of heart failure because of its hemodynamics symptom that can improve the patient at present.But this type of medicine of numerous bibliographical informations is neutral to the influence of life, does not prolong patient's life.The cardiac glycoside medicine can not be prevented and treated ventricular hypertrophy.
After the eighties, people recognize that gradually myocardial hypertrophy, remodeling ventricle are the features of heart failure, also are simultaneously decision heart failure sickness rate, the factor of course of disease progress and mortality rate.Ventricular hypertrophy often is secondary to hypertension and myocardial infarction.Ventricular hypertrophy is usually directed to the change of ventricular structure, and remodeling ventricle (remodeling) promptly takes place.Remodeling ventricle comprises myocardial cell hypertrophy, Interstitial cell such as fibroblast proliferation, the collagen hypertrophy, and the compliance of heart reduces simultaneously, penetrates the blood function and also is subjected to obvious influence.Along with the generation and the development of myocardial hypertrophy, ventricular hypertrophy, the incidence rate of arrhythmia, heart failure, sudden death improves.Therefore, myocardial cell hypertrophy, ventricular hypertrophy are the pathology cores of CHF, and using pharmaceutical intervention and reverse myocardial hypertrophy, remodeling ventricle is the effective means of control CHF.
Myocardial hypertrophy, ventricular hypertrophy and feritin-angiotensin-aldosterone system increased activity, the sustained activation of neuro-endocrinology hormone is relevant with orthosympathetic lasting excitement.In recent years clinical therapeutic strategy to chronic heart failure changes, from short-term improve the hematodinamics measure, transfer secular reparation control to.Purpose is by inhibition and myocardial hypertrophy, the related stimulus of ventricular hypertrophy, mediation factor, thereby improves the biological function of cardiac muscle, changes the biological property of failure heart.There is clinical research to show, adopt angiotensin converting enzyme inhibitor or beta-blocker class medical treatment chronic heart failure, even it is early stage what treat, some medicine is not obvious to hemodynamic change, but cardiac muscle is still had secular biological effect, can prevent or delay the development of myocardial hypertrophy, ventricular hypertrophy.Beta-blocker for example: forbade being used for heart failure before the eighties, but a large amount of experiments and clinical data prove that this class medicine can prevent the development of myocardial hypertrophy, ventricular hypertrophy and reduce the incidence rate of arrhythmia, heart failure, sudden death.US and European heart failure treatment guide is thought: the patients with heart failure of all stable disease all need be used beta-blocker, unless contraindication is arranged, and will use as early as possible, reuse when other therapies is invalid do not waited until.Equally, unless patients with heart failure has contraindication maybe can not tolerate, also need to use indefinite duration angiotensin-convertion enzyme inhibitor and angiotensin receptor antagonist.
Heart failure does not have corresponding name of disease in the Chinese medicine ancient books, but the description to some diseases is very similar to the description of heart failure to modern medicine in the Chinese medicine ancient books.As " fluid-retention in thorax with difficulty in respiration " (treatise on Febrile Diseases); " cough with dyspnea must not crouch, or edema due to disorder of QI all over " (Compendium of Material Medica); " water has begun also, slightly swelling of the eyelids, and as the shape that has newly crouched, its notable and rashing pulsation of common carotid artery, in time, coughed.Puffiness of the legs, abdomen are big, and its water becomes." (" interior warp ").The dyspnea that occurs when this is similar to heart failure, orthopnea and edema, jugular phlebectasia.These are described among " the syndrome of dyspnea " be dispersed in more in the traditional Chinese medical science, " edema ".Traditional Chinese medical science described " breathing heavily, can not put down for sleeping in, edema, notable and rashing pulsation of common carotid artery " etc., very similar to modern medicine to the description of heart failure.
Radix Scrophulariae is the root of Scrophulariaceae herbaceos perennial Radix Scrophulariae, is famous Chinese medicine.Beginning is stated from Shennong's Herbal, classifies middle product as, and nature and flavor hardship, sweet, salty, cold can be gone into lung meridian, stomach warp, kidney channel, has YIN nourishing, and pathogenic fire reducing promotes the production of body fluid, removing heat from blood, effects such as detoxifcation.Modern pharmacological research shows, Radix Scrophulariae contains compositions such as Radix Scrophulariae element, monoterpene glycoside, micro-volatile oil, sterol, volatile alkaloid, saccharide, fatty acid, has that the leukocyte of making raises, resists myocardial ischemia, an effect such as coronary blood flow increasing, blood pressure lowering, blood sugar lowering, analgesic and antifungal.But to the control remodeling ventricle, the effect of myocardial hypertrophy, chronic heart failure does not appear in the newspapers.
Summary of the invention
Technical problem to be solved by this invention provides the new purposes of Chinese medicine Radix Scrophulariae in pharmacy.
The present invention relates to the new purposes of Chinese medicine Radix Scrophulariae in preparation control remodeling ventricle medicine, relate in particular to the Chinese medicine Radix Scrophulariae and prevent and treat purposes in myocardial hypertrophy, hypertrophic neuropathy and the chronic heart failure medicine in preparation.
The above-mentioned effect of the Chinese medicine Radix Scrophulariae that the present invention relates to and purposes are not seen relevant report.
Radix Scrophulariae involved in the present invention is the dry root of goatweed Radix Scrophulariae Scrophularia ningpoensis Hemsl., with its water extract or ethanol extraction.
Radix Scrophulariae involved in the present invention is excavated when stem and leaf is withered in the winter time, removes rhizome, plumelet, fibrous root and silt, shines or dries by the fire to half-dried, stacks 3～6 days, repeatedly for several times to dry.
It is cylindrical that Radix Scrophulariae involved in the present invention is class, and the centre is slightly thick or upper coarse and lower fine, the microbend that has, long 6～20cm, diameter 1～3cm.Surface lark or taupe have irregular longitudinal furrow, horizontal hole skin and sparse band and mark of fibrous root.Matter is solid, frangibility not, section black is little glossy.Gas is special like caramel, sweet in the mouth, little hardship.
The extracting method of the above-mentioned Radix Scrophulariae water extract of the present invention is a conventional method of the prior art, gets Radix Scrophulariae that is:, decocts with water 2～3 times, boils 30～45 minutes at every turn, and collecting decoction concentrates, and is dried to dry extract or granule is standby.
The extracting method of the above-mentioned Radix Scrophulariae ethanol extraction of the present invention is a conventional method of the prior art, that is: get Radix Scrophulariae 40%～95% alcohol heat reflux and extract each 30～60 minutes 2～3 times, merge extractive liquid,, reclaim ethanol, concentrate, be dried to dry extract or granule is standby.
Art-recognized, myocardial hypertrophy, remodeling ventricle are because abnormal hemodynamics and neuroendocrine disturbance results of interaction.Heart is when the abnormal hemodynamics that the multiple reason of reply causes, a series of variation has taken place autonomic nerve.The neuroendocrine factor is possible even more important than the hemodynamics factor in the pathogenesis of ventricular hypertrophy.Have now found that the neuroendocrine factor and the autocrine/paracrine factor that participate in the myocardial hypertrophy ventricular hypertrophy mainly contain: catecholamine, Angiotensin II (Ang II), aldosterone, blood vessel endothelium element-1 (ET-1), fibroblast growth factor etc.Find that during heart overload, local sympathetic activity improves, changes of Catecholamine Content obviously increases in the circulation.Plasma epinephrine concentration and ventricular hypertrophy degree are proportionate.There are some researches show, all can bring out myocardial hypertrophy, ventricular hypertrophy at medium-term and long-term norepinephrine or the isoproterenol of injecting inferior high dose of laboratory animal.Persistent sympathetic excitability strengthens, except that by influence hemodynamics and directly to heart effect bring out or increase the weight of the ventricular hypertrophy, cause that also renin secretion is too much, cause feritin-angiotensin-aldosterone system (RAAS) activation of whole body and heart local organization, and further make sympathetic excitability enhancing, neuroendocrine excessive activation, form vicious cycle.Adopt angiotensin-convertion enzyme inhibitor and beta-blocker to have the enhancing of blocking-up sympathetic excitability, the formed vicious cycle effect of neuroendocrine excessive activation, its curative effect is affirmed by clinical practice in recent years.
The present invention adopts domestic and international academia respectively, and isoproterenol, Levothyroxinnatrium sodium and three kinds of methods of pressure over loading of extensive use prepare myocardial hypertrophy, the remodeling ventricle model of mice and rat.Experimental result shows that significantly increasing with left cardiac index whole-heartedly all appears in three kinds of animal patterns, myocardial hypertrophys such as cardiac muscular tissue's Angiotensin II (Ang II) concentration raising, the feature of remodeling ventricle, carry out the Radix Scrophulariae intervention experiment, the result confirms, Radix Scrophulariae can obviously suppress three kinds of animal pattern myocardial hypertrophys, remodeling ventricle.
The present invention implements by following technical proposals:
By techniques well known, mouse subcutaneous injection (sc) isoproterenol 2mg/kg/d, 7d prepares myocardial hypertrophy, ventricular hypertrophy model continuously; SD rats by intraperitoneal injection (ip) Levothyroxinnatrium sodium 0.3mg/kg/d, continuous 7～10d, preparation myocardial hypertrophy, ventricular hypertrophy model; And rat is the ventral aorta between the incomplete ligation of the silver brain clip left and right sides renal artery of 0.5mm with internal diameter, makes it external diameter and is narrowed to 0.5mm, preparation pressure over loading remodeling ventricle model.Animal pattern is oral Radix Scrophulariae extracting solution respectively, captopril and drinking water, observe the plump index variation of animal cardiac muscle, measure the Angiotensin II (Ang II) of rat myocardium of left ventricle tissue and the cyclic adenosine monophosphate (cAMP) in the blood plasma, the variation of aldosterone (ALD) concentration with radio immunoassay.The result shows: Radix Scrophulariae can reduce plasma cAMP concentration, points out it to have the effect of the sympathetic excitability of inhibition; Can reduce the Ang II of cardiac muscular tissue again, and plasma aldosterone concentration, illustrate that Radix Scrophulariae has the activatory effect of blocking-up feritin-angiotensin-aldosterone system (RAAS), compare with normal group, the plump index of model group animal cardiac muscle, myocardium Ang II content, plasma cAMP, ALD concentration obviously raises, (P＜0.05).
Experiment confirm, Radix Scrophulariae causes relevant stimulation, the mediation factor of myocardial hypertrophy, ventricular hypertrophy by inhibition, thereby improves the symptom of myocardial hypertrophy, ventricular hypertrophy and the biological function of cardiac muscle.Effect with the myocardial hypertrophy of preventing and treating, remodeling ventricle can prepare the medicine of preventing and treating myocardial hypertrophy, remodeling ventricle, and then can prevent or delay generation, the development of heart failure, reduces the incidence rate of myocardial hypertrophy, ventricular hypertrophy patient arrhythmia, heart failure, sudden death.Its mechanism of action and inhibition feritin-angiotensin-aldosterone system activity suppress neuro-endocrinology hormone and activate, and it are relevant to suppress orthosympathetic lasting excitement.
Beneficial effect excrescence of the present invention is present: the Chinese medicine Radix Scrophulariae is inexpensive, be easy to get, has anti-myocardial hypertrophy, the new role of remodeling ventricle, control heart failure, do not see obvious acute toxicity, with its further Application and Development in the control congestive heart failure, for the quality of life of improving patients with heart failure, it is significant to reduce ARR incidence rate, sudden death rate and late mortality rate.
According to statistics, the sickness rate of heart failure is about 1.0%-1.5%.The annual sickness rate of over-65s population reaches about 10%.Although in the past among the 10-20, the treatment of chronic heart failure has been obtained very much progress, 5 years case fatality rate of CHF patient are still up to 50%.Research and analyse and think, the prognosis of heart failure is the same with malignant tumor, even poorer than malignant tumor.Therefore, in a single day chronic heart failure develops in the hemodynamics variation obviously, leans on cardiac glycoside Drug therapy very wise move absolutely not.Use as early as possible and have inhibition feritin-angiotensin-aldosterone system activity, suppressing neuro-endocrinology hormone activates, and the inhibition sympathetic nerve continues excited medicine Radix Scrophulariae especially provided by the invention, to preventing and treating myocardial hypertrophy, ventricular hypertrophy, improve the biological function of cardiac muscle, have bigger clinical generalization value.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail.
The used Radix Scrophulariae of following examples of the present invention meets the relevant every regulation under each medical material item of text of Chinese Pharmacopoeia version in 2005.Medical material has passed through processed such as clean system, cutting, the process of preparing Chinese medicine, pulverizing, is tested and appraised, and each medical material material object of distinguishing the flavor of conforms to title, and quality meets state-promulgated pharmacopoeia standard (concrete medical material evaluation way is carried out with reference to standards of pharmacopoeia).
The preparation of the Radix Scrophulariae water extract (decocting liquid) that following examples of the present invention are used comprises the steps: to get Radix Scrophulariae, decocts with water 2～3 times, boils 30～45 minutes at every turn, and collecting decoction concentrates, and is dried to dry extract or granule is standby.Facing the time spent adds water and is configured to debita spissitudo.
The preparation of the ethanol extraction that following examples of the present invention are used comprises the steps: to get Radix Scrophulariae and adds 40%～95% alcohol heat reflux and extract 2～3 times, and each 30～60 minutes, merge extractive liquid, reclaimed ethanol, concentrates, and is dried to dry extract or granule is standby.Facing the time spent adds water and is configured to debita spissitudo.
Embodiment 1 (the anti-isoproterenol of Radix Scrophulariae causes the mice remodeling ventricle and observes)
Select the 20-22g mice for use, be divided into 5 groups at random: normal control group, model group, metoprolol group and Radix Scrophulariae high and low dose group.Except that the normal control group, each organizes continuous 7d back subcutaneous injection isoproterenol 2mg/kg/d, every day 1 time, causes the myocardial hypertrophy model.The normal saline of normal group mouse back subcutaneous injection equal volume, continuous 7 days.Treatment group 1h after giving isoproterenol irritates stomach and gives Radix Scrophulariae decocting liquid 39g/ (kg.d) * 7d, 19.5g/ (kg.d) * 7d and metoprolol 60mg/ (kg.d) * 7d; Normal group, model group are irritated the normal saline that stomach gives equal volume.Water 12h is can't help in fasting after the last administration, gets blood and cardiac muscle then and carries out every analysis.
1.1 the plump exponential mensuration of mouse cardiac muscle
Mice is weighed, and plucking eyeball, to get blood standby, takes off cervical vertebra and puts to death, and opens the thoracic cavity fast and cores dirty, remove atrial tissue, cut off, separate left and right ventricle along interventricular septum, the normal saline rinsing is dehematized, and uses the filter paper suck dry moisture, and electronic balance accurately takes by weighing left ventricular mass and weight whole-heartedly.Calculate weight/body weight (HW/BW) whole-heartedly, left ventricular mass/body weight (LVW/BW) is designated as plump whole-heartedly index (HWI) respectively, left ventricular hypertrophy index (LVWI).
1.2 plasma cAMP assay
Get blood, add the 50 μ L anticoagulants of EDTA solution.The centrifugal 10min of refrigerated centrifuge 3500rpm gets supernatant cAMP content to be measured.Concrete grammar is undertaken by agent box description.
1.3 the AngII of ventricular organization concentration determination
Get the about 40mg of cardiac muscular tissue of mice, shred rapidly in frozen water, add normal saline homogenate fast in the ice bath environment of 4ml pre-cooling, be prepared into 1% tissue homogenate, the centrifugal 5min of 1000r/min gets supernatant and measures Ang II.Concrete operation method is pressed the test kit description.
The result shows that model group animal hearts index obviously increases, and the large and small dosage group of Radix Scrophulariae all has the effect that obviously reduces cardiac index, the results are shown in Table 1.
The anti-isoproterenol of table 1 Radix Scrophulariae causes observation (cardiac index, the x ± s) of the loose effect of mouse cardiac muscle
Compare * P＜0.05, * * P＜0.01 with model group
The serum sample of every group of 10 mices of random choose is surveyed cAMP.Concrete grammar is: get 0.1ml blood plasma, add dehydrated alcohol 1ml, mixing, the centrifugal 10min of 4000rpm gets supernatant A, and lower floor continues to add 75% ethanol 1ml, mixing, the centrifugal 10min of 4000rpm gets supernatant B, A and B merging place 60 ℃ of water-bath water-baths to vapor away ethanol, add 0.05M acetate buffer solution 2ml in the residue, mixing is therefrom got 0.1ml and is added 0.05M acetate buffer solution 0.2ml again, mixing is therefrom got 0.1ml solution again and is carried out the cAMP content detection.The cAMP assay is undertaken by the test kit description.Results model group mice obviously raises than normal group plasma cAMP concentration, and large and small dosage group of Radix Scrophulariae and metoprolol group obviously reduce mice plasma cAMP concentration (seeing Table 2).
Table 2 Radix Scrophulariae to isoproterenol cause myocardial hypertrophy mice plasma cAMP influence (x ± s, n=10)
Compare with model group,
*P＜0.05,
*P＜0.01
Cardiac muscular tissue's sample of 10 mices of every group of random choose is surveyed Ang II.Concrete grammar is: get the about 40mg of cardiac muscular tissue of mice, add the homogenate fast in the ice bath environment of 4ml normal saline, make 1% homogenate, operate by Angiotensin II test kit description.The result shows that the model group mice obviously raises than normal group mouse cardiac muscle Ang II content, and heavy dose of group of Radix Scrophulariae and metoprolol group have the effect of obvious reduction mouse cardiac muscle Ang II content, the results are shown in Table 3.
Table 3 Radix Scrophulariae to isoproterenol cause myocardial hypertrophy mouse cardiac muscle AngII content influence (x ± s, n=10)
Compare with model group,
*P＜0.05,
** P＜0.01
Ethanol extraction with Radix Scrophulariae is studied, and finds also to have the isoproterenol of minimizing to cause the exponential effect of mouse heart.
Embodiment 2 (the Radix Scrophulariae antithyroidin causes the loose effect of rat heart muscle and observes)
Select for use the male SD rat of 220-250g to be divided into 5 groups (11 every group) at random: to be respectively the normal control group, model group, captopril 40mg/kg, Radix Scrophulariae high dose group (Radix Scrophulariae 27g/kg), Radix Scrophulariae low dose group (13.5g/kg).Except that the normal control group, each organizes continuous 7d lumbar injection Levothyroxinnatrium 0.25mg/kg/d, every day 1 time, preparation myocardial hypertrophy model.The normal saline of normal group lumbar injection equal volume, 7d continuously.Radix Scrophulariae high and low dose group is irritated stomach Radix Scrophulariae decocting liquid 27g/kg, 13.5g/kg when giving Levothyroxinnatrium, continuously gastric infusion 9d; Normal group is irritated the normal saline that stomach gives equal volume; Captopril group is according to the continuous gastric infusion 9d of 40mg/kg every day.Water 12h is can't help in fasting after the last administration, gets blood and cardiac muscle then and carries out every analysis.
2.1 the plump exponential mensuration of rat heart muscle
Rat weigh (BW) back abdominal aortic blood.Open the thoracic cavity fast and core dirtyly, remove atrial tissue, cut off along interventricular septum, separate left and right ventricle, the normal saline rinsing is dehematized, and uses the filter paper suck dry moisture, and electronic balance accurately takes by weighing left ventricular mass and weight whole-heartedly.Calculate weight/body weight (HW/BW) whole-heartedly, left ventricular mass/body weight (LVW/BW) is designated as plump whole-heartedly index (HWI) respectively, left ventricular hypertrophy index (LVWI).
The result shows that the cardiac index of rat model obviously increases, and Radix Scrophulariae high dose group and Captopril group obviously reduce the heavy index of the heart of animal pattern, the results are shown in Table 4.
Table 4 Radix Scrophulariae antithyroidin cause the loose effect of rat rat heart muscle observation (x ± s, n=11)
Compare with model group,
*P＜0.05,
*P＜0.01
Ethanol extraction with Radix Scrophulariae is studied, and finds also to have the thyroxine of minimizing to cause the exponential effect of mouse heart.
2.2 the Ang II of cardiac muscular tissue assay
Get the about 200mg of cardiac muscular tissue of rat, add the homogenate fast in the ice bath environment of 2ml normal saline, the centrifugal 10min of 3500rpm gets supernatant 200 μ l and adds normal saline 800 μ l, makes 2% homogenate, operates by Angiotensin II test kit description.Simultaneously, carry out protein determination by Coomassie brilliant blue albumen testing cassete description.The result, compare with the normal group animal, Ang II content highly significant in the model group animal cardiac muscle tissue raises (P＜0.01), and Radix Scrophulariae high dose group and Captopril group were irritated stomach after 9 days, compares Ang II highly significant reduction (P＜0.01) in the myocardium of left ventricle tissue with model group; Ang II and model group comparison there was no significant difference in the Radix Scrophulariae low dose group myocardium of left ventricle tissue (P〉0.05).The results are shown in Table 5.
Table 5 Radix Scrophulariae to Levothyroxinnatrium cause myocardial hypertrophy rat heart muscle AngII content influence (x ± SD, n=11)
Compare with model group,
*P＜0.05,
*P＜0.01
Embodiment 3 (the anti-ventral aorta constriction of Radix Scrophulariae causes the effect of rat remodeling ventricle and observes)
Rat is with 3% pentobarbital sodium 0.1ml/100g intraperitoneal injection of anesthesia, it is fixing to face upward the position, open the abdominal cavity, passivity is separated ventral aorta, it with internal diameter the ventral aorta between the incomplete ligation of the silver brain clip left and right sides renal artery of 0.5mm, make it external diameter and be narrowed to 0.5mm, preparation pressure over loading remodeling ventricle model.The sham operated rats animal only separates ventral aorta, does not do ligation.Postoperative intramuscular injection penicillin 1 * 104Ukg-1d-1 is total to 3d, prevention infection.
2 weeks after the modeling, operation group rat random packet, 11 every group.Administration every day 1 time, 20ml/kg/d, 8 weeks of successive administration.1. Radix Scrophulariae high dose group: irritate stomach and give Radix Scrophulariae decocting liquid 27g/kg.2. Radix Scrophulariae low dose group: irritate stomach and give Radix Scrophulariae decocting liquid 13.5g/kg.3. Captopril group: irritate stomach and give captopril aqueous solution 40mg/kg.4. sham operated rats and model group rat oral gavage give distilled water 20ml/kg.
3.1 to hemodynamic influence
After 8 weeks, 25% urethane intraperitoneal injection of anesthesia rat, separate common carotid artery, insert the polystyrene conduit to aorta, after physiograph record systolic arterial pressure (SAP), auterial diastole pressure (DAP), heart rate (HR) are led in connection eight, continuation with conduit deeply to left ventricle, record left ventricular systolic pressure (LVSP), left ventricular end diastolic presssure (LVEDP), left ventricular pressure rising maximal rate (+dp/dtmax), left ventricular pressure decline maximal rate (dp/dtmax) etc.
The result shows, the ventral aorta constriction is after 10 weeks, the model group animal blood pressure, no matter be that systolic pressure or diastolic pressure all are significantly higher than sham operated rats (P＜0.01), heart rate is significantly accelerated (P＜0.01), simultaneously+dp/dtmax obviously reduces (P＜0.01), and diastolic function is described, shrinks significantly and reduce.After the high low dose therapy of Radix Scrophulariae, animal blood pressure all significantly reduces (P＜0.01), and heart rate significantly slows down (P＜0.01), and remarkable rising+dp/dtmax (P＜0.01).Show that the Radix Scrophulariae treatment when bringing high blood pressure down, significantly reduces pressure over loading rat heart rate faster, and can improve diastolic function to a certain extent, the results are shown in Table 6.
Table 6 Radix Scrophulariae to the hemodynamic influence of ventral aorta constriction rat (x ± s, n=8)
Continuous table 6
Annotate: compare with model group,
*P＜0.05,
*P＜0.01; SAP: systolic arterial pressure, DAP: auterial diastole is pressed, LVSP: left ventricular systolic pressure, LVEDP: left ventricular end diastolic presssure ,+dp/dtmax ,-dp/dtmax: be respectively left ventricular pressure and rise and the decline maximal rate HR: heart rate.
3.2 to plasma aldosterone (ALD) content influence
Carotid artery is got blood, the EDTA anticoagulant, and the centrifugal 10min of refrigerated centrifuge 3500rpm gets supernatant, with measured by radioimmunoassay ALD content.Concrete grammar is undertaken by the test kit description.
The result shows, compares model group aldosterone content highly significant increase (P＜0.01) with sham operated rats.Compare the high low dose group of Radix Scrophulariae, Captopril group plasma aldosterone content highly significant reduction (P＜0.01) with model group.The results are shown in Table 7.
Table 7 Radix Scrophulariae to the ventral aorta constriction cause remodeling ventricle rat plasma aldosterone content influence (x ± s, n=8)
Annotate: compare with model group,
*P＜0.05,
** P＜0.01
3.3 influence to cardiac index
After left side chamber systolic and diastolic function is measured and finished and get blood, open the rat thoracic cavity fast and core dirtyly, remove atrial tissue, cut off, separate left and right ventricle along interventricular septum.Rinsing is dehematized in the ice-cold normal saline, uses the filter paper suck dry moisture, and electronic balance accurately takes by weighing left ventricular mass and weight whole-heartedly.Calculate weight/body weight (HW/BW) ratio whole-heartedly, left ventricular mass/body weight (LVW/BW) ratio is designated as plump whole-heartedly index (HWI) respectively, left ventricular hypertrophy index (LVWI).
The result shows, compares model group cardiac index highly significant increase (P＜0.01) with sham operated rats.Compare with model group, Captopril group cardiac index (LVWI, HWI) highly significant reduction (P＜0.01), Radix Scrophulariae high dose group cardiac index significantly reduces (P＜0.05), though Radix Scrophulariae low dose group cardiac index has decline, difference does not have significance (P〉0.05).The results are shown in Table 8.
Table 8 Radix Scrophulariae to the influence (cardiac index) of ventral aorta constriction rat remodeling ventricle (x ± s, n=11)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
3.4 to cardiac muscular tissue's Angiotensin II (Ang II) assay
Get the about 200mg of cardiac muscular tissue of rat, add the homogenate fast in the ice bath environment of 2ml normal saline, the centrifugal 10min of 3500rpm, centrifugal, get supernatant and be 10% myocardium homogenate extracting solution.Get 200 μ l10% cardiac muscle homogenate extracting solution and add normal saline 800 μ l, be 2% homogenate extracting solution.Getting the homogenate of 2% cardiac muscular tissue operates by AngII test kit description.Carry out determining the protein quantity simultaneously, operate by Coomassie brilliant blue albumen testing cassete description.The result represents with the Ang II content in every milligram of albumen.
The result shows, compares the Ang II content highly significant increase (P＜0.01) of model group cardiac muscle with sham operated rats.Compare with model group, the high low dose group of Radix Scrophulariae, Captopril group, myocardium Ang II content highly significant reduction (P＜0.01) the results are shown in Table 9.
Table 9 Radix Scrophulariae to the ventral aorta constriction cause remodeling ventricle rat heart muscle Ang II content influence (x ± s, n=11)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
3.5 cardiac muscular tissue's Endothelin (ET-1) assay
Get 10% rat heart muscle homogenate, operate by Endothelin test kit description.The result represents with the ET-1 content in every milligram of albumen.
The result shows, compares the ET-1 content highly significant increase (P＜0.01) of model group cardiac muscle with sham operated rats.Compare with model group, Radix Scrophulariae high dose group, Captopril group, myocardium ET-1 content highly significant reduction (P＜0.01), Radix Scrophulariae low dose group ET-1 content significance reduces (P＜0.05).The results are shown in Table 10.
Table 10 Radix Scrophulariae causes the influence of remodeling ventricle rat heart muscle ET-1 content to the ventral aorta constriction) (x ± s, n=11)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
3.6 cardiac muscular tissue's hydroxyproline content is measured
Get 2% rat heart muscle homogenate, operate by hydroxyproline test kit description.The result represents with the hydroxyproline content in every milligram of albumen.
The result shows, compares model group rat heart muscle hydroxyproline content highly significant increase (P＜0.01) with sham operated rats.With model group relatively, Radix Scrophulariae high dose group, the hydroxyproline content highly significant reduction (P＜0.01) of Captopril group cardiac muscle, though Radix Scrophulariae low dose group hydroxyproline content has decline, difference does not have significance (P〉0.05), the results are shown in Table 11.
Table 11 Radix Scrophulariae to the ventral aorta constriction cause remodeling ventricle rat heart muscle hydroxyproline content influence (x ± s, n=11)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01
(Congestive heart failure CHF) is the deterioration circulation pathophysiological process that neuro humor factor and cardiac remodeling cause in chronic heart failure.After the eighties, people recognize that gradually myocardial hypertrophy, remodeling ventricle are the features of heart failure, also are simultaneously decision heart failure sickness rate, the principal element of course of disease progress and mortality rate.Angiotensin II (Ang II), aldosterone (ALD), the long-term chronic activation of the Endothelin neuroendocrine cell factors such as (ET-1) promotes myocardial remodelling, increases the weight of myocardial damage and cardiac function and worsens, and wherein Ang II and ALD are considered to promote the principal element of cardiac remodeling.Chronic heart failure (CHF) is the end stage eventually of the multiple heart disease that causes of the various causes of disease, now generally acknowledged its basic reason that development takes place be neuroendocrine by long-term activate the remodeling ventricle that causes (Colucci WS.Molecular andcellular mechanisms of myocardial failure[J] .Am J Cardiol, 1997.80:15L-25L).
The activation of RAAS causes that the secretion of Angiotensin II (Ang II) and aldosterone (ALD) increases, AngII has the stronger effect that causes myocardial fibrosis, it can directly act on cardiac fibroblast (cardiac fibroblasts by the mediation of AT1 receptor, CFs) cause the synthetic increase of collagen (Shen Jingping, Li Ruifeng.et al.The Responseness of the Fibroblasts from theMyocardium-Infarcted Rats to Angiotensin II.ISSN 100723949 Chin JArterioscler, 2002,10 (2): 115-117).ALD has and is independent of Ang II and the ill effect to heart that is added on Ang II mutually, not only cause retention of sodium and water, rising blood pressure, increase blood volume and ventricle load, effect (the Claude D that also has adjusting cardiac hemodynamics and blood pressure effect and myocardial hypertrophy, remodeling ventricle, Jeansebastien S, Anne G.et al.Cardiac aldosterone production and ventricularremodeling[J] .Kidney Int, 2000,57:346).Exist interaction between ALD and the Ang II: Ang II can stimulate ALD synthetic on the one hand; ALD can increase the combination of tissue to Ang II again on the other hand, make the biological effect of Ang II strengthen (Lijin P.Petrov V.Induction of cardiac fibrosis byaldosterone.J Mol Cell Cardiol, 2000,32 (3): 865-879).During remodeling ventricle, endothelin level (ET-1) level obviously raises, ET has vasoconstrictive, promote vascular smooth muscle cell curing, hypertrophy, various biological effects such as extracellular matrix is synthetic, the release of somatomedin and adhesion molecule and expression play an important role in hypertension incidence, its positive inotropic action can increase energy consumption, induce the myocardial cell hypertrophy, cause arrhythmia, further worsen the state of an illness.In addition, Ang II can stimulate the synthetic of ET-1, and ALD can increase the quantity of ET receptor, and collagen is synthetic to raise thereby make.
3 equal display model animal hearts indexes of experiment of the above embodiment of the present invention increase, and the AngII of cardiac muscular tissue content increases.Wherein the incomplete ligation of ventral aorta causes cardiac afterload to continue to increase, and sympathetic activation strengthens, and causes the RAAS activation, the neuroendocrine factor imbalance obviously, Ang II, ET in the cardiac muscular tissue of left chamber, the ALD in the circulation all significantly increases.The activation of above-mentioned neuroendocrine system impels the left ventricular hypertrophy index significantly to increase.Systolic pressure of this model group (SAP) and diastolic pressure (DAP) obviously raise, cardiac index LVWI, HWI, and hydroxyproline (Hyp) content significance increases, and Hyp increases the myocardium interstitial collagen hamartoplasia of reaction.These models have successfully reacted the main pathological characters of remodeling ventricle.
Experiment of the present invention shows: Radix Scrophulariae water extract has myocardial hypertrophy due to the significantly anti-multiple reason, the remodeling ventricle effect, and its mechanism of action is obviously relevant with the activation of inhibition neuroendocrine system.Simultaneously its have certain bring high blood pressure down, decreased heart rate, the hemodynamic effect of improvement.Hemodynamic improvement is also helped it produce anti-myocardial hypertrophy, remodeling ventricle, the prevention heart failure takes place and development.Experiment of the present invention shows that also the Radix Scrophulariae ethanol extraction has exploitation value aspect control remodeling ventricle and the heart failure.
Claims (4)
1. Radix Scrophulariae is as the application of unique crude drug in preparation control remodeling ventricle medicine.
2. Radix Scrophulariae is prevented and treated application in hypertrophic neuropathy and the chronic heart failure medicine as unique crude drug in preparation.
3. Radix Scrophulariae is as the application of unique crude drug in the preparation control ARR medicine relevant with myocardial hypertrophy and heart failure.
4. according to claim 1 or 2 or 3 described purposes, it is characterized in that Radix Scrophulariae is the dry root of goatweed Radix Scrophulariae Scrophularia ningpoensis Hemsl., with its water extract or ethanol extraction.
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| 华浩明.养阴活血法干预心室重塑的研究.<<中国博士学位论文>>.2007,21-22,40-46,48-53. |
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