CN102349891A - Pharmaceutical application of imperatorin in treatment of hypertension complicated with myocardial hypertrophy and heart protection - Google Patents
Pharmaceutical application of imperatorin in treatment of hypertension complicated with myocardial hypertrophy and heart protection Download PDFInfo
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- CN102349891A CN102349891A CN2011102314705A CN201110231470A CN102349891A CN 102349891 A CN102349891 A CN 102349891A CN 2011102314705 A CN2011102314705 A CN 2011102314705A CN 201110231470 A CN201110231470 A CN 201110231470A CN 102349891 A CN102349891 A CN 102349891A
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Abstract
The invention relates to pharmaceutical application of imperatorin in treatment of hypertension complicated with myocardial hypertrophy and heart protection. The imperatorin is furocoumarin compound imperatorin, which is derived from the extracts of traditional Chinese medicines dahurian angelica and cnidium fruit; and the imperatorin has no toxic or side effects when used for treating hypertension complicated with myocardial hypertrophy and heart protection related to NO way. Research shows that the imperatorin has treatment effect on hypertension complicated with myocardial hypertrophy, and has protection action on heart through NO way.
Description
Technical field
The invention belongs to the Chinese medicine extract technical field, be specifically related to the medicinal usage that a kind of imperatorin is used for hypertensive patients myocardial hypertrophy and Cardioprotective.
Background technology
Hypertension is one of modal cardiovascular and cerebrovascular disease, and Epidemiological study shows that China's hypertension has characteristics such as prevalence height, disability rate height, mortality rate height.Simultaneously, hypertensive disease is long, and the later stage is attended by the generation of complication again, also is the main risk factor of coronary heart disease, apoplexy, renal failure.Wherein left megalocardia cause people's attention all the more as hypertensive main complication.
Hypertensive treatment comprises Drug therapy and non-drug therapy, and its Chinese medicine brings high blood pressure down and can reduce cardiovascular complication incidence rate and mortality rate effectively.And the progress of apoplexy, coronary events, heart failure, kidney disease, hypertension worsened and all unknown cause death have protective action.For the old people, hypertension therapeutic more can reduce the generation of coronary heart disease significantly.So in hypertensive treatment and control procedure, Drug therapy occupy leading decisive status.Though be used to treat the medicine of high blood pressure disease at present many types are arranged; But purpose based on the generation that hypertension therapeutic is required simultaneously reduce complication; The research and the progress of application of many target spots, multiduty antihypertensive medicine are rapid; The particularly appearance of novel depressor such as beta-blocker, calcium antagonist and angiotensin converting enzyme inhibitor has improved the present situation that hypertension drug is treated to a great extent.
But calcium antagonist commonly used at present all obtains through chemosynthesis, and certain toxic and side effects is all arranged.
Summary of the invention
In order to overcome the deficiency that above-mentioned prior art exists; The object of the present invention is to provide a kind of imperatorin to be used for the medicinal usage of hypertensive patients myocardial hypertrophy and Cardioprotective; Avoided toxic and side effects; And find that imperatorin has therapeutical effect to the concurrent myocardial hypertrophy of hypertension, and heart there is protective effect through the NO approach.
In order to achieve the above object, the technical scheme that the present invention adopted is:
A kind of imperatorin is used for the medicinal usage of hypertensive patients myocardial hypertrophy and Cardioprotective.
Described imperatorin is a furocoumarin chemical compound imperatorin; This furocoumarin chemical compound imperatorin comes from the extract of Chinese medicine Radix Angelicae Dahuricae Fructus Cnidii, the treatment Cardioprotective relevant with the NO approach that this furocoumarin chemical compound imperatorin is used for the concurrent myocardial hypertrophy of hypertension.
Through pharmacodynamic study, prove that imperatorin of the present invention can be used for the treatment Cardioprotective relevant with the NO approach of the concurrent myocardial hypertrophy of hypertension.For the checking imperatorin of the present invention medicinal effects, except composition detection, the inventor also to this composition carried out further cell membrane chromatography (cell membrane chromatography, CMC).CMC is a kind of bionic biological affinity chromatography method, and the specificity that can measure between medicine and compound molecule and cell membrane and membrane receptor interacts.With the myocardial cell membrane chromatography model of SD rat, be contrast in the experiment of the present invention, the imperatorin effective ingredient carried out effective ingredient kept checking with the verapamil.Experimental result shows that under the CMC reserve, the Radix Angelicae Dahuricae of the present invention is similar with verapamil reservation chromatographic behavior with the effective ingredient imperatorin in the Fructus Cnidii.Myocardial cell membrane and membrane receptor there is effect.In a word, the inventor will use in the research the Radix Angelicae Dahuricae and Fructus Cnidii effective ingredient, finds that imperatorin has therapeutical effect to the concurrent myocardial hypertrophy of hypertension, and through the NO approach heart is had protective effect.Further test of pesticide effectiveness checking, imperatorin be to the not influence of normal myocardial cell, and myocardial cell hypertrophy due to the AngII is had inhibitory action.Through SHR rat and two kinds of modelling verifications of 2K1C mice imperatorin can suppress that the left heart is plump, the protection heart, and this mechanism maybe be relevant with the NO approach.
The specific embodiment
Below in conjunction with embodiment the present invention is done more detailed explanation.
Embodiment 1:
Experiment is to the effect of imperatorin to hypertrophic cardiomyocytes after inducing; The myocardial cell that at first produces due to the Ang II is loose; Promptly obtain former generation myocardial cell of SD rat with enzyme digestion; The cell in 4～10 generations is adopted in experiment; With 0.125% trypsinization myocardial cell; Counting is made into single cell suspension, with every hole 10
4Individual cell inoculation is in 24 well culture plates, and every hole 1mL moves into 37 ℃ CO
2In the incubator, when cell grows to 80% fusion, carry out dosing.Adopt the Ang II of 10,1 and 0.1 μ mol/L to induce myocardial cell, every hole 1mL.At 37 ℃, 5%CO
2And under the saturated humidity condition, simultaneously every hole mix [
3H]-leucine continuation cultivation 48h.After the Ang II of employing 10,1 and 0.1 μ mol/L induces myocardial cell 48h.The Ang II that finds 1 μ mol/L can obviously induce cardiac muscle cell protein synthetic, and effect is better than two other concentration of Ang II, and the Ang II of 1 μ mol/L can make the cardiac muscle cell protein synthetic ratio up to 128% ± 5%.Test the intervention effect of imperatorin to hypertrophic cardiomyocytes then, the Ang II of imperatorin and 1 μ mol/L that promptly adopts 10,1 and 0.1 μ mol/L is at 37 ℃, 5%CO
2Under the saturated humidity condition, behind the co-cultivation myocardial cell 48h, the myocardial cell hypertrophy due to the discovery imperatorin is induced Ang II is concentration dependent ground and suppresses, and the hypertrophic cardiomyocytes protein synthesis is also suppressed by concentration dependent ground simultaneously.Wherein, the imperatorin of 10 μ mol/L almost can suppress the loose and protein synthesis increase by the myocardial cell due to the Ang II of 1 μ mol/L fully; There is the intervention of imperatorin down in myocardial cell hypertrophy and the L-NAME of experiment due to the PE, promptly adopts imperatorin, 100 μ mol/L PE and the 1 μ mol/LL-NAME of 10,1 and 0.1 μ mol/L, is 5%CO 37 ℃ and concentration
2Under the saturated humidity condition, cultivate 48h after, the myocardial cell hypertrophy due to the inhibition PE that imperatorin can concentration dependent induces and cardiac muscle cell protein is synthetic increases.But add the above-mentioned effect that 1 μ mol/L L-NAME can obviously suppress imperatorin.
Like this on the myocardial cell level, prove that imperatorin has the loose effect of myocardial cell due to PE or the AngII that suppresses.It maybe be relevant with the NO approach.
Embodiment 2: imperatorin is to the effect of SHR rat left side heart plumpness and myocardial fibrosis
The experiment imperatorin is at first investigated it to the exponential influence of plumpness to the effect of SHR rat left side heart plumpness and myocardial fibrosis, and what promptly imperatorin was dose dependent has the downward modulation effect to the plump index of the left heart (LVW/BW), and is better than captopril.The left ventricular mass (LVW) of the heavy dose of group of imperatorin reduces and has significance meaning (P＜0.01) than the SHR matched group, but the dose groups reversing left heart is plump in the imperatorin, and still there were significant differences (P＜0.001) but compare with the WKY matched group; Right ventricle's weight (RVW) of each dose groups of imperatorin does not reduce because of the reduction of left ventricular mass (LVW), sees table 1.The heavy dose of group of imperatorin even to a certain degree rise has been arranged right ventricle's index (RVW/BW) makes the heart constituent ratio more reasonable.
Table 1
Annotate:
*P＜0.01,
*P＜0.05vs SHR group.
Experiment is to the effect of the SHR myocardial cell of hypertrophy, and promptly imperatorin has the inhibitory action of dose dependent equally to the SHR myocardial cell of hypertrophy, sees table 1 again, and the myocardial cell of the short diameter of myocardial cell＜30 μ m belongs to normal cell;＞30 μ m and＜myocardial cell of 45 μ m belongs to slight loose; The myocardial cell of＞45 μ m belongs to serious loose.Can from table 1, see dosage and heavy dose of slight hypertrophy zone of all myocardial cell of SHR having been adjusted in the imperatorin.Wherein in the imperatorin effect of dosage just the effect with captopril is suitable.Experiment is to the sedimentary influence of collagen in the cardiac muscle, and promptly collagen deposition is often gone with the loose companion of myocardial cell in the cardiac muscle.The SHR left side heart is plump, and myocardial cell is loose, and collagen deposition is very serious in its myocardial cell simultaneously.Visible from table 1, imperatorin has inhibitory action equally to collagen deposition.And the imperatorin heavy dose has statistical significance (P＜0.05) to the improvement effect of collagen deposition.Experiment is to the adjustment of serum myocardial fibrosis index level; Be that PCIII, CIV, HA and LN in the serum all can be used as the index that SHR rat left chamber plumpness causes myocardial fibrosis; Imperatorin can make above-mentioned myocardial fibrosis index level descend in blood pressure lowering, sees table 2.Record numerical value more near normal WKY.The decline of part index number has statistical significance, and wherein HA descends significantly (P＜0.01), the decline of other index also in various degree have a statistical significance.
Table 2
Annotate:
*P＜0.01, * P＜0.05vs SHR group.
Experiment is to the effect of index of correlation in the blood plasma, promptly in the blood plasma Ang II with ALD because just there is very big-difference in the different content in animal body itself of SHR and WKY kind, see table 3.Imperatorin and positive drug captopril all can reduce the content of Ang II and ALD in the blood plasma accordingly, see table 3, but are not that the content of Ang II and ALD is approaching in the WKY blood plasma.But; Imperatorin to above-mentioned two indexs effect and competitive angiotensin converting enzyme inhibitor--captopril has identical trend; And dosage and heavy dose of group are compared difference for Ang II horizontal down-regulation and model contrast SHR group and are had statistical significance (P＜0.05 in the imperatorin; Table 2-3); Compare with model contrast SHR group for the ALD horizontal down-regulation simultaneously and also have significant statistical significance (table 3 is seen in P＜0.01).Imperatorin has improved simultaneously the content of total NOS and iNOS in the blood plasma again, the level that is had near the WKY rat more, and the rise of above-mentioned two indexs is dose dependent, see and show 2-3.Dose groups is compared with model contrast SHR group for the rise of NOS and iNOS level with heavy dose of group and is had significance meaning (P＜0.01 in the imperatorin; P＜0.05; See table 3), the content of total NOS and iNOS even reached and negative control WKY organizes same level in the blood plasma of the SHR after the heavy dose of group of imperatorin is handled.The captopril positive controls only slightly is better than the imperatorin small dose group to the adjusting of the content of total NOS and iNOS, sees table 3.
Table 3
Annotate:
*P＜0.01, * P＜0.05vs SHR group.
Experiment is promptly constructed the SHR matched group to the influence of collagen deposition and Fiber Distribution, and average ventricle wall is the thickest in the left ventricle section of integral body earlier, and ventricular chamber is minimum, and the blood vessel wall that the while myocardial cell is wrapped in is the thickest; But naked eyes are differentiated myocardial cell from 10 * 10 photos, by should being that shuttle shape or strip become circle or ellipse; And collagen fiber are emitting shape and distribute between myocardial cell, cut apart myocardial cell is single.
The heavy dose of group of imperatorin: also be distributed with collagen fiber around the blood vessel in myocardial cell and the cardiac muscle, but collagen fiber layer is thin than the SHR group around the blood vessel; Collagen fiber between myocardial cell are the strip distribution simultaneously, do not form emitting shape as yet; Myocardial cell is out of shape lessly, and great majority remain strip or shuttle shape.
The WKY matched group: ventricle wall is thin, and ventricular chamber is bigger, and obviously the blood vessel wall that distributes in the myocardial cell is thin; Myocardial cell almost is not out of shape, and does not also almost have collagen fiber to distribute therebetween; Collagen fiber also only are very thin one decks that tunica adventitia should have.
Imperatorin has inhibitory action to left heart plumpness, simultaneously relevant blood level irregular change is had adjusting.Imperatorin can be used as the clinical preceding screening of medicaments of resisting hypertension.
Embodiment 3:
The experiment imperatorin suppress myocardial hypertrophy effect and NO by way of relation, at first adopt one-sided renal artery stenosis art to set up animal model, i.e. the preceding mice fasting 12h of operation freely drinks water.Adopt 20% Ethylurethanm (5mL/Kg) intraperitoneal injection of anesthesia mice morning next day, treating that mice does not have behind the eye blink response it is lain on the back is fixed on the operating-table left abdominal part preserved skin, the about 1 * 1cm of operative region
2, using 1% iodine tincture and 75% ethanol disinfection skin respectively, about 0.5cm under the rib is parallel to MCL 1cm place opening in the left side, and openings of sizes is about 1～2cm, exposes organ in the abdomen.With tweezers gripping fritter antiseptic gauze, get into from edge, abdominal cavity, mice left side, the internal organs such as the intestines and stomach of left kidney top are dialled to the right side, abdominal cavity, left kidney and main blood vessel are exposed.The reuse tweezers separate the left side renal artery with the glass minute hand with the renal veins passivity, and carefully peel off fatty tissue on the arteries etc., make the left side main renal artery free fully; Use the tweezers threading, carefully the left side renal aorta is pricked extremely with surgical thread apart from the about 0.3cm of kidney base of a fruit place, and observed left kidney and do not have tangible necrosis, pale, the congestion phenomenon after fixing, resets the left side intra-abdominal organ, and takes out gauze, sews up sterilization.Freshly prepared penicillin G procaine 10,000 U/20g of intramuscular injection, a continuous week of postoperative is injected the penicillin prevention infection every day.Do not touch right kidney in the operation process, internal organs do not shift out the abdominal cavity.Postoperative fasting one day.Do not prick extremely behind the free left renal artery of surgical groups, all the other operate same model group.Mice body weight steady and stabilized growth after the modeling, each organizes there was no significant difference.15mgkg
-1D
-1Imperatorin can bring high blood pressure down and heart rate significantly, sees table 4.Mice left ventricular wall after simultaneously imperatorin is handled is than model group also attenuation.
Table 4
Annotate: * P＜0.05vs model group.
Experiment is to the inhibitory action of 2K1C model mice myocardial hypertrophy; Promptly calculate gained cardiac mass index (HW/BW); Can find the cardiac index of comparing the model group mice after the imperatorin low dose is around intervening (the imperatorin low dose 4.54 ± 0.29mg/g that reduces to have statistical significance; Model group 6.60 ± 0.35mg/g; P＜0.01), sees table 5.The cross section of cardiac muscle also has the variation of same trend simultaneously, sees table 5 secondary series.The medium and small circumvascular fibrosis of myocardial cell gap fibrosis and heart in the heart is carried out quantitatively, find that the imperatorin low dose just all has inhibitory action in various degree to above-mentioned fibrosis, sees table 5 third and fourth column data.The result shows that imperatorin has the disconnected effect of anti-drag to L-NAME to the inhibitory action of NO to a certain extent.Even under the situation that L-NAME exists, imperatorin still can have inhibitory action to left heart plumpness.
Table 5
Annotate:
*P＜0.01, * P＜0.05vs model group.
The influence that experiment is expressed eNOS and index of correlation, promptly three kinds of hypotypes of the NOS that detects at us always have only eNOS to detect, and also detect for its phosphorylation (P-eNOS) simultaneously.Find that this protein content difference in each group of eNOS is little; But the albumen difference after its phosphorylation is but very big; Sham operated rats is consistent with the P-eNOS protein expression of the model group of imperatorin intervention; But model+placebo group but significance minimizing the protein content of P-eNOS, see table 6.Find that in sxemiquantitative PCR imperatorin has the adjusting that is not quite similar for the molecular marker of myocardial hypertrophy, reduced BNP, PIN and ANP; SERCA and eNOS have been raised; There is not obvious effect for iNOS.Wherein imperatorin is consistent to the regulating action of eNOS and BNP (seeing table 6) for the regulating action of eNOS and BNP mRNA and imperatorin in blood plasma.
Table 6
Annotate:
*P＜0.01vs model group.
After having set up the renal hypertension mouse model, verified imperatorin protection heart, when the reversing left heart is plump the NO approach also had protective effect, and imperatorin reversing left heart plumpness is via the NO approach.
Claims (2)
1. an imperatorin is used for the medicinal usage of hypertensive patients myocardial hypertrophy and Cardioprotective.
2. imperatorin according to claim 1 is used for the medicinal usage of hypertensive patients myocardial hypertrophy and Cardioprotective; It is characterized in that: described imperatorin is a furocoumarin chemical compound imperatorin; This furocoumarin chemical compound imperatorin comes from the extract of Chinese medicine Radix Angelicae Dahuricae Fructus Cnidii, the treatment Cardioprotective relevant with the NO approach that this furocoumarin chemical compound imperatorin is used for the concurrent myocardial hypertrophy of hypertension.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445228A (en) * | 2002-03-14 | 2003-10-01 | 北京同源医药科技有限公司 | Application of active ingredient of coumarin category distilled from dahurian angelica in preparing medicine for curing high blood pressure and its extracting method |
| CN1973835A (en) * | 2006-12-12 | 2007-06-06 | 西安交通大学 | Use of ammidin in preparing medicine for treating cadiac and cerebral vasular diseases |
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- 2011-08-12 CN CN2011102314705A patent/CN102349891A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445228A (en) * | 2002-03-14 | 2003-10-01 | 北京同源医药科技有限公司 | Application of active ingredient of coumarin category distilled from dahurian angelica in preparing medicine for curing high blood pressure and its extracting method |
| CN1973835A (en) * | 2006-12-12 | 2007-06-06 | 西安交通大学 | Use of ammidin in preparing medicine for treating cadiac and cerebral vasular diseases |
Non-Patent Citations (2)
| Title |
|---|
| ZHANG YAN，等: "Furanocoumarins-imperatorin inhibits myocardial hypertrophy both in vitro and in vivo", 《FITOTERAPIA》, vol. 81, 31 December 2010 (2010-12-31), pages 1188 - 1195, XP027487793, DOI: doi:10.1016/j.fitote.2010.07.023 * |
| 刘笑笑 等: "欧前胡素的提取分离方法和药理学研究进展", 《现代生物医学进展》, vol. 10, no. 20, 31 October 2010 (2010-10-31), pages 3954 - 3956 * |
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Application publication date: 20120215 |