Angiotensin-convertion enzyme inhibitor and the pharmaceutical composition of enkephalinase inhibitorTechnical field
The present invention relates to angiotensin-convertion enzyme inhibitor (ACEI) and enkephalinase inhibitor pharmaceutical composition andIts purposes, belongs to field of medicaments.
Background technology
Hypertension is one of modal chronic disease, is also the topmost risk factor of cardiovascular and cerebrovascular disease, its apoplexy,The disabling of the major complications such as myocardial infarction, heart failure and chronic kidney disease, fatality rate are high, seriously consume medical resource, giveFamily and society bring heavy burden.The major therapeutic goals of hypertension is the generation reducing cardiovascular complication to greatest extentWith dead overall risk, need to treat all reversibility cardiovascular risk factors, subclinical target organ damage and various alsoThe clinical disease deposited [hypertension prevention and control guide revision committee of China. China hypertension prevention and control guide 2010. China cardiovascular diseasesMagazine, 2011；39 (7): 579].
Heart failure (abbreviation heart failure) is the common complication in hypertension later stage, and its pathomechanism is ventricular pump blood or fullHypofunction, cardiac output can not meet the needs of organism metabolism, and tissue, organ hemoperfusion are not enough, occur pulmonary circulation and/orCongestion of systemic circulation, is the most also the various heart disease clinical syndrome that develops into severe stage, also referred to as congestive heart failure.The feature of heart failure is left ventricular hypertrophy or expansion, causes that neuroendocrine is not normal, circulatory function abnormal, typical clinical condition occursShape, such as cardiopalmus tachypnea, dyspnea, fluid retention (edema), weak (when particularly moving) etc..Chronic heart failure refers to persistently depositHeart failure state, can stablize, deteriorate or lose compensatory.
Heart failure is one of major reason of cardiovascular patient disability and death, and the whole world estimated 26,000,000 people suffer fromThere is heart failure.According to the statistics of World Health Organization (WHO), the incidence rate of heart failure has reached 1.9%, and the lifelong ill probability of the mankind reaches 20%,2 years case fatality rate of heart failure are 37%, and 6 annual death rate are up to 82%.In the U.S., health statistics display national healthcare expense expenditure1-2% for heart failure treat.China's heart failure sickness rate is the highest, and heart failure prevalence is estimated 1.26%, estimates about 4,000,000About people.
The common drug of clinical treatment heart failure includes diuretic, cardiac glycoside, non-glycoside inotropic agent, feritin-bloodAngiotensin-aldosterone system (RAAS) inhibitor, beta-blockers etc..Angiotensin converting enzyme inhibitor (ACEI) isControl the common drug of hypertension clinically, the activity of its main Angiotensin-converting enzyme inhibition (ACE), reduces vasotoniaElement II (Ang II) and the content of aldosterone, can reduce Kallidin I degraded simultaneously, promotes that prostaglandin discharges, thus vasodilator,Reduce blood pressure.ACEI conventional clinically has captopril, enalapril, benazepril, lisinopril, ramipril, Fu XinPuli, cilazapril, perindopril etc..
Ang II is a kind of biological effect thing crucial in RAAS, and it and specific receptors AT1 combine and can smooth by mediate vascularFlesh shrinks, vassopressin and Aldosterone Secretion release (retention of sodium and water), the release of sympathetic nerve catecholamine increase etc. a series ofEffect.The pathophysiological mechanism of heart failure relates to RAAS activation, aldosterone increase etc., therefore ACEI is applied not only to treat hypertension, withTime also be treatment heart failure (time especially with low ejection fraction) basic pharmaceutical.Left ventricular hypertrophy is the important pathology base of heart failurePlinth, ACEI has anti-proliferative effect, the cardiac hypertrophy of energy reversing hypertension patient concurrently.ACEI reverses remodeling ventricle mainly by reducingLoad, the proliferative effect of suppression Ang II and sympathetic activity, the cardiac hypertrophy of suppression aldosterone induction and interstitial before and after ventricleWith perivascular fibrosis etc. [Chinese Medical Association's angiopathy credit meeting. angiotensin converting enzyme inhibitor is in cardiovascular diseasesApplication China Consensus of experts. Chinese Journal of Cardiology, 2007,35 (2): 97].Study of evidence based medicine shows, at light, the moderate heartDecline in patient, dead relative risk 16% can be lowered with enalapril for a long time.Totally seeing, ACEI is that in RAAS inhibitor, heart failure is treatedImitate a relatively good class, but still have the obstinate heart failure curative effect of more than 1/2 to react the best, it would be highly desirable to improve.
Enkephalinase inhibitor is compound or its precursor that a class can suppress enkephalinase activity.Enkephalinase is onePlanting neutral endopeptidase, degradation in vivo several endogenous vasoactive peptide, including on atrial natriuretic peptide (ANP), Kallidin I and kidneyGland medullarin.Suppression enkephalinase i.e. can increase the level of these materials, to vasoconstriction, sodium retention, myocardial remodelling andNeuroendocrine excessive activation.Especially it is emphasized that the concentration that the important effect of enkephalinase suppression is ANP increases, ANP hasThere is powerful expansion blood vessel, row's sodium, diuresis, suppression RAAS and suppression sympathetic nervous system excited and then reduce circulation volume, alleviateCardiac load and the effect of regulation water-electrolyte balance, be internal most important RAAS antagonist hormonal, at the therapy apparatus of heart failureSystem is occupied critical role.Existing market has the most single enkephalinase inhibitor class medicine, but is mainly used in treating childDiarrhoea；Sha Ku is than the experimental prodrug that bent (sacubitril, also known as AHU-377) is a kind of enkephalinase inhibitor, onceTry out in treatment hypertension [Bavishi C, et al.Role of neprilysin inhibitor combinations inhypertension:insights from hypertension and heart failure trials.Eur HeartJ.2015；36(30):1967-1973】.
On Present clinical, heart failure treatment overall efficiency is not satisfactory.Therefore, for improving the treatment of ACEI treatment chronic heart failureEffect, reduces patients with heart failure admission rate, hospital stays and mortality risk further, and patent of the present invention provides ACEI to press down with enkephalinaseThe compositions of preparation, by both economic benefits and social benefits (Mutiple Targets) RAAS inhibitory action and other potential cooperative effect, reaches more effectiveThe purpose for the treatment of chronic heart failure.
Summary of the invention
It is an object of the invention to the deficiency overcoming ACEI medicine to exist, it is provided that a kind of performance in terms of heart failure treated effectMore excellent compound medicament composition.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition, including
(1) angiotensin-convertion enzyme inhibitor (ACEI) of pharmaceutical dosage；
(2) enkephalinase inhibitor of pharmaceutical dosage；
(3) acceptable carrier on pharmaceutics.
Described ACEI is selected from captopril (Captopril), enalapril (Enalapril), benazepril(Benazepril), lisinopril (Lisinopril), ramipril (Ramipril), fosinopril (Fosinopril), westDraw Puli (Cilazapril), perindopril (Perindopril), imidapril (Imidapril), quinapril(Quinapril), delapril (Delapril), spirapril (Spirapril), the one of alacepril (Alacepril), containAmount is 1.25～75mg.
Described enkephalinase inhibitor is the ratio one of bent (sacubitril) etc. selected from husky storehouse, and content is 10～120mg.
By further research, the content of ACEI be respectively captopril (12.5～75mg), enalapril (2.5～30mg), benazepril (5～30mg), lisinopril (2.5～30mg), ramipril (1.25～15mg), fosinopril (10～30mg), cilazapril (1.25～5mg), perindopril (2～8mg), imidapril (2.5～10mg), quinapril (10～30mg), delapril (7.5～45mg), spirapril (6～25mg), alacepril (25～75mg) etc., the work of above-mentioned substanceProperty metabolite or salt content are equal to corresponding above-mentioned substance content.
By further research, the content of enkephalinase inhibitor be husky storehouse than song 10～120mg, further preferred 20～100mg, active metabolite or the salt content of above-mentioned substance are equal to corresponding above-mentioned substance content.
The study find that, enkephalinase inhibitor is alone slight hypotensive effect, can be obviously improved Plasma ANP concentration, whenWhen share with ACEI, the anti-heart failure effect (detailed in Example) of the latter can be strengthened.In the present invention, the underlying diseases of heart failure is causedBased on essential hypertension and hypertensive heart disease, it is also possible to caused by Other diseases, such as coronary heart disease, rheumatic heart diseaseDeng.
Term " pharmaceutical dosage " refers to the purpose for reaching effectively to control or treat disease, and clinician is according to diseased individualsDiseased individuals is granted the dosage of medicine by coincident with severity degree of condition.It is to be understood that the medicine pharmaceutical dosage that the present invention provides is not to thisThe restriction of invention, but preferred to the present invention, it is generally the case that this dosage preferably in the range of, this medicine can be to illThe effective therapeutic effect of individual generation.Diseased individuals refers to the self-existent life entity suffering from disease, in the present invention, lifeThe body espespecially mankind.Should be appreciated that in prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat,Mices etc. carry out converting to draw pharmaceutical dosage or the dosage range that applicable corresponding animal is suitable for.
Compound in the pharmaceutical composition that the present invention provides can grant diseased individuals, also in identical preparation simultaneouslyThe most in succession grant diseased individuals.If in succession grant diseased individuals, then second (or additional) active component is grantedDelay should not result in the loss of the beneficial effect that active ingredient combination brings.If grant diseased individuals, compositions simultaneouslyIn compound can be mixed in same pharmaceutical dosage forms, it is also possible to independently deposit with same dosage form?.If independently existing with same dosage form, then pharmaceutical composition can flexible depositing with " Combined drug box " form?." Combined drug box " is a kind of case type container, the drug regimen of one or more dosage forms built-in and operation instructions thereof,ACEI class medicine the most described in the present invention and enkephalinase inhibitor sand storehouse are than song.
It is a further object to provide the one in the ACEI containing pharmaceutical dosage and active metabolite thereof, medicineDrug regimen with a kind of and pharmaceutically suitable carrier in the enkephalinase inhibitor of dosage and active metabolite thereof or its estersThing purposes in the medicine for preparing treatment heart failure.
The dosage form of the pharmaceutical composition that the present invention provides includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, delaysRelease tablet formulations, single chamber controlled release tablet, dual chamber controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, intestinalMolten, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release glueCapsule, the capsule containing micropill or small pieces, pH dependent form capsule, granule, oral liquid, membrane or the patch containing micropill or small piecesEtc. dosage form, wherein preferred tablet, capsule or granule.
The compound preparation of the present invention can take once a day or twice, or with slow release or controlled fashion every day or every other dayTake once, the most daily 1-2 time.
The invention has the beneficial effects as follows: the pharmaceutical composition that the present invention provides has obvious synergism, i.e. Synergistic treatmentThe effect of chronic heart failure.Present invention also offers above-mentioned pharmaceutical dosage ACEI and the medicine group of enkephalinase inhibitor compositionCompound purposes in the medicine for preparing treatment heart failure.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, all according to thisThe equivalent of any this area that summary of the invention is carried out, belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1. prepares husky storehouse than bent 20mg/ enalapril 5mg sheet (1000 amounts)
Preparation method: adjuvant is crossed 80 mesh sieves, drying for standby.Take 25g calcium phosphate dibasic anhydrous, 5g enalapril maleate byAccording to equal increments method mix homogeneously, it is separately added into Sha Ku according to recipe quantity more poly-than song, microcrystalline Cellulose, carboxymethylstach sodium and crosslinkingDimension ketone, makes soft material with 2% Gonak, and 20 mesh sieves are pelletized, and 40 DEG C are dried about 2h, 20 mesh sieve granulate, controlThe water content of granule processed is 2-3%, is mixed homogeneously with magnesium stearate, Pulvis Talci by dried granule, and semi-finished product detect,Measure content, be pressed into 1000 with tablet machine.Noting lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps awayLight preserves.
Embodiment 2. prepares husky storehouse than bent 30mg/ ramipril 2.5mg sheet (1000)
Preparation method: adjuvant is vertical compression adjuvant, drying for standby.Take the ramipril of recipe quantity and microcrystalline Cellulose 30g byAccording to equal increments method mix homogeneously, obtain mixed powder 1；Weigh the residue microcrystalline Cellulose of recipe quantity, lactose, cross-linked carboxymethyl fiberElement sodium, colloidal silica, with husky storehouse than bent abundant mixing, obtain mixed powder 2；By the sourest with the mountain of recipe quantity to mixed powder 1 and mixed powder 2Glyceride mix homogeneously, obtains and finally mixes powder intermediate, the mixed powder intermediate of detection, is pressed into 1000.Preparation process notes keep awayLight, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.
Embodiment 3. prepares husky storehouse than bent 40mg/ benazepril 10mg capsule (1000 amounts)
Preparation method: by supplementary material 80 mesh sieve, drying for standby.Take 40g sand storehouse to pass according to equivalent than bent, 10g benazeprilIncreasing method mix homogeneously, is separately added into lactose, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose, mix homogeneously,Making soft material with 2% hypromellose cellulose solution, 20 mesh sieves are pelletized, and 40 DEG C are dried about 2h, 20 mesh sieve granulate, control containing of granuleThe water yield is 2-3%, is mixed homogeneously with magnesium stearate by dried granule, and semi-finished product detect, and measures content, loads hollowCapsule and get final product.
Embodiment 4. enalaprils/Sha Ku is than the Qu Zufang therapeutical effect to Heart Failure Wistar Rats
One, method
1. animal: Wistar rat 40, male and female half and half, body weight 200--240g, dynamic purchased from Chinese Academy of Sciences's Shanghai experimentThing center.
2. modeling method: use ventral aorta constriction method (cardiac afterload increase) to make chronic heart failure rat model.GreatlyMus row 4% pentobarbital sodium intraperitoneal injection of anesthesia, per kilogram of body weight injection 40mg, xiphoid-process median incision of lower abdomen, abdomen is opened in layeringChamber, dissociates ventral aorta in the above passivity of renal artery branch, is placed in parallel for 7# syringe needle on ventral aorta, performs the operation with 4#Ventral aorta and syringe are together ligatured by silk thread, are then slowly withdrawn from by syringe, close abdomen, and layering is sewed up.Make rat abdomen masterArtery diameter constriction is 0.7mm.Normal group open after abdomen will operation silk thread through ventral aorta, except not constriction ventral aorta withOutward, other operations are identical with operation group.Normal nursing 3 weeks, measures hematodinamics index, to determine Chronic heart failure modelThe most successful.
3. packet is administered and Indexs measure: by the Heart Failure Wistar Rats random packet after above-mentioned modeling success, separately set normal controlGroup rat 10, each group is administered or disposition is shown in Table 1.Employing gastric infusion, every day 1 time, continuous 3 weeks.Measure administration respectivelyBefore, be administered after different time rat heart rate (HR), PEP (PEP), left room diastolic time (LVET), Pulse pressure(SV), often divert one's attention output (CO).Use non-invasive cardiac function hemodynamic monitoring system.Connect Electrocardiographic limbs to leadConnection, synchronous recording electrocardiogram and cardiac impedance rank differential map.Record 8-10 cardiac cycle, seek its meansigma methods.System is adopted automaticallyIndex of correlation is calculated with Kubicek formula.Separately take rat vein blood 1ml, be used for detecting Plasma ANP concentration (ELISA method).
4. statistical procedures: all experimental datas, measurement data mean ± standard deviation (X ± S) represents, mean between two groupsRelatively check with t, enumeration data X 2 test.Total data uses SPSS10.0 software to be analyzed.
Two, result
1, modeling situation: (1) ordinary circumstance: observe rat ordinary circumstance on the 3rd week in Post operation, to evaluate degree of heart failure,Result shows: ventral aorta constriction method occurs after causing rat 3 weeks that obvious symptoms of heart failure, model group rats activity significantly reduce,Pawl back of the body cyanosis, edema, hypourocrinia, there were significant differences with Normal group.(2) blood stream rheology: the 3rd week operation group andControl rats changes of cardiac function situation is shown in Table 2.Model group HR is risen to 471 ± 57.8 beats/min by 381+52.4 beat/min,LVET is foreshortened to 52.5+22.3ms, SV and CO by 80.3+24.0ms and is all remarkably decreased, 3 weeks hearts after hints model group rat operationDirty function is decreased obviously, and matched group cardiac function indices is the most unchanged.Compare HR, LVET, CO, SV between group and all have significanceDifference, illustrates model group modeling success.(3) pathological observation: model group Electronic Speculum finding: cardiac muscle T pipe and sarcoplasmic reticulum pond are all in heightSpend to extremely expanding into big string, have the big series winding in place to be connected into a small bundle of straw, etc. for silkworms to spin cocoons on.The mitochondrion stove that myocardial mitochondria hypertrophy under sarolemma becomes a small bundle of straw, etc. for silkworms to spin cocoons on, hasDissolve.Cardiac muscle sarolemma local dissolution, edema, meromyarian fibrolysis.The muscle fiber being dispersed in has collections dissolving.Cardiac muscle interfascicular is micro-Vasodilation, endotheliocyte pinocytotic vesicle increases.Normal group Electronic Speculum finding: for normal myocardium tissue, all meets following condition:Core euchromatin and heterochromatin are clearly demarcated, have great circle kernel.Have abundant kernel to work in coordination with chromatin, have around chromatin andGrain.Perinuclear space is narrow and consistent.Mitochondrion is complete, big and ridge is clear.Cardiac muscle T pipe and sarcoplasmic reticulum are few and do not expand.SarolemmaLower without edema.
The 3rd week operation group of table 1 and control rats changes of cardiac function situation
[note], initially with 30 rat modelings, after modeling dead 4, the most finally has 26 survivals.
Often the 3rd week measured value of group compares with this group respectively on the 1st week: * P ＜ 0.05, * * P ＜ 0.01；Model group and matched groupComparison:△P ＜ 0.05,△△P ＜ 0.01.
2, enalapril/Sha Ku is than the bent comparison with enalapril: after 3 weeks treat, compare with model group, enalaprilGroup, enalapril/Sha Ku all significantly improves than the song group Heart Failure Wistar Rats hemodynamics of the 6th week, shows as heart rate and PEPDecline, LVET and CO rises, and enalapril group, enalapril/Sha Ku point out the obvious therapeutic action to heart failure than Qu Zujun.ThisOutward, comparing with enalapril group, enalapril/Sha Ku substantially increases than song group Plasma ANP concentration, the decline of hemodynamics PEP,CO rises the most notable, points out the therapeutical effect to heart failure to have some superiority.
Within 6th week, respectively group Cardiac Function in Rat and Plasma ANP situation compare (n=10) to table 2
Compare with matched group: * P ＜ 0.05, * * P ＜ 0.01；Compare with model group:△P ＜ 0.05,△△P ＜ 0.01；With depend onThat Puli's group compares:#P ＜ 0.05.
Three, discuss
This research uses ventral aorta constriction legal system to make chronic heart failure rat model.During heart failure, hemodynamic abnormalities is to produceThe pathophysiological basis of raw clinical congestive symptom.Left Ventricular Global Dysfunction causes CO to reduce and left room diastolic time extends, and the former leadsCausing histoorgan hemoperfusion not enough, the latter causes Pulmonary Vascular to snap rising.Using constriction rat aorta, build-up of pressure is bornLotus pathologic increases, and cardiac work increases, and causes left heart failure, ultimately results in and decline whole-heartedly.Experimental result shows: ventral aorta constrictionObvious symptoms of heart failure occurred after 3 weeks, has significant difference with Normal group.Model group rats activity significantly reduces, pawl back of the body purpleDark purple, edema, compare with matched group and have significant difference.Prompting modeling group Cardiac Function in Rat declines, and systemic blood perfusion reduces.The heartDirty merit is shunk and diastolic dysfunction causes CO to reduce respectively and LVEDP (LVEDP) increases.Along with cardiac outputMinimizing, have activated various neuroendocrine regulatory mechanism, make peripheral circulation resistance increase, peripheral blood is redistributed.
Experimental result shows: model group HR dramatically speeds up；LVET shortens, SV and CO is all remarkably decreased, and hints model group is big3 weeks cardiac functions of Mus Post operation are decreased obviously, and matched group cardiac function indices is the most unchanged, and modeling success is described.This realityTest the non-invasive cardiac function hemodynamic monitoring system of employing, under rat waking state, measure cardiac function hematodinamics refer toMark, overcomes and uses traumatic measuring method under narcotism, thus avoid animal status (clear-headed or anesthesia) withAnd operational approach (invasive or non-invasive) is different and the interference to Cardiac Function in Rat that causes.Model group rats perform the operation 3 weeks after heartShrink and diastolic function the most substantially reduces, illustrate that model group rats heart contraction and diastolic function are decreased obviously.
This Preliminary Study confirm enalapril/Sha Ku than Qu Erlian prescription at the significant curative effect that heart failure is treated: controlled through 3 weeksAfter treatment, comparing with model group, enalapril/Sha Ku all significantly improves than the song group Heart Failure Wistar Rats hemodynamics of the 6th week,Showing as heart rate and PEP declines, LVET and CO rises, rat plasma ANP concentration the most substantially increases, the comprehensive prompting of these resultsObvious therapeutic action to heart failure.Additionally, compare with enalapril group, enalapril/Sha Ku substantially increases than song group ANP concentrationHeight, PEP declines, CO rises the most notable, points out this prescription that the therapeutical effect of heart failure is had some superiority.
Embodiment 5. ramiprils/Sha Ku is than the Qu Zufang therapeutical effect to Heart Failure Wistar Rats
One, method
1. animal: Wistar rat 48, male and female half and half, body weight 205--245g, dynamic purchased from Chinese Academy of Sciences's Shanghai experimentThing center.
2. modeling method: with embodiment 4.
3. packet is administered and Indexs measure: by the Heart Failure Wistar Rats random packet after above-mentioned modeling success, separately set normal controlGroup rat 12, each group is administered or disposition is shown in Table 4.Employing gastric infusion, every day 1 time, continuous 3 weeks.Measure administration respectivelyBefore, be administered after different time rat heart rate (HR), PEP (PEP), left room diastolic time (LVET), Pulse pressure(SV), often divert one's attention output (CO).Use non-invasive cardiac function hemodynamic monitoring system.Connect Electrocardiographic limbs to leadConnection, synchronous recording electrocardiogram and cardiac impedance rank differential map.Record 8-10 cardiac cycle, seek its meansigma methods.System is adopted automaticallyIndex of correlation is calculated with Kubicek formula.Separately take rat vein blood 1ml, be used for detecting Plasma ANP concentration (ELISA method).
4. statistical procedures: all experimental datas, measurement data mean ± standard deviation (X ± S) represents, mean between two groupsRelatively check with t, enumeration data X 2 test.Total data uses SPSS 10.0 software to be analyzed.Two, result
1, modeling situation: (1) ordinary circumstance: observing rat ordinary circumstance on the 3rd week in Post operation, result shows: abdomen is activelyThe narrow method of rugosity occurs after causing rat 3 weeks that obvious symptoms of heart failure, model group rats activity significantly reduce, pawl back of the body cyanosis, edema, urineAmount reduces, and there were significant differences with Normal group.(2) blood stream rheology: the 3rd week operation group and control rats cardiac functionSituation of change is shown in Table 3.Model group HR rises, and LVET shortens, SV and CO is remarkably decreased, 3 weeks hearts after hints model group rat operationDirty function is decreased obviously, and matched group cardiac function indices is the most unchanged, prompting modeling success.(3) pathological observation: model groupElectronic Speculum is shown in that cardiac muscle T pipe and sarcoplasmic reticulum pond all expand into big string in height to extreme, has big series winding the in place to be connected into a small bundle of straw, etc. for silkworms to spin cocoons on.Myocardial mitochondriaThe mitochondrion stove dissolving that hypertrophy becomes a small bundle of straw, etc. for silkworms to spin cocoons on, has under sarolemma.Cardiac muscle sarolemma local dissolution, edema, meromyarian fibrolysis.It is dispersed inMuscle fiber have collections dissolving.Normal group Electronic Speculum has no above-mentioned pathological change.
The 3rd week operation group of table 3 and control rats changes of cardiac function situation
[note], initially with 36 rat modelings, after modeling dead 5, the most finally has 31 successes.
Often the 3rd week measured value of group compares with this group respectively on the 1st week: * P ＜ 0.05, * * P ＜ 0.01；Model group and matched groupComparison:△P ＜ 0.05,△△P ＜ 0.01.
2, ramipril/Sha Ku is than the bent comparison with ramipril: after 3 weeks treat, compare with model group, ramiprilGroup, ramipril/Sha Ku all significantly improves than the song group Heart Failure Wistar Rats hemodynamics of the 6th week, shows as heart rate and PEPDecline, LVET and CO rises, and ramipril group, ramipril/Sha Ku point out the obvious therapeutic action to heart failure than Qu Zujun.ThisOutward, comparing with ramipril group, ramipril/Sha Ku substantially increases than song group Plasma ANP concentration, the decline of hemodynamics PEP,CO rises the most notable, points out the therapeutical effect to heart failure to have some superiority.
Within 6th week, respectively group Cardiac Function in Rat and Plasma ANP situation compare table 4
Compare with matched group: * P ＜ 0.05, * * P ＜ 0.01；Compare with model group:△P ＜ 0.05,△△P ＜ 0.01；With thunderMeter Pu Li group compares:#P ＜ 0.05.
Three, discuss
Experimental result shows: model group HR dramatically speeds up；LVET shortens, SV and CO is all remarkably decreased, and hints model group is big3 weeks cardiac functions of Mus Post operation are decreased obviously, and matched group cardiac function indices is the most unchanged, and modeling success is described.This realityTest the non-invasive cardiac function hemodynamic monitoring system of employing, under rat waking state, measure cardiac function hematodinamics refer toMark, overcomes and uses traumatic measuring method under narcotism, thus avoid animal status (clear-headed or anesthesia) withAnd operational approach (invasive or non-invasive) is different and the interference to Cardiac Function in Rat that causes.Model group rats perform the operation 3 weeks after heartShrink and diastolic function the most substantially reduces, illustrate that model group rats heart contraction and diastolic function are decreased obviously.
This Preliminary Study confirmed that ramipril/Sha Ku has significant curative effect when being used for heart failure rat than Qu Zufang: through treatment in 3 weeksAfter, comparing with model group, ramipril/Sha Ku all significantly improves than the song group Heart Failure Wistar Rats hemodynamics of the 6th week, tableBeing now heart rate and PEP decline, LVET and CO rising, rat plasma ANP concentration the most substantially increases, and the comprehensive prompting of these results is rightThe obvious therapeutic action of heart failure.Additionally, compare with ramipril group, ramipril/Sha Ku substantially increases than song group ANP concentration,PEP declines, CO rises the most notable, points out this prescription that the therapeutical effect of heart failure is had some superiority.