CN109172808A - Natriuretic peptide GNP is used to prepare the purposes of the drug for the treatment of pulmonary hypertension correlation indication or heart failure merging pulmonary hypertension - Google Patents
Natriuretic peptide GNP is used to prepare the purposes of the drug for the treatment of pulmonary hypertension correlation indication or heart failure merging pulmonary hypertension Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The present invention relates to the new applications of natriuretic peptide GNP, are specifically related to the purposes that natriuretic peptide GNP is used to prepare the drug for the treatment of pulmonary hypertension correlation indication or heart failure merging pulmonary hypertension.Effect experiment of the invention confirms that natriuretic peptide GNP has the effect of significantly treating pulmonary hypertension, thus can be prepared to the drug for the treatment of pulmonary hypertension correlation indication or heart failure merging pulmonary hypertension, has wide medicine promotional value.
Description
Technical field
The present invention relates to the new applications of natriuretic peptide GNP, are specifically related to natriuretic peptide GNP and are used to prepare treatment pulmonary hypertension
Related indication or heart failure merge the purposes of the drug of pulmonary hypertension.
Background technique
Natriuretic peptide (Natriuretic Peptide, NP) refers to a kind of with compared with biologies such as forced-ventilated sodium, diuresis, expansion blood vessels
Active polypeptide.These polypeptides have homology and identical receptor system genetically.Currently, being obtained from mammal
Natriuretic peptide include: atrial natriuretic peptide, brain natriuretic peptide and c-type natriuretic peptide.Atrial natriuretic peptide is mainly secreted by atrial muscle cell, brain natriuretic peptide mainly by
Ventricular muscle cell secretion, c-type natriuretic peptide are mainly secreted by vascular endothelial cell and are locally playing blood vessel dilatation and antiproliferative work
With.Patent of invention " a kind of natriuretic peptide and its gene and purposes " (patent No.: ZL that inventor proposed in 2013
201310127277.6；Authorize publication number: CN103159847B), which disclose a kind of from the green mamba snake in East Africa
Natriuretic peptide.This is a kind of completely new natriuretic peptide, is the newcomer of natriuretic peptide family, referred to as GNP, i.e. G type natriuretic peptide.This benefit sodium
Peptide GNP, including recombination natriuretic peptide and artificial synthesized natriuretic peptide can be applied to preparation treatment acute heart failure, acute mistake generation
Repay patient after heart failure, acute myocardial infarction AMI intervention of coronary artery, chronic heart failure, older patients with acute antetheca cardiac muscle stalk
The dead drug for merging systolic heart failure patient.
It is more than one kind of certain dividing value that pulmonary hypertension (pulmonary hypertension), which refers to that pulmonary artery pressure increases,
Haemodynamics and pathological and physiological condition, can lead to right heart failure, can be a kind of independent disease, are also possible to complication,
It can also be syndrome.Pulmonary hypertension is a kind of common disease, frequently-occurring disease, common sympton include: expiratory dyspnea, fatigue, it is out of strength,
Exercise tolerance lowers, syncope, angina pectoris or pectoralgia, hemoptysis, hoarseness etc..Since pulmonary hypertension disability rate and case fatality rate are equal
It is very high, therefore cause the great attention of people.
Currently, there is no the report about the drug that natriuretic peptide is used to prepare to treatment cost arterial hypertension correlation indication.
Summary of the invention
The purpose of the present invention is to provide the new applications of natriuretic peptide GNP a kind of.
Treatment pulmonary hypertension correlation indication is used to prepare the present invention provides natriuretic peptide GNP or heart failure merges pulmonary artery
The purposes of the drug of high pressure.
Purposes according to the present invention, the drug include recombination natriuretic peptide or artificial synthesized natriuretic peptide.As before
It is described, in the ZL 201310127277.6 that applicant proposes, a kind of completely new natriuretic peptide GNP is disclosed for the first time, is provided simultaneously
Recombination natriuretic peptide or artificial synthesized natriuretic peptide.
Further, the drug further includes pharmaceutically acceptable excipient, carrier or diluent.It is related pharmaceutically
Excipient, carrier or the diluent of receiving can refer to existing pharmaceuticals industry technology.
Effect experiment of the invention confirms that natriuretic peptide GNP has the effect of significantly treating pulmonary hypertension, thus can incite somebody to action
Recombination natriuretic peptide or artificial synthesized natriuretic peptide are prepared into treatment pulmonary hypertension correlation indication or heart failure merges pulmonary artery height
The drug of pressure has wide medicine promotional value.
Detailed description of the invention
Fig. 1 shows that the pulmonary systolic pressure of each group changes percentage.
Fig. 2 shows that the pulmonary artery diastolic blood pressure of each group changes percentage.
Fig. 3 shows that the mean pulmonary arterial pressure of each group changes percentage.
Fig. 4 shows the aortic systolic pressure of each group.
Fig. 5 shows the aortic diastolic blood pressure of each group.
Fig. 6 shows the mean aortic pressure of each group.
Fig. 7 shows the left ventricular systolic pressure of each group.
Fig. 8 shows the left room end diastolic pressure of each group.
Fig. 9 shows the intraventricular pressure rise/fall maximum rate (dp/dt Max.) of each group.
Figure 10 shows the intraventricular pressure rise/fall minimum-rate (dp/dt Max.) of each group.
Figure 11 shows the administration front and back groups of animals changes in heart rate of each group
Specific embodiment
1. experimental raw: GNP.
Character: white freeze-dried powder；Specification and content: 0.25mg/ branch, 98.16%；Preservation condition: (- 20 DEG C) of freezing dry
Dry preservation；Preparation method: test sample is taken, 4 DEG C, 10000rpm, is centrifuged 10min.After centrifugation, quantitative physiological saline solution is drawn,
And it is diluted to required concentration；Condition: 2~8 DEG C of Preservation in sterile condition is kept in after preparation；Validity period after preparation: 24 hours.
2. experimental animal: Beagle dog.
Grade: regular grade；Size of animal and gender: 28 (half male and half female)；Age: about 12-18 week old；Weight: 8~
11kg；Source: Guangzhou General Pharmacological Research Institute Co., Ltd..
3. animal packet and mark
3.1 animal packet
Group design: sham-operation group, solvent control group, drug control group, GNP dosage group.
Size of animal: sham-operation group, solvent control group every group 6；Drug control group, GNP dosage group every group 8；Gender
Ratio: half male and half female.
Group technology: test carries out in batches, is grouped at random according to weight, and every wheel 4-6 is only (every group of 1-2 is only).3.2 dynamic
Object mark
After random grouping, is marked using overbit and cage card as the identification of animal, test number, animal are indicated on cage card
Germline, number of animals, processing factor, expected test beginning and ending time, remark information etc..
4. dose design and administration
4.1 dose design
The basic, normal, high dosage setting of this test GNP is 200,500,900ng/kg/min.If drug control group recombinates human brain
Sodium peptide rhBNP 200ng/kg/min, solvent control group give isometric physiological saline.Sham-operation group separately is set, does not establish the acute heart
Failure model gives isometric physiological saline.
Specific dose design is shown in Table 6.
6 GNP of table designs table to Beagle dog acute heart failure evaluating drug effect test dose
4.2 administration
Administration frequency: single-dose, GNP group 200,500,900ng/kg/min accumulation administration.
Administration route: intravenous drip, it is consistent with the quasi- approach of this product clinic.
Administration time: 30min.
5. establishing animal model
In this test, inventor using digital blood vessel development subtract shadow (digitalsubtraction angiography,
DSA) minimally invasive interventional method (number of patent application: 201510994802.3) implantable pacemaker.DSA ensures that pacing electrode is accurately planted
Enter to right ventricular apex；Minimally Invasive Surgery reduces the wound to animal to the full extent, and postoperative care is simple, animal convalescence
Short, the death rate is low, and modeling is high-efficient.Detailed step is as follows:
Fasting: Beagle dog at least fasting 12hr, free water before testing.
Anesthesia: 3% yellow Jackets 1mL/kg induced anesthesia of intravenous injection, 0.5mL/kg maintain anesthesia.
Implantable pacemaker: the operation right jugular vein of blunt separation, it is (negative that digital blood vessel development subtracts shadow intervention guidance stimulating electrode
Pole) implantation right ventricular apex position, anode and pacemaker module are sewn in strength dorsal sc pouch.
It paces modeling: postoperative care 3~7 days, when Beagle dog restores substantially, opening pacemaker, start to pace.Pace-making ginseng
Number: pulsewidth: 0.5~0.8mA, pacing frequency: 240 times/min, pacing cycle: 2-3 weeks；Refer to preceding animal itself heart function is paced
Mark compares, and ejection fraction (EF), left room are shortened score (FS), end-diastolic volume (EDV), end systolic volume (ESV) etc. and gone out
Existing significant change prompts animal model modeling success.
6. Testing index
6.1 Color Sonography
Beagle dog heart is checked using colorful Doppler ultrasound diagnostic apparatus (U.S. GE, Vivid i):
Left heart function: chamber interval thickness (IVS), left ventricular posterior wall thickness (LVPW), end systolic diameter (LVS), end-diastolic
Score is shortened in phase internal diameter (LVD), end systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), left room
(FS), stroke output (SV).
Testing time: before modeling, after modeling (before administration), after administration.
6.2 haemodynamics
After ultrasonic judgment models success, Beagle dog at least fasting 12h before being administered, 3% yellow Jackets 1mL/kg induction
Anesthesia, 0.5mL/kg maintain anesthetized animal, blunt separation right femoral vein of performing the operation, right femoral artery, left femoral artery, digital blood vessel development
Subtract shadow intervention intubation (5F, 80cm, Japanese Terumo) to pulmonary artery, left ventricle, left femoral artery, using polygraph
(U.S. Biopac, MP150) tests pulmonary arterial pressure, left ventricular pressure, aortic pressure.
1) pulmonary arterial pressure (PVP)
Pulmonary systolic pressure (PSP), pulmonary artery diastolic blood pressure (PDP), mean pulmonary arterial pressure (PMP).
Testing time: after modeling (before administration), administration start 10,20,30min；10 after administration, 20,30min.
2) left ventricular pressure (LVP)
Left ventricular systolic pressure (LVSP), left room end diastolic pressure (LVEDP), intraventricular pressure rise/fall maximum rate (±
Dp/dt Max., ± dp/dt Min.).
Testing time: after modeling (before administration), administration start 10,20,30min；10 after administration, 20,30min.
3) aortic pressure (AVP)
Aortic systolic pressure (ASP), aortic diastolic blood pressure (ADP), mean aortic pressure (AMP).
Testing time: after modeling (before administration), administration start 10,20,30min；10 after administration, 20,30min.
6.3 heart rate (HR)
Beagle dog four limbs are subcutaneously inserted needle electrode, are examined using polygraph (U.S. Biopac, MP150)
Mark II lead electrocardiogram of standard, is tested heart rate (HR).
Testing time: before modeling, after modeling (before administration), administration start 10,20,30min；10 after administration, 20,
30min。
6.4 blood plasma cyclic guanosine monophosphate (cGMP) concentration
Sample type: the anticoagulant blood plasma of EDTA.
Acquisition time: before modeling, after modeling (before administration), after administration.
Detection method: ELISA.
Detection kit: U.S. R&D, Cat:KGE003.
6.5 blood biochemical
Sample type: it is clear that separation gel promotees blood coagulation.
Acquisition time: before modeling, after modeling (before administration), after administration.
Testing index: myocardium enzyme (CKL), creatine kinase isozyme (CK-MB), lactic dehydrogenase (LDH), creatinine
(CREA), urea nitrogen (UREAL), glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminease (AST), total bilirubin (BILT).
6.6 statistical analysis
Test data is indicated with Mean ± SEM, is first examined using LEVENE between group and is carried out homogeneity test of variance, when variance is neat
When (P > 0.05), using one-way analysis of variance (ANOVA) carry out statistical test；One-way analysis of variance shows that difference has system
When meter learns meaning (P≤0.05), then (Dunnett method) is examined to be compared group difference using DunnettShi t；Single factor test
When variance analysis shows no significant difference (P > 0.05), then statistical analysis terminates.
When heterogeneity of variance (P≤0.05), statistical is carried out using Kruskal-Wallis H rank sum test (K-W method)
Analysis.When Kruskal-Wallis H rank sum test shows that difference is statistically significant (P≤0.05), using Mann-
Whitney U examines (M-W method) to be compared group difference；When Kruskal-Wallis H rank sum test shows difference without system
When meter learns meaning (P > 0.05), statistical analysis terminates.The conspicuousness of front and back difference to be administered in paired t-test comparative group.
7. evaluating drug effect test result
7.1 parameters of left ventricular function
1) ejection fraction (EF%)
After modeling, model group Beagle dog ejection fraction (EF%) is remarkably decreased (P < 0.01) than sham-operation group.With solvent
Control group is compared, after positive drug BNP 200ng/kg/min administration, EF% apparent increase (P < 0.05).Test sample GNP
After 200ng/kg/min administration, EF% is in raising trend；After GNP500ng/kg/min administration, EF% is more obvious than solvent control group
It increases (P < 0.05)；After GNP900ng/kg/min administration, EF% significantly increases (P < 0.01).GNP500ng/kg/min pairs
The improvement of EF% is substantially better than 200ng/kg/min dosage (P < 0.05), and GNP900ng/kg/min imitates the improvement of EF%
Fruit is also significantly better than GNP (200 ng/kg/min) (P < 0.01), shows preferable dose-effect relationship.GNP 500ng/
After kg/min and 900 ng/kg/min administration, EF% value is higher than BNP 200ng/kg/min (n=8).
Compared with before modeling, ejection fraction (EF%) is remarkably decreased (P < after GNP administration group Beagle dog (n=8) modeling
0.01).After giving GNP 200ng/kg/min, EF% gives GNP 500ng/ compared with (P < 0.05) significantly raised after modeling respectively
After kg/min and 900ng/kg/min, EF% is compared with significantly raising (P < 0.01) after modeling.With 200ng/kg/min dose comparison,
GNP 500ng/kg/min and 900ng/kg/min (P < 0.01) more significant to the improvement of EF%, and 900ng/kg/min is imitated
Fruit is better than 500ng/kg/min (P < 0.05).GNP 200-900ng/kg/min shows good dose-effect to the improvement of EF%
Relationship.
Compared with before modeling, ejection fraction (EF%) is remarkably decreased (P < after BNP administration group Beagle dog (n=8) modeling
0.01).After BNP 200ng/kg/min administration, EF% is compared with (P < 0.05) significantly raised after modeling.
Compared with before modeling, EF% is remarkably decreased after solvent control group modeling, and after giving physiological saline, EF% is still maintained at
Level (P < 0.01) lower than 40%.EF% is without significant change (P > 0.05) before and after sham-operation group modeling.
2) score (FS%) is shortened in left room
After modeling, each left room of Model B eagle dog (n=8) shortens score (FS) and is remarkably decreased (P < than sham-operation group
0.01).After GNP500ng/kg/min, 900ng/kg/min administration, FS% raising (P < 0.01) more significant than solvent control group.
After BNP200ng/kg/min and GNP200ng/kg/min administration, FS% has the raising of respective degrees.GNP900ng/kg/min pairs
The improvement of FS% is apparently higher than BNP200ng/kg/min (P < 0.05), and is significantly higher than GNP200ng/kg/min dosage
(P < 0.01).GNP500ng/kg/min dosage is significantly better than GNP200ng/kg/min dosage (P < to the improvement of FS%
0.05) preferable dose-effect relationship, is showed.
FS% is substantially less than before modeling (P < 0.01) after GNP group Beagle dog (n=8) modeling.After administration, 500ng/
FS% significantly improves (P < 0.01) after kg/min and 900ng/kg/min dose ratio modeling.500 ng/kg/min of GNP and
900ng/kg/min dosage is significantly better than 200ng/kg/min (P < 0.01) to the improvement of FS%.GNP 200-900ng/
Kg/min shows good dose-effect relationship to the improvement of EF%.
After BNP administration group animal (n=8) modeling, FS% is substantially less than before modeling (P < 0.01).BNP 200 ng/kg/
After min administration, FS% level is than significantly improving (P < 0.05) after modeling.
After solvent control group modeling, FS% is remarkably decreased, and after giving physiological saline, FS% is still maintained at 20% or less level
(P < 0.01).FS% is without significant change (P > 0.05) before and after sham-operation group modeling.
3) left room end systolic volume (ESV)
After modeling, left room end systolic volume (ESV) is significantly higher than sham-operation group.After giving BNP or GNP, especially GNP
After 500ng/kg/min and 900ng/kg/min administration, ESV reduces obvious.
After GNP administration group (n=8) Beagle dog modeling, ESV is significantly higher than before modeling (P < 0.01, P < 0.05).GNP
After 500ng/kg/min, 900ng/kg/min administration, ESV is decreased obviously, wherein after 900 ng/kg/min administration, ESV is significant
Lower than (P < 0.01) after modeling.GNP 900ng/kg/min effect is better than 500ng/kg/min (P < 0.05) and 200ng/kg/
min.GNP 200-900ng/kg/min shows apparent dose-effect relationship to the improvement degree of ESV.
After BNP administration group (n=8) Beagle dog modeling, ESV is significantly higher than before modeling (P < 0.01), BNP 200ng/
After kg/min administration, ESV starts to reduce.
After modeling, solvent control group ESV is significantly raised, and after giving physiological saline, ESV is still maintained at higher level (P <
0.05).ESV is without significant change (P > 0.05) before and after sham-operation group modeling.
4) left room end-diastolic volume (EDV)
Modeling Beagle dog EDV is apparently higher than sham-operation group (* P < 0.05, * * P < 0.01).GNP200 ng/kg/min,
After 500ng/kg/min and 900ng/kg/min administration, EDV is successively reduced, and 900ng/kg/min effect is the most obvious.GNP
500ng/kg/min and 900ng/kg/min is better than BNP200ng/kg/min to the improvement degree of EDV.
After GNP administration group (n=8) Beagle dog modeling, EDV apparent increase (P < 0.05).After tri- dosage administrations of GNP,
EDV is on a declining curve.EDV is down to level before modeling after GNP 900ng/kg/min administration.
After BNP administration group (n=8) Beagle dog modeling, EDV apparent increase (P < 0.05).After administration, EDV and modeling
After compare no significant difference (P > 0.05).
Compared with before modeling, EDV is significantly raised after solvent control group modeling, and after giving physiological saline, EDV is still maintained at
Higher level (* P < 0.05).EDV no significant difference (P > 0.05) before and after sham-operation group modeling.
5) end systolic diameter (LVS)
After modeling, animal pattern LVS is more significantly raised (* * P < 0.01) than sham-operation group, after tri- dosage group administrations of GNP
LVS is on a declining curve.
After GNP administration group (n=8) Beagle dog modeling, LVS significantly increases (* * P < 0.01).GNP200 ng/kg/
After min, 500ng/kg/min and 900ng/kg/min administration, LVS is successively reduced.Wherein, 900 ng/kg/min of GNP is administered
Afterwards, LVS significantly reduces (#P < 0.05), and effect is obvious.
After BNP administration group (n=8) Beagle dog modeling, LVS is noticeably greater than before modeling (* * P < 0.01). 200ng/kg/
After min administration, LVS is begun to decline.
After solvent control group modeling, LVS is significantly increased, and after giving physiological saline, LVS is still maintained at higher level (* * P <
0.01).LVS is without significant changes (P > 0.05), model stability before and after sham-operation group modeling.
6) diastolic dimensions (LVD)
After each group modeling, LVD is substantially less than sham-operation group (P < 0.01).After tri- dosage group administrations of GNP, LVD is gradually
It reduces.
After GNP administration group (n=8) Beagle dog modeling, LVD before modeling than significantly increasing, after three dosage administrations, LVD
The effect successively reduced is presented.
After BNP administration group (n=8) Beagle dog modeling, LVD is than significantly increasing (P > 0.05) before modeling. BNP
After 200ng/kg/min administration, it is on close level after LVD and modeling.
After solvent control group modeling, LVD is significantly raised, and after giving physiological saline, LVS is still maintained at higher level (* P <
0.05).LVS is without significant change (P > 0.05) before and after sham-operation group modeling.
7) Pulse pressure (SV)
After modeling, stroke output (SV) compared with sham-operation group in raising trend, each administration group SV and sham-operation group and
Solvent control comparison among groups are without significant difference (P > 0.05).
After GNP administration group (n=8) Beagle dog modeling, SV is on a declining curve.After tri- dosage administrations of GNP, SV is obviously risen
It is high, wherein 500ng/kg/min and 900ng/kg/min is more significant (* * P < 0.01, * P < 0.05) to the improvement of SV, substantially
It is horizontal before restoring to modeling.After BNP administration group (n=8) Beagle dog modeling, SV before modeling compared with reducing, BNP 200ng/kg/
After min administration, SV is in significantly raised trend.
Before and after solvent is to group and sham-operation group modeling, the interior front and back Beagle dog (n=6) SV is organized without significant difference (P >
0.05)。
8) chamber interval thickness (IVS)
After modeling, comparison among groups, Beagle dog cardiac septum thickness (IVS) than before modeling without significant change, BNP and
After GNP is administered respectively, IVS is in reduction trend.
Before and after the modeling of each group Beagle dog, after administration, IVS no significant difference (P > 0.05).
9) left ventricular posterior wall thickness (LVPW)
After modeling, solvent control group, after the administration of BNP and GNP administration group, left ventricular posterior wall thickness (LVPW) and sham-operation group
Between without significant difference (P > 0.05).
After each group modeling, no significant difference before left ventricular posterior wall thickness (LVPW) and modeling, each group Beagle dog administration front and back
LVPW is also without significant difference (P > 0.05).
7.2 pulmonary artery pressure
1) pulmonary systolic pressure (PSP)
After the administration of heart failure Beagle dog, pulmonary systolic pressure (PSP) is on a declining curve.BNP 200ng/kg/min dosage
10min is administered, PSP is substantially less than solvent control group (##P < 0.01), and 20min, PSP and solvent control group significant difference is administered
(#P < 0.05).After tri- dosage administrations of GNP, PSP is obviously begun to decline.Wherein, 20min is administered in 500ng/kg/min dosage,
PSP is significantly lower than solvent control group (* P < 0.05), in administration 20min, is better than BNP 200ng/ to the improvement degree of PSP
kg/min.It is administered after 30min (after being administered), for each administration group PSP significantly lower than (Fig. 1) before administration, antihypertensive effect is obvious.
2) pulmonary artery diastolic blood pressure (PDP)
After modeling, solvent control group pulmonary artery diastolic blood pressure (PDP) is apparently higher than sham-operation group (#P < 0.05).After administration,
PDP is decreased obviously.30min after 20min to administration is administered in GNP 500ng/kg/min dosage, and PDP is substantially less than solvent pair
It is the most significant to the improvement degree of pulmonary artery diastolic blood pressure according to group (* * P < 0.01).The administration of GNP 900ng/kg/min dosage
30min after 20min to administration, PDP are significantly lower than solvent control group (* P < 0.05).It is dynamic that GNP shows apparent diastole lung
Arteries and veins, reduces the effect of diastolic pressure, and effect is substantially better than BNP under 500ng/kg/min and 900ng/kg/min dosage
200ng/kg/min (Fig. 2).
3) mean pulmonary arterial pressure (PMP)
After administration, mean pulmonary arterial pressure (PMP) is decreased obviously.After being extremely administered after GNP 500ng/kg/min administration
30min, PMP are significantly lower than solvent control group (* * P < 0.01, * P < 0.05), and 20min is administered extremely in 900 ng/kg/min of GNP
30min after administration, PMP are significantly lower than solvent control group (#P < 0.05).BNP 200ng/kg/min be administered during to giving
30min after medicine, PMP are substantially less than solvent control group (△ △ P < 0.01, △ P < 0.05).GNP 500ng/kg/min
(Fig. 3).GNP 500ng/kg/min is the most obvious to the antihypertensive effect performance of PMP, and is substantially better than BNP 200ng/kg/min
Dosage.
7.3 aortic pressures (AVP)
After modeling, solvent control group aortic pressure is slightly increased than sham-operation group；After administration, aortic systolic pressure relaxes
Open pressure, mean arterial pressure is lower than solvent control group.Aortic systolic pressure, diastolic pressure, mean arterial pressure are poor without statistics between each group
Different (P > 0.05) (Fig. 4, Fig. 5 and Fig. 6).
7.4 left ventricular pressure
After modeling, the left room diastasis pressure (LVEDP) of Beagle dog, intraventricular pressure declines maximum rate (dp/dt
Min. it) increases, after administration, two indexes are on a declining curve.After GNP 500ng/kg/min administration, left ventricular systolic pressure (LVSP) and the heart
Intraventricular pressure, which rises maximum rate (dp/dt Max.), raising trend (Fig. 7 to Figure 10).
7.5 hearts rate (HR)
Solvent control group increases (* * P < 0.01, * P < 0.05) than sham-operation group HR；GNP 500ng/kg/min is than false
Operation group HR increases (#P < 0.05)；BNP 200ng/kg/min reduces (△ P < 0.05) than solvent control group HR.(Mean±
SEM, n=6 or 8)
After modeling, Beagle dog heart rate is significantly raised.Solvent control group heart rate terminates in 10min, 30min, administration
There were significant differences with sham-operation group by 10min, 30min (* * P < 0.01, * P < 0.05, #P < 0.05).After BNP or GNP administration,
Heart rate is significantly lower than solvent control group, and BNP 200ng/kg/min reduces significant in administration 30min and administration end 10min heart rate
(△ P < 0.05) (Figure 11).
7.6 blood plasma cGMP
Blood plasma cGMP (R&D, cat:KGE003, the range of linearity: 2.1-500 pmol/mL) is detected using ELISA method.Group
Between compare, each group blood plasma cGMP is on close level before Beagle dog modeling；After modeling, model dog cGMP concentration is increased.BNP
After 200ng/kg/min administration, cGMP is significantly raised, is significantly higher than solvent control group and sham-operation group (* * P < 0.01).GNP
After 500ng/kg/min and 900ng/kg/min administration, cGMP is apparently higher than sham-operation group (#P < 0.05, △ P < 0.05), GNP
After three dosage administrations, blood plasma cGMP concentration is in raising trend between dosage, with solvent control group without significant difference.
After modeling, before Beagle dog plasma cGMP concentration is higher than modeling.After BNP 200ng/kg/min administration, cGMP is dense
Degree is apparently higher than after modeling (#P < 0.05).After tri- dosage group administrations of GNP, blood plasma cGMP level is between three dosage in liter
High trend, with after modeling without significant difference.
7.7 blood parameters
Before and after each group Beagle dog modeling, ALT, AST, CK, CKMB, UREA, CREA, the biochemical indicators such as LDH, BILT with
Compare no significant difference (P > 0.05) after administration.
8 conclusions
Beagle dog minimally invasive intervention implantable heart pacer, 240 times/min at DSA are persistently paced 2-3 weeks, ejection fraction
(EF%), score (FS%) is shortened in left room, and the parameters of left ventricular function such as cardiac output (SV) are decreased obviously, and pulmonary arterial pressure significantly increases,
Beagle dog shows apparent acute heart failure physiological characteristic；And post-operative recovery is fast, the death rate is low, and model success rate is high.
Under this experimental condition, BNP 200ng/kg/min, GNP 200ng/kg/min, 500ng/kg/min, 900 ng/
After kg/min administration, EF%, FS%, the parameters of left ventricular function apparent increase such as SV.Wherein, GNP 500 ng/kg/min and 900ng/
Kg/min dosage is the most significant to acute heart failure Beagle dog's heart function improvement, and the effect of above two dosage is better than GNP
200ng/kg/min and BNP 200ng/kg/min.Capacity (ESV) is shunk in the left room of heart failure animal, and end-diastolic volume (EDV) is received
Contracting latter stage internal diameter (LVS), diastolic dimensions (LVD) before modeling than significantly increasing, after the GNP for giving BNP or three dosage, with
Upper index is in be decreased obviously trend.Chamber interval thickness (IVS), the indexs such as left ventricular posterior wall thickness (LVPW) are before and after modeling, administration
Front and back is without significant difference.
Heart failure Beagle dog hemodynamic responses are mainly manifested in the significant raising of pulmonary arterial pressure.BNP 200 ng/kg/
After min, GNP 200ng/kg/min, 500ng/kg/min, 900ng/kg/min administration, pulmonary systolic pressure, diastolic pressure, averagely
Pulmonary arterial pressure is remarkably decreased.GNP 500ng/kg/min, 900ng/kg/min are better than the improvement degree of pulmonary arterial pressure
GNP200ng/kg/min and BNP200ng/kg/min dosage.Before and after modeling, Beagle dog aortic pressure without significant changes,
After GNP 500ng/kg/min administration, aortic systolic pressure, diastolic pressure, Mean Arterial are pressed with raising trend.GNP 500ng/kg/
After the administration of min dosage, left ventricular systolic pressure (LVSP) and intraventricular pressure rise maximum rate (dp/dt Max.) and have raising trend.It makes
After mould, left room diastasis pressure (LVEDP), intraventricular pressure declines maximum rate (dp/dt Min.) and increases, GNP 200ng/
After kg/min, 500ng/kg/min, 900ng/kg/min and BNP 200ng/kg/min administration, two indexes are on a declining curve.
After Beagle dog heart failure modeling, before heart rate is apparently higher than modeling, after administration, heart rate decline.
Blood plasma cGMP concentration, may be compensatory related with animal after heart failure itself than increasing before modeling after Beagle dog modeling.
After BNP 200ng/kg/min administration, cGMP is significantly raised.After tri- dosage administrations of GNP, blood plasma cGMP concentration is in three dosage
Between be in raising trend.Sampled plasma time 30min after starting administration in this experiment, pulmonary artery pressure is after starting administration
10min decreased significantly, and GNP acts on endothelial cell receptor, promotes the second messenger cGMP raised time may be earlier
Time, administration 30min detection when may have already passed by peak value.Perhaps the vasodilator effect of GNP depends on other approach again,
Its detailed mechanism of action needs further to be studied.
Before and after the modeling of each group Beagle dog and administration front and back, blood parameters are without significant difference, after prompting GNP administration
Apparent liver reaction of renal toxicity is not caused, drug has preferable safety.Each group Beagle dog weight is suitable, before and after modeling
Without significant difference.
In conclusion GNP shows good reduction pulmonary artery height as natriuretic peptide family newcomer in this test is total
(especially pulmonary artery diastolic blood pressure) function and effect are pressed, prompt GNP that can be used to prepare the medicine for the treatment of pulmonary hypertension correlation indication
Object.Meanwhile in Beagle dog animal model Therapy study, 200-900 ng/kg/min GNP intravenous drip can be significantly improved
Heart function alleviates heart failure, shows obvious drug dose-effect relation, prompts GNP that can be used to prepare treatment heart failure with lung
The drug of arterial hypertension Related complication.
Claims (3)
1. the use that natriuretic peptide GNP is used to prepare the drug for the treatment of pulmonary hypertension correlation indication or heart failure merging pulmonary hypertension
On the way.
2. purposes according to claim 1, it is characterised in that: the drug includes recombination natriuretic peptide or artificial synthesized
Natriuretic peptide.
3. purposes according to claim 2, it is characterised in that: the drug further includes pharmaceutically acceptable figuration
Agent, carrier or diluent.
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Citations (3)
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|---|---|---|---|---|
| US20060025367A1 (en) * | 1999-05-24 | 2006-02-02 | Mayo Foundation For Medical Education And Research, A Minnesota Corporation | Adenovirus vectors encoding brain natriuretic peptide |
| CN103159847A (en) * | 2013-04-12 | 2013-06-19 | 叶亮 | Natriuretic peptide, as well as gene and use thereof |
| CN107260853A (en) * | 2017-06-28 | 2017-10-20 | 江苏省中医院 | It is a kind of that there is Traditional Chinese medicine compound composition for the treatment of heart failure effect and preparation method and application |
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2018
- 2018-11-02 CN CN201811300501.6A patent/CN109172808A/en active Pending
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|---|---|---|---|---|
| US20060025367A1 (en) * | 1999-05-24 | 2006-02-02 | Mayo Foundation For Medical Education And Research, A Minnesota Corporation | Adenovirus vectors encoding brain natriuretic peptide |
| CN103159847A (en) * | 2013-04-12 | 2013-06-19 | 叶亮 | Natriuretic peptide, as well as gene and use thereof |
| CN107260853A (en) * | 2017-06-28 | 2017-10-20 | 江苏省中医院 | It is a kind of that there is Traditional Chinese medicine compound composition for the treatment of heart failure effect and preparation method and application |
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