CN109908325A - UFP-101 is inhibiting cardiac muscle cell's β1receptor alienation and the application in preparation treatment antiarrhythmic medicament - Google Patents
UFP-101 is inhibiting cardiac muscle cell's β1receptor alienation and the application in preparation treatment antiarrhythmic medicament Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, it provides UFP-101 and is inhibiting cardiac muscle cell's β1receptor alienation and the application in preparation treatment antiarrhythmic medicament, UFP-101, which is pre-processed, can significantly reduce the generation of Acute Myocardial Ischemia in Rats Earlier Post-Operation Arrhythmia, so that it is determined that application of the UFP-101 in preparation treatment antiarrhythmic medicament.The present invention is through testing, and UFP-101 can significantly reduce the expression of ischemic region myocardial cell membrane β1receptor as the result is shown, generates and inhibits the effect of β1receptor excessive activation, it is thus possible to significantly reduce the generation of Acute Myocardial Ischemia in Rats Earlier Post-Operation Arrhythmia.In addition experimental result shows that UFP-101 does not have an impact heart rate；Influence to haemodynamics is smaller.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to UFP-101 is inhibiting cardiac muscle cell's β1receptor alienation and making
Application in standby treatment antiarrhythmic medicament.
Background technique
Occur serious ischemic arrhythmia after acute myocardial infarction AMI, including ventricular premature beat, Ventricular Tachycardia and
Ventricular fibrillation etc. is the major reason for causing sudden cardiac death.Acute myocardial infarction AMI early stage is felt with sympathetic nerve and heart
The excessive activation of nerve, sympathetic nerve excessive activation on the one hand can by discharge a large amount of catecholamines act on cardiac muscle cell β 1 by
On the other hand body can induce cardiac muscle cell's β1receptor and alienation occurs, the two causes electro physiology disorder jointly and leads to various ischemics
Property arrhythmia cordis occur.At the same time, include some researches show that Cardiac sensory nerve activation can discharge a large amount of sensory neuropeptides
Calcitonin gene-related peptide, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 and orphanin peptide etc..There is multinomial research to confirm acute myocardial infarction AMI early stage, sympathetic mind
A variety of neuropeptides that neurotransmitter and Cardiac sensory nerve through discharging are discharged, which exist, to interact, and adjusts myocardial damage jointly
And arrhythmia cordis (bibliography: Wang LL, Han Y, Guo Z, et al. Esmolol activates endogenous
Neurokinin activity inhibiting infarction-induced arrhythmias in rats:novel
Mechanisms of anti-arrhythmia [ J ] Regul Pept, 2013,186:116-122.).
Orphanin peptide is a kind of neuropeptide being made of 17 amino acid, and receptor NOP has higher with classical opiate receptor
Homology, but the biological effect that mediates of nociceptin receptor signal path and classical Opioid Receptor System function are different greatly.
Orphanin peptide and its receptor are distributed widely in the multiple systems of whole body, organ and tissue, more for pain, depression and immune response etc.
Kind pathologic-physiological reaction has adjustment effect.About the relationship between orphanin peptide and cardiovascular system, animal experiments show that acute
Myocardial ischemia can cause cardiac muscle, spinal cord and the expression of chest section dorsal root ganglion orphanin peptide significantly to increase and suffer from spontaneous angina pectoris
Detect that orphanin peptide content significantly increases in the blood plasma of person.And in animal experiments by by exogenous orphanin peptide vein or side
When the ventricles of the brain are administered, there is the decline of heart rate and blood pressure.It is lonely that the endogenous generated under pathological conditions cannot be still specified at present
Deltorphin delta and the effect whether having the same of the exogenous orphanin peptide given, but can affirm nociceptin receptor signal path and the heart
There is close connection between vascular system.And we are further investigations have shown that is excessively discharged after acute myocardial ischemia is interior
Source property orphanin peptide being capable of inducing ischemic arrhythmia cordis generation (bibliography: Han Y, Guo Z, Wang LL, et al.
Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-
Associated ventricular arrhythmias via PKC-dependent mechanism in rats [ J ] Br
J Pharmacol, 2013,170(3): 614-623.).
UFP-101[N-(Bn)Gly-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-
Arg-Lys-Asn-Gln-NH2] it is a species specific nociceptin receptor antagonist, in recent years, it is lonely to be widely used in research
The various biological actions of deltorphin delta receptor signaling pathways.It is played in view of nociceptin receptor signal path in acute myocardial ischemia process
Effect, make it possible potential treatment means of the UFP-101 as ischemic arrhythmia.
Summary of the invention
The present invention provides UFP-101 to inhibit cardiac muscle cell's β1receptor alienation and treat in antiarrhythmic medicament in preparation
Application, UFP-101, which is pre-processed, can significantly reduce the generation of Acute Myocardial Ischemia in Rats Earlier Post-Operation Arrhythmia, so that it is determined that
Application of the UFP-101 in preparation treatment antiarrhythmic medicament.
The ventricular arrhythmia that the arrhythmia cordis induces for acute myocardial ischemia, including ventricular premature beat, room property are aroused in interest
It overruns and ventricular fibrillation.
The present invention is through testing, and UFP-101 can significantly reduce the expression of ischemic region myocardial cell membrane β1receptor as the result is shown,
It generates and inhibits the effect of β1receptor excessive activation, it is thus possible to significantly reduce the hair of Acute Myocardial Ischemia in Rats Earlier Post-Operation Arrhythmia
It is raw.In addition experimental result shows that UFP-101 does not have an impact heart rate；Influence to haemodynamics is smaller；Clinically, inhibit
β1receptor signal path can result in the decline of heart rate and blood pressure, have a biggish Dose-Dependent Effects to haemodynamics, and II
Class antiarrhythmic drug, that is, beta-2 adrenoceptor retarding agent can also cause while playing anti-arrhythmia decreased heart rate with
And blood stream rheology, although and of the invention the experimental results showed that UFP-101 and containing by reduction cell membrane β1receptor
It measures and then the excessive activation of β1receptor access is inhibited to play anti-ischemic arrhythmia effect, but do not observe it to the heart
Rate has an impact, also relatively slight for other Index Influences of heart function.
The antiarrhythmic drug clinically used at present is broadly divided into following four classes: I class: sodium channel blocking agent；II class:
Beta-2 adrenoceptor retarding agent；III class: over reach potential duration medicine；IV class: calcium channel blocker.Further study show that
The effect of UFP-101 is similar to II class antiarrhythmic drug, that is, beta-2 adrenoceptor retarding agent, and being mainly reflected in it can press down
Cell membrane β1receptor caused by acute myocardial ischemia processed increases, and then inhibits β1receptor excessive activation to play and inhibit the ischemic rhythm of the heart
Not normal effect.
But influence of the UFP-101 for heart rate and haemodynamics is then incomplete with beta-2 adrenoceptor retarding agent
It is identical, in an experiment, do not observe that UFP-101 has a significant impact heart rate.UFP-101 and beta-2 adrenoceptor retarding agent
It is able to suppress the excessive activation of acute myocardial ischemia early stage β1receptor access and then plays anti-ischemic arrhythmia effect, but
It is that beta-2 adrenoceptor retarding agent but can be by inhibiting β1receptor access to reduce heart rate, reduction cardiac output, for blood flow
Mechanics and heart function have biggish inhibiting effect.But the UFP-101 under this test dose concentration for heart rate without influence, it is right
In heart function other indexs (such as LVSP and LVEDP) there are of short duration inhibiting effect, exist with beta-2 adrenoceptor retarding agent
Apparent difference.
Detailed description of the invention
Fig. 1 is data analysis chart of the UFP-101 to each index of different time sections heart function before and after myocardial ischemia in rats；Fig. 2
It is UFP-101 to percentage of each index of different time sections heart function compared with (baseline level) before ischemic after myocardial ischemia in rats
Delta data statistical chart, note: compared with CAO group, *P <0.05。
Fig. 3 is the influence result figure that UFP-101 expresses cell membrane after myocardial ischemia in rats and whole-cell component β1receptor；
In figure: A-B:Western-Blot histogram；C:Western-Blot statistical chart, note: compared with Sham group,a P< 0.05, with U+
CAO group compares,b P<0.05。
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art answer
It should be appreciated that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form repair
Change or replace, but these modifications and replacement are fallen within the protection scope of the present invention.
Embodiment 1: the foundation and grouping of Model of Acute Myocardial Ischemia
Experimental material and equipment: compound UFP-101 (CAS:849024-68-6) of the present invention is mm Suppliers institute
?；Membrane protein extraction kit: Invent company；Rabbit-anti rat β 1-AR, Na/K-ATPase, GAPDH primary antibody and goat-anti rabbit
HRP-IgG secondary antibody: Abcam company, Britain；AlC-V8 toy ventilator: that Coulter Corp, Shanghai Australia；RM6240BD electro physiology
Signal recorder: Chengdu Instruement Factory.
Experimental animal: experimental animal selects cleaning grade male SD rat 60,250-280g, is purchased from liberation army military science
Research institute's Experimental Animal Center, credit number: SCXK(army) 2012-0004,6~8 week old, adaptable fed 1 week.Zoopery
Ratify through Ethics Committee, Mountain Western Medicine S University.
Experimental animal grouping: using random digits table be divided into 3 groups (n=10): sham-operation group (Sham group), the left hat of ligation
Shape artery descending anterior branch (coronary artery) group (CAO group) and nociceptin receptor antagonist (UFP-101) pretreated group (U+CAO group).Sham
Group only opens chest threading but does not ligature coronary artery；CAO group ligatures ramus descendens anterior arteriae coronariae sinistrae after opening chest；U+CAO group is before ligaturing coronary artery
10 min inject specific nociceptin receptor antagonist UFP-101(1 × 10 by 1 mL/kg through tail vein-9 Mol/L), remaining 2
Group gives equal capacity physiological saline.
It establishes Model Rats with Acute Myocardial Ischemia: being referred to as 25% urethane (1.2 g/ with mass fraction after rat quality
Kg intraperitoneal injection of anesthesia) is carried out, rat dorsal position is fixed on connection Biological Signal Collecting System record standard II on station
Lead electrocardiogram, and signal acquisition conduit is placed in left ventricle through right internal jugular vein.Tracheotomy is placed in tracheal catheter, connection
Toy ventilator implements mechanical ventilation, and ventilator tidal volume is set as 8 mL/kg, 70 times/min of respiratory rate.Stablize 15 min
Afterwards, physiological saline or UFP-101 are injected separately into through tail vein by 1 mL/kg.Chest is opened in the 4th intercostal space of left side after 10 min, with
For the looper of 5-0 atraumatic suture from left auricle of heart right border inserting needle, pulmonary conus left border goes out needle ligation ramus descendens anterior arteriae coronariae sinistrae.And
Visible II lead electrocardiogram occurs ST sections and gradually raises and gradually merge with QRS wave afterwards, and the myocardium anterior tissue color that loses color then goes out
Existing cyanosis, can there is arrhythmia cordis appearance, prompt modeling success.
Embodiment 2: the collection analysis of arrhythmia cordis data and scoring
Arrhythmia cordis in 1 h after each group rat coronary ligation is counted and analyzed and is scored arrhythmia cordis and (is referred to
Document: Miller LE, Hosick PA, Wrieden J, et al. Evaluation of arrhythmia scoring
Systems and exercise-induced cardioprotection [ J ] Med Sci Sports Exerc, 2012,
44(3): 435-441.), specific standards of grading are as follows: 0 point, occurring 50 room morning of < after coronary ligation in 1 h altogether
(ventricular ectopic beats, VEB), including single-shot room morning, room morning bigeminy, room morning trigeminy.1 point, occur >=
50 VEB.2 points, there is 1 ~ 5 ventricular tachycardia (ventricular tachycardia, VT).3 points, there are >=6 VT.4 points, out
Existing 1 ventricular fibrillation (ventricular fibrillation, VF).5 points, there are 2 ~ 5 VF.
The record of heart function and analysis: 5 index (left ventricular of Cardiac Function in Rat will be embodied
systolic pressure (LVSP)、left ventricular end diastolic pressure (LVEDP)、
heart rate (HR)、 LV+dp/dtmaxAnd LV-dp/dtmax) recorded, with 15 min and coronary artery before coronary ligation
Totally 5 time hop counts evidences are compared and analyze by 1-15 min, 16-30 min, 31-45 min and 46-60 min after ligation.
Arrhythmia cordis result: UFP-101 pretreatment can significantly reduce ischemia/reperfusion in rats arrhythmia cordis and occur, VEB number,
The VT+VF duration and arrhythmia cordis scoring be decreased obviously (P < 0.05 orP < 0.017), it is shown in Table 1.
After table 1:3 group rat coronary occlusion in 1 h add up arrhythmia cordis comparison (n=10)
* P < 0.01；aCompared with Sham group,bCompared with U+CAO group,P < 0.05；ACompared with Sham group,BWith U+CAO group
Compare,P < 0.017
1 result of table prompt Acute Myocardial Ischemia in Rats early stage may occur in which (in 1 h) serious ischemic arrhythmia include VEB,
VT and VF, and UFP-101 can substantially reduce VEB frequency, reduce the VT+VF duration and reduce arrhythmia cordis and comment
Point, effectively inhibit the generation of acute myocardial ischemia early stage ischemic arrhythmia.
Heart function result: experimental result is shown in Fig. 1 and 2,1-15min after coronary ligation, U+CAO group rat LVSP decline (P<
0.05), LVEDP rise (P < 0.05), remaining index is then not statistically significant, show UFP-101 on heart rate without influence, for
The influence of heart hydromechanics is also smaller, prompt again by inhibit β1receptor access activation, beta-blocker clinic with
And zoopery be acknowledged as it is larger to heart rate and hemodynamic effects, and when UFP-101 with 1 × 10-9 Mol/L is pressed
Ischemic arrhythmia can be significantly inhibited when 1mL/kg intravenously administrable, but on heart rate without influence, to hemodynamic effects compared with
It is small.
Embodiment 3:Western-Blot: tissue memebrane protein is extracted using the processing of Membrane protein extraction kit, cracking is added
Liquid dispenses -80 DEG C of preservations.Total protein is extracted by normal step in addition, weighing portion of tissue, dispenses -80 DEG C of preservations.Egg will be dispensed
Brix carries out protein quantification with BCA method, after successively carrying out PAGE gel electrophoresis, transferring film, 5% skimmed milk power closing, 2 h, adds
Enter 4 DEG C of incubations after β 1-AR primary antibody (diluted concentration is 1:1 000) shakes up, shaking table is overnight, and secondary antibody is added and is incubated at room temperature 1 h.
TBST cleaning, 3 times × 10 min.The gray value of each protein band is measured using Quantity One image analysis software.Cell
In membrane component, its expression is reflected with the ratio of β 1-AR band gray value and internal reference Na/K-ATPase gray value；Full cell
In component, its expression is reflected with the ratio of β 1-AR band gray value and internal reference GAPDH gray value.
Statistical method: for statistical analysis using SPSS13.0 software, normal distribution measurement data is with mean ± standard
Difference () indicate, more comparison among groups use one-way analysis of variance, and Multiple range test uses LSD- between grouptIt examines, examines
Level α=0.05.Non-Gaussian Distribution measurement data withM(P 25 ,P 75) indicate, it usesKruskal-Wallis HIt examines, two in group
Two compare useMann-Whitney UIt examines, and inspection level α ' is pressedBonferroniMethod is corrected.
Western-Blot result: experimental result is shown in Fig. 3, after giving UFP-101, compared with simple ligation group (CAO group),
Cell membrane β1receptor, which is expressed, after coronary ligation significantly reduces (P < 0.05).This result prompts UFP-101 anxious by reducing
Property myocardial ischemia after myocardial cell membrane β1receptor expression, inhibit the excessive activation of β1receptor to play anti-ischemic arrhythmia and make
With.
The UFP-101 pretreatment of this experiment is before myocardial ischemia before 10 min i.e. coronary occlusion (CAO)
10 min are through rat tail vein drug administration by injection, research shows that UFP-101 inhibits the mechanism of action of ischemia/reperfusion in rats arrhythmia cordis can
It can be expressed with cell membrane β1receptor after reduction acute myocardial ischemia and then inhibit the excessive activation of β1receptor related.
Claims (4)
1.UFP-101 is inhibiting the application in cardiac muscle cell's β1receptor alienation.
2.UFP-101 the application in preparation treatment antiarrhythmic medicament.
3. application according to claim 2, wherein the arrhythmia cordis is the ventricular rhythm of acute myocardial ischemia induction
It is not normal, including ventricular premature beat, Ventricular Tachycardia and ventricular fibrillation.
4. application according to claim 2, for the UFP-101 using intravenous injection administration, UFP-101 concentration is 1 × 10-9 Mol/L, dosage 1mL/kg.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111228261A (en) * | 2020-04-10 | 2020-06-05 | 郭政 | Application of orphanin enkephalin receptor specific antagonist C-24 in preparation of medicine for treating arrhythmia |
| CN111249279A (en) * | 2020-04-10 | 2020-06-09 | 郭政 | Application of orphanin enkephalin receptor specific antagonist J-113397 in preparation of medicine for treating arrhythmia |
| CN111249278A (en) * | 2020-04-10 | 2020-06-09 | 郭政 | Application of nociceptin receptor specific antagonist SB-612111 in preparation of drugs for treating arrhythmia |
| CN111265663A (en) * | 2020-04-10 | 2020-06-12 | 郭政 | Application of orphanin enkephalin receptor specific antagonist in preparation of arrhythmia treatment drug |
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2019
- 2019-04-11 CN CN201910287056.2A patent/CN109908325A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 熊畅等: "内源性孤啡肽通过调节 β1肾上腺素能受体对大鼠缺血性心律失常的影响", 《天津医药》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111228261A (en) * | 2020-04-10 | 2020-06-05 | 郭政 | Application of orphanin enkephalin receptor specific antagonist C-24 in preparation of medicine for treating arrhythmia |
| CN111249279A (en) * | 2020-04-10 | 2020-06-09 | 郭政 | Application of orphanin enkephalin receptor specific antagonist J-113397 in preparation of medicine for treating arrhythmia |
| CN111249278A (en) * | 2020-04-10 | 2020-06-09 | 郭政 | Application of nociceptin receptor specific antagonist SB-612111 in preparation of drugs for treating arrhythmia |
| CN111265663A (en) * | 2020-04-10 | 2020-06-12 | 郭政 | Application of orphanin enkephalin receptor specific antagonist in preparation of arrhythmia treatment drug |
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