CN110169963A - Application of the p-Coumaric Acid as preparation for the drug of diastole airway smooth muscle - Google Patents
Application of the p-Coumaric Acid as preparation for the drug of diastole airway smooth muscle Download PDFInfo
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- CN110169963A CN110169963A CN201910562115.2A CN201910562115A CN110169963A CN 110169963 A CN110169963 A CN 110169963A CN 201910562115 A CN201910562115 A CN 201910562115A CN 110169963 A CN110169963 A CN 110169963A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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Abstract
Application the invention belongs to medical science technical field more particularly to p-Coumaric Acid as preparation for the drug of diastole airway smooth muscle.Present invention finds application of the p-Coumaric Acid in the drug that preparation is used for diastole airway smooth muscle, it was found that p-Coumaric Acid has significant intervention effect to the contraction of high potassium and acetylcholine stimulation tracheal smooth muscle, can be used for the treatment of the respiratory diseases such as asthma；The present invention passes through Ca in detection to experiment mice isolated tracheal circular muscle tension and airway smooth muscle cells2+It detects, discovery p-Coumaric Acid has the ability for alleviating airway of patient with asthma obstruction, and it is to inhibit flow of calcium ions due to blocking LVDCCs and NSCCs ion channel, while activating caused by BKCa ion channel that this diastole, which acts on,.Application of the p-Coumaric Acid in the drug that preparation is used for diastole airway smooth muscle is the new application of p-Coumaric Acid, which is of great significance.
Description
Technical field
The invention belongs to medical science technical fields more particularly to p-Coumaric Acid to be ready for use on as chronic obstructive pulmonary disease processed
The application of the drug of diastole airway smooth muscle.
Background technique
Airway smooth muscle contracts last and calcium sensitivity raising are one of asthma, the cardinal symptom of chronic obstructive pulmonary disease.
In the therapeutic agent of above-mentioned respiratory disease, bronchodilatation class drug such as glucocorticoid etc. is common medicine clinically
Object.Long-time service in view of clinical hormone medicine can generate the drawbacks such as drug resistance and side effect, develop more secure and reliable
Bronchodilator becomes the main path to solve the above problems.Common drug used in treatment asthma includes salbutamol at present
(Salbutamol), Terbutaline (Terbutaline) etc..
P-Coumaric Acid (p-coumaric acid, p-CA), also known as p-Coumaric Acid, are the main of cell wall in plant
One of ingredient, p-Coumaric Acid are widely present in various plants, in green pepper, carrot, tomato, strawberry, pineapple and garlic etc.
P-Coumaric Acid all rich in, but p-Coumaric Acid is only widely used in weight-reducing as a kind of phenolic acid in medicinal, resists at present
Cancer etc. is not yet applied in terms of diastole airway smooth muscle treats asthma, chronic obstructive pulmonary disease.
Summary of the invention
Present invention aims in plant storage p-Coumaric Acid abundant obtain wider medical value, through grinding
Study carefully the new application the invention proposes p-Coumaric Acid as drug, i.e., p-Coumaric Acid is as preparation for diastole airway smooth muscle
The application of drug can be applied to the drug of the symptom of airway obstruction when asthma or patients with chronic obstructive pulmonary diseases breaking-out are alleviated in treatment
In.
The technical solution for realizing the object of the invention is drug of the p-Coumaric Acid as preparation for diastole airway smooth muscle
Using.
Wherein, the drug be by p-Coumaric Acid block LVDCCs, NSCCs ion channel come inhibit flow of calcium ions,
BKCa ion channel is activated to reduce cell turgidity, for treating the drug of the respiratory diseases such as asthma.
Moreover, the dosage form of the drug includes at least capsule, tablet, oral preparation and microcapsule formulation.
Moreover, the administration mode of the drug includes at least injection, oral and subcutaneous administration.
Compared with prior art, the beneficial effect of the technical solution is: present invention finds p-Coumaric Acids to use in preparation
Application in the drug of diastole airway smooth muscle, it was found that p-Coumaric Acid stimulates tracheal smooth muscle to high potassium and acetylcholine
Shrinking has significant intervention effect, can be used for the treatment of the respiratory diseases such as asthma；The present invention passes through to the in vitro gas of experiment mice
Ca in the detection of pipe ring Muscle tensility and airway smooth muscle cells2+Detection, discovery p-Coumaric Acid, which has, alleviates airway of patient with asthma
The ability of obstruction, and this diastole effect is due to having blocked LVDCCs, NSCCs and activation BKCaCaused by equal calcium channels.
LVDCCs, NSCCs ion channel are blocked, BK is activatedCaEqual calcium channels can alleviate airway smooth muscle contracts last and calcium is sensitive
Property improve, to alleviate asthma and symptoms of chronic obstructive pulmonary disease.P-Coumaric Acid is used for the medicine of diastole airway smooth muscle in preparation
In object application be p-Coumaric Acid new application, due to p-Coumaric Acid be in plant one of main component of cell wall and at present it is right
Coumaric acid is applied only to weight-reducing, anticancer etc., therefore the new application is of great significance.
Detailed description of the invention
Fig. 1 is that the pre- pinned sheepshank fruit of p-Coumaric Acid (p-CA) diastole acetylcholine-induced tracheal smooth muscle is schemed；Wherein figure a is
It acts on the diastole of acetylcholine-induced tracheal smooth muscle.Scheme the influence that b is the high potassium induction tracheal smooth muscle of p-CA diastole.Figure
C is the amount effect curve obtained by figure a and figure b data；
Fig. 2 is the influence of p-Coumaric Acid (p-CA) to the tracheal smooth muscle tension of acetylcholine-induced；
Fig. 3 is p-Coumaric Acid (p-CA) by lowering Ca intracellular2+Carry out diastole bronchus smooth muscle；
Fig. 4 is p-Coumaric Acid (p-CA) by blocking LVDCCs come the high potassium induction tracheal smooth muscle of diastole；
Fig. 5 is the Ca that p-Coumaric Acid (p-CA) is mediated by NSCCs after exclusion LVDCCs effect2+Interior stream carrys out the high potassium of diastole and lures
Airway smooth muscle；
Fig. 6 is that p-Coumaric Acid (p-CA) can block completely the electric current of NSCCs to carry out diastole bronchus smooth muscle；
Fig. 7 is that p-Coumaric Acid (p-CA) participates in that BK is activated to carry out diastole bronchus smooth muscle in Muscle tensility level；
Fig. 8 is that p-Coumaric Acid (p-CA) has enhancing BKCaThe effect of electric current.
Specific embodiment
The present invention is illustrated in detail with reference to the accompanying drawings and examples, the contents of the present invention are not limited to following
Embodiment.
Case study on implementation 1, the contraction of the airway smooth muscle of p-Coumaric Acid (p-CA) energy diastole acetylcholine-induced.
1) separation of mouse isolated tracheal
6-8 weeks male adult BALB/c mouse is bought, cervical approach is taken off and puts to death mouse, is fixed on dissection plate, the spray of 75% alcohol
Disinfection mouse body surface is spilt, and cuts off skin, cuts along ventrimeson to neck, removes thymus gland and connective tissue, and whole is removed from from small
To tracheal tissue, throat, transversal tracheae simultaneously removes, tracheal tissue is placed in the high calcium liquid of pre-cooling rat heart.Further dissecting
Separated under mirror main tracheae and with hook to tracheae it is flat after be put into perfusion slot.
2) detection of airway of mice smooth muscle tension
Cleaning perfusion system: it unloads perfusion slot and is placed in alcohol ultrasound after 10 minutes, be changed to ultrapure water and equally handle
2-3 times.Hook and hanging rod are gently floated 2 times with alcohol, then are rinsed 3 times with ultrapure water, and equipment, high calcium liquid rinse are then attached
3 times, 6mL high calcium liquid is finally added into slot.
The debugging of system: hanging hanging rod opens that oxygen main valve, ambassador's oxygen can be opened by starting walks logical 5 minutes, and opens water-bath
Pot is to 37 DEG C, and later, adjusting air valve is to uniformly continuous minute bubbles in placing groove, hanging hanging rod again.Open transducer switch simultaneously
Each 100 Hz of channel sampling frequency is adjusted, then carries out baseline zeroing, then calibration system is carried out by reference substance 3.00g calibration
System.Calibration finishes, and click starts to test.
3) airway smooth muscle contraction of p-Coumaric Acid (p-CA) diastole acetylcholine-induced
All channels are changed liquid 1 time for every 15 minutes, are amounted to 4 times, and are changed after liquid every time to the preload of tracheae 250-300mg.
Pre-stimulation is carried out with 100 μM of ACH, tension reaches 750mg or more, can carry out the gas that p-Coumaric Acid intervenes Acetylcholine-induced
The experiment of pipe smooth muscle contraction determines that p-CA diastole ACH shrinks the dose-effect curve of tracheal smooth muscle in advance.
Fig. 1 show the pre- pinned sheepshank fruit figure of p-Coumaric Acid (p-CA) diastole acetylcholine-induced tracheal smooth muscle；Wherein
Scheme a to act on the diastole of acetylcholine-induced tracheal smooth muscle for it.Scheme the shadow that b is the high potassium induction tracheal smooth muscle of p-CA diastole
It rings.Figure c is the amount effect curve obtained by figure a and figure b data.
Above the results showed that p-CA diastole bronchus smooth muscle 503nhibiting concentration IC50Concentration is 2.76 ± 0.09mM, small
Continual and steady pre- contraction, after p-CA is added, the p-CA of 0.63mM-3.98mM can occur under the conditions of 100 μM of ACH for mouse tracheae
The tracheal smooth muscle blockage effect of ACH initiation can be significantly inhibited, and shows apparent dose dependent.
Implementation case column 2, p-Coumaric Acid (p-CA) is by lowering cell turgidity and Ca intracellular2+Carry out diastole bronchus smooth muscle.
Area by detecting cell at Confocal establishes effect of the p-CA to cell turgidity, in addition, selecting Fura-
2AM dyes airway smooth muscle cells to detect intracellular Ca2+Then 100 μM of ACH are added to cause intracellular Ca in level2+Increasing
Add, 3.98mMp-CA+100 μM of ACH is added further come the effect for verifying its diastole bronchus smooth muscle is and intracellular Ca2+Concentration
It is closely related.The result shows that 100 μM of ACH can dramatically increase Ca in smooth muscle cell2+3.98mMp- is added in horizontal (p < 0.001)
CA can completely inhibit the intracellular Ca of ACH initiation2+It increases (p < 0.001).
Fig. 2 and Fig. 3 show p-CA by reducing smooth muscle cell tension and Ca intracellular2+Carry out diastole bronchus smooth muscle.Fig. 2
For its influence to the tracheal smooth muscle tension of acetylcholine-induced.Fig. 3 is it by lowering Ca intracellular2+It is smooth to carry out diastole tracheae
Flesh.
Case study on implementation 3, the Ca that p-Coumaric Acid (p-CA) passes through blocking LVDCCs, NSCCs2+It is smooth that interior stream carrys out diastole tracheae
Flesh.
1) the pre- contraction of the airway smooth muscle of the high potassium induction of p-CA diastole
Pre-stimulation is carried out with 100 μM of ACH after structural equation is complete, tensile strength reaches 750mg or more, can be formally real
It tests, p-Coumaric Acid is then added and carries out the pre- contraction for intervening the tracheal smooth muscle that high potassium induces.So that it is determined that the high potassium of ESSB diastole
The pre- dose-effect curve for shrinking tracheal smooth muscle.
It is above-mentioned the results showed that isolated mouse annulus trachealis is in 80mM K+Under the conditions of steady and sustained pre- contraction occurs, when
After p-Coumaric Acid (p-CA) is added, the p-CA of 0.63-6.30mM can but significantly inhibit 80mM K+The tracheal smooth muscle of initiation is shunk
Effect, and show apparent dose dependent.Wherein, p-CA diastole bronchus smooth muscle 503nhibiting concentration IC50Concentration is
1.60±0.09mM。
2) p-CA is by blocking LVDCCs, NSCCs electric current come diastole bronchus smooth muscle
The electric current of whole-cell recording technique LVDCCs passes through Ba2+Instead of Ca2+, pulse is set as voltage clamp.Its pulse protocol are as follows:-
50ms is clamped down under 50mV, is recorded 300ms, is returned and clamp down on 50ms under -50mV.Repeat the above process -40mV to+40mV, step
Every 10s increases 10mV, then is separately added into positive blocking agent nifedipine and p-Coumaric Acid and the variation for recording whole process electric current.
The electric current of whole-cell recording technique NSCCs is by being added K+Non-selective blockers TEA-Cl, LVDCCs blocking agent Nifedipine,
The blocking agent Niflumic acid of Cl-.Pulse is set as current clamp.Its pulse protocol are as follows: cell is clamped down in -60mV, ramp
From -80mV to+60mV, electric current is analyzed under step-length 500ms, selection -70mV.Then, acetylcholine-induced NSCCs is added
Then electric current is added p-CA and records the variation of whole process electric current.
In acetylcholine stimulation tracheal smooth muscle, after blocking the channel LVDCCs completely using 10 μM of Nifedipine,
0mM Ca2+With 2mM Ca2+Under the conditions of be added 3.98mMp-CA, contraction can block completely (p < 0.01) by the p-CA of 3.98mM.
In terms of the intervention effect to NSCCs electric current, eliminating, K channel, the channel Cl and LVDCC effect are outer, 3.98mM p-CA
Still the opening of the NSCCs by acetylcholine activation can be blocked.Experimental result shows that 3.98mMp-CA can part blocks LVDCCs
Electric current.
Fig. 4, Fig. 5 and Fig. 6 show p-CA and pass through the Ca of blocking LVDCCs, NSCCs2+It is smooth that interior stream carrys out diastole diastole tracheae
Flesh.Fig. 4 is p-CA by blocking LVDCCs come the high potassium induction tracheal smooth muscle of diastole；Fig. 5 is that p-CA is made by excluding LVDCCs
The Ca mediated with rear NSCCs2+Interior stream carrys out the high potassium induction tracheal smooth muscle of diastole.Fig. 6 is the electric current that p-CA can block NSCCs completely
Carry out diastole bronchus smooth muscle.
Experiment case study 4, p-Coumaric Acid (p-CA) is by increasing BKCaOpening carry out diastole bronchus smooth muscle.
1) p-CA has the tracheal smooth muscle contraction of diastole TEA, Paxiline induction
K is induced by the way that 100 μM of ACH are addedCaOpening, 10mM TEA is then added and inhibits KCaOpen and cause
The further contraction of tracheal smooth muscle, finally can promote K with 3.98mM p-CACaOpen again, to illustrate p-CA diastole gas
The effect of pipe smooth muscle may be with KCaAnd BKCaIt is related.3.98mMp-CA is due to again in the effect of diastole bronchus smooth muscle
Have activated BKCaCa2+It outflows (p < 0.001).
2) whole-cell recording technique BKCaElectric current confirm that p-CA passes through open BKCaDiastole bronchus smooth muscle is carried out in channel
Whole-cell recording technique BKCaElectric current, pulse protocol are as follows: clamp down on 50ms under -70mV, record 300ms, return -
50ms is clamped down under 70mV.- 60mV to+40mV is repeated the above process, the every 10s of step increases 10mV, then sequentially adds to tonka-bean
Acid and blocking agent Paxiline and the variation for recording whole process electric current.
The electric current recorded when the result shows that 3.98mM p-CA is added constantly increases compared with the control, the change of this electric current
Change can be blocked completely by 1 μM of Paxiline, to illustrate that the open electric current of p-CA is BKCaElectric current.The experiment is furtherly
Bright p-Coumaric Acid can be by enhancing BKCaOpen diastole mouse tracheal smooth muscle.
Fig. 7 and Fig. 8 show p-CA and passes through activation BKCaCarry out diastole bronchus smooth muscle.Fig. 7 is that p-CA joins in Muscle tensility level
Carry out diastole bronchus smooth muscle with activation BK；Fig. 8 is that p-CA has enhancing BKCaThe effect of electric current.
To sum up, embodiment 1-4's the experiment proves that blocking LVDCCs, NSCCs ion channel to inhibit by p-Coumaric Acid
Flow of calcium ions, activation BKCa ion channel reduce cell turgidity, to illustrate p-Coumaric Acid as preparation for diastole gas
The application of the drug of road smooth muscle has the ability of the symptom of airway obstruction when alleviating asthmatic patient breaking-out, has and greatly answer
Use prospect.It can wherein be significantly inhibited in embodiment 1 by using the p-CA that mouse in vitro tissue tests discovery 0.63mM-3.98mM
The tracheal smooth muscle blockage effect that ACH causes, it is seen that the p-Coumaric Acid of 0.63mM-3.98mM dosage can effectively diastole air flue it is smooth
Flesh.Application of the p-Coumaric Acid in the drug that preparation is used for diastole airway smooth muscle is the new application of p-Coumaric Acid, due to perfume (or spice)
Beans acid is one of main component of cell wall and p-Coumaric Acid is applied only to weight-reducing, anticancer etc. at present in plant, therefore should
New application is of great significance.
Claims (4)
1. application of the p-Coumaric Acid as preparation for the drug of diastole airway smooth muscle.
2. application of the p-Coumaric Acid according to claim 1 as preparation for the drug of diastole airway smooth muscle, special
Sign is: the drug is to block LVDCCs and NSCCs ion channel to inhibit flow of calcium ions by p-Coumaric Acid, is swashed simultaneously
BKCa ion channel living reduces cell turgidity to treat the drug of asthma and chronic obstructive pulmonary disease.
3. application of the p-Coumaric Acid according to claim 1 as preparation for the drug of diastole airway smooth muscle, special
Sign is: the dosage form of the drug includes at least capsule, tablet, oral preparation and microcapsule formulation.
4. application of the p-Coumaric Acid according to claim 1 as preparation for the drug of diastole airway smooth muscle, special
Sign is: the administration mode of the drug includes at least injection and takes orally.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112691126A (en) * | 2021-01-25 | 2021-04-23 | 中南民族大学 | Application of usnea longissima extract in preparation of drugs for relaxing airway smooth muscle |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513426A (en) * | 2009-03-06 | 2009-08-26 | 中国人民解放军第二军医大学 | Cinnamylate lipoid substance and application thereof in the preparation of leukotriene A4 hydrolytic enzyme functional regulating medicine |
| KR20180008258A (en) * | 2016-07-13 | 2018-01-24 | 경희대학교 산학협력단 | A pharmaceutical composition having the effect of preventing or treating of respiratory disease comprising the p-coumaric acid |
-
2019
- 2019-06-26 CN CN201910562115.2A patent/CN110169963A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513426A (en) * | 2009-03-06 | 2009-08-26 | 中国人民解放军第二军医大学 | Cinnamylate lipoid substance and application thereof in the preparation of leukotriene A4 hydrolytic enzyme functional regulating medicine |
| KR20180008258A (en) * | 2016-07-13 | 2018-01-24 | 경희대학교 산학협력단 | A pharmaceutical composition having the effect of preventing or treating of respiratory disease comprising the p-coumaric acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112691126A (en) * | 2021-01-25 | 2021-04-23 | 中南民族大学 | Application of usnea longissima extract in preparation of drugs for relaxing airway smooth muscle |
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