CN114099511A - Application of liensinine in preparation of medicine for treating pulmonary hypertension - Google Patents
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Abstract
The invention discloses application of liensinine in preparation of a medicine for treating pulmonary hypertension. The invention belongs to the technical field of biological medicines. The invention constructs a pulmonary hypertension disease mouse model through hypoxia (10%) induction. After liensinine is injected into the abdominal cavity, the conditions of fur, diet, activity, death and the like of the pulmonary hypertension mouse model are observed. As a result, the liensinine (shown in formula I) has the effects of remarkably improving the pulmonary vascular remodeling of the pulmonary hypertension animal, relieving right ventricular hypertrophy and right heart failure, improving the living quality (improving food intake and water intake) of the pulmonary hypertension animal and improving the survival rate of the pulmonary hypertension animal. Therefore, the proposal of the invention provides new technology for preventing and treating pulmonary hypertensionThe operation means also enables the liensinine to have wide application prospect in the aspect of preventing and treating pulmonary hypertension diseases.
Description
Technical Field
The invention relates to a new application of Liensinine (4- [ [ (1R) -6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl ] methyl ] -2- [ [ (1R) -1- [ (4-hydroxyphenyl) methyl ] -6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl ] oxy ] enol), in particular to an application of Liensinine in preparing a medicine for treating pulmonary hypertension. The invention belongs to the technical field of biological medicines.
Background
Pulmonary Arterial Hypertension (PAH) is a destructive disease characterized by progressive Pulmonary arteriolar remodeling, causing Pulmonary vascular resistance and elevated Pulmonary Artery pressure, which in turn progresses to right heart failure and even death. The treatment of PAH has been updated over the last 20 years, with great progress being made and targeted drug therapy improving the prognosis and survival of patients. However, there is no effective cure available, which can only slow or stop the progression of the disease.
The pathogenesis of pulmonary hypertension is the result of the combined action of multiple internal, external and interactive factors, wherein the most important cause is hypoxia. Hypoxia causes changes in pulmonary angiogenesis including the accumulation of fibroblasts in the pulmonary artery adventitia, proliferation and migration of smooth muscle cells in the pulmonary artery, proliferation and migration of endothelial cells in the pulmonary artery, resulting in vascular remodeling and neointima formation, leading to vessel occlusion, increased pulmonary artery pressure and pulmonary artery resistance. At present, the proliferation and the anti-apoptosis of pulmonary artery smooth muscle cells are important mechanisms for the pulmonary vascular remodeling. The pulmonary vascular remodeling is the pathological basis of the continuous development of the PAH disease and also is the main reason of poor curative effect of the medicine.
Over the last 20 years, multiple PAH-targeting drugs have been gradually approved for the market, and currently, the PAH-targeting drugs mainly target three major signaling pathways that contribute to the pathogenesis of PAH: endothelin pathway, nitric oxide pathway and prostacyclin pathway, more than ten kinds of targeted drugs have been applied to clinic in three major treatment pathways, which are mainly divided into the following five categories: 1. prostacyclin analogs, mainly epoprostenol, iloprost, prostil, beraprost; 2. prostacyclin receptor agonists, selelpager; 3. endothelin receptor antagonists, mainly bosentan, ambrisentan and maxitane; 4. phosphodiesterase type 5 inhibitors, mainly sildenafil, tadalafil and vardenafil; 5. a guanylate cyclase agonist, riociguat. Although the use of these targeted drugs plays an important role in the treatment of PAH, the clinical use of the drugs is limited by the side effects of the drugs. For example, prostacyclin analogs can cause adverse reactions such as headache, flushing, diarrhea, hypotension, and pain at the site of entry and infection of the pathway; prostacyclin receptor agonists can cause headache, diarrhea, nausea, vomiting, and mandibular pain; endothelin receptor antagonists cause elevated transaminases, peripheral edema and anemia; phosphodiesterase type 5 inhibitors cause headache, flushing, myalgia and visual disturbances; guanylate cyclase agonists cause side effects such as digestive symptoms, hypotension and hemoptysis. Therefore, the treatment prospect of the existing targeted drugs is not optimistic, and the search for new therapeutic drugs is a problem to be solved at present.
Liensinine (4- [ [ (1R) -6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl ] methyl ] -2- [ [ (1R) -1- [ (4-hydroxyphenyl) methyl ] -6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl ] oxy ] phenol) is a dibenzyltetrahydroisoquinoline alkaloid, and is present in embryo buds of lotus seed plants in the family Nymphaeaceae. Researches show that liensinine has pharmacological properties of arrhythmia resistance, hypertension resistance and the like, and is often used for preventing and treating cardiovascular diseases. Some researches in recent years also find that liensinine also has an anti-tumor effect. Liensinine inhibits the proliferation of pancreatic cancer cells by regulating the cell cycle S-phase arrest and promoting mitochondrial apoptosis. In addition, the composition also has the effects of blocking adrenal alpha receptors and inhibiting intracellular calcium release. However, no research report on the application of the drug to Pulmonary Arterial Hypertension (PAH) has been found.
The invention researches the effect of liensinine on pulmonary hypertension, and the result shows that the compound can effectively improve pulmonary vascular remodeling of pulmonary hypertension animals, relieve right ventricular hypertrophy and right heart failure, improve the living quality (improve food intake and water intake) of the pulmonary hypertension animals and improve the survival rate of the pulmonary hypertension animals, so the compound can be used as a novel medicament for preventing and treating the pulmonary hypertension and is used for preventing and treating the pulmonary hypertension.
Disclosure of Invention
The invention aims to provide application of Liensinine (4- [ [ (1R) -6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl ] methyl ] -2- [ [ (1R) -1- [ (4-hydroxyphenyl) methyl ] -6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl ] oxy ] phenol) in prevention and treatment of pulmonary hypertension diseases.
In order to achieve the purpose, the invention adopts the following technical means:
the invention constructs a pulmonary hypertension disease mouse model through hypoxia (10%) induction. After liensinine was administered by intraperitoneal injection, the conditions of coat, diet, activity, death, etc. of the pulmonary hypertension mouse model were observed. The result shows that the Liensinine can obviously improve the pulmonary vascular remodeling of the rat with the pulmonary hypertension induced by hypoxia, relieve the right ventricular hypertrophy and the right heart failure, improve the living quality (improve the food intake and water intake) of the pulmonary hypertension animal and improve the survival rate of the pulmonary hypertension animal, namely the Liensinine (Liensinine) has the effect of preventing and treating the pulmonary hypertension disease through research.
Therefore, on the basis of the research, the invention provides the application of Liensinine in preparing the medicine for treating pulmonary hypertension, and the chemical structural formula of the Liensinine is shown as the formula I:
preferably, the liensinine achieves the purpose of treating the pulmonary hypertension by relieving pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving right ventricular hypertrophy and right heart failure of the patient with the pulmonary hypertension.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel medicine for preventing and treating pulmonary hypertension, namely liensinine, which can be used for preventing and treating pulmonary hypertension. The liensinine can achieve the purpose of treating the pulmonary hypertension by relieving the pulmonary vascular remodeling of the patient with the pulmonary hypertension and relieving the right ventricular hypertrophy and the right heart failure of the patient with the pulmonary hypertension. Therefore, the invention provides a new technical means for preventing and treating pulmonary hypertension, and leads liensinine to have wide application prospect in the aspect of preventing and treating pulmonary hypertension diseases.
Drawings
FIG. 1 shows the survival rates of normoxia + solvent group, normoxia + liensinine group, hypoxia + solvent group and hypoxia + liensinine group at different days, which indicates that liensinine can increase the survival rate of pulmonary hypertension animals;
FIG. 2 is a graph showing the food intake, water intake and body weight changes of rats in different days in the normoxic + solvent group, the normoxic + liensine group, the hypoxia + solvent group and the hypoxia + liensine group, which illustrates that the food intake and water intake of rats are gradually reduced due to hypoxia, and the weight reduction of the rats with pulmonary hypertension can be remarkably inhibited and the food intake and water intake of the rats with pulmonary hypertension can be increased after the liensine is treated by the medication;
FIG. 3 is a cross-sectional photograph of a typical small pulmonary blood vessel of a normoxic and solvent group, a normoxic and liensinine group, an anoxia and solvent group and a hypoxia and liensinine group, which shows that liensinine can significantly improve pulmonary vascular remodeling of a rat with pulmonary hypertension;
FIG. 4 is a comparison of the right ventricular pressure of rats with pulmonary hypertension in the normoxic + solvent group, the normoxic + liensinine group, the anoxic + solvent group and the anoxic + liensinine group, which illustrates that liensinine can reduce the right ventricular pressure of rats with pulmonary hypertension;
fig. 5 shows the right ventricular hypertrophy of rats in different days in the normoxic + solvent group, the normoxic + liensinine group, the hypoxia + solvent group and the hypoxia + liensinine group, which indicates that liensinine can significantly improve the right ventricular hypertrophy of rats with pulmonary hypertension;
*P<0.05，**P<0.01。
Detailed Description
The present invention is further described below in conjunction with specific examples, and the advantages and features of the present invention will become more apparent as the description proceeds. These examples are merely illustrative and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1 use of liensinine in the treatment of pulmonary hypertension
1. Animal and experimental reagents:
mice (strain: Kunming mice, purchased from Liaoning Biotechnology GmbH, Inc.).
2. Establishing a hypoxia-induced pulmonary hypertension model:
healthy Kunming male mice 24 (with a weight of 20-25 g) were randomly divided into two groups, namely an experimental group and a control group, according to the weight balance principle. Mice in the control group were bred in a standard sterile breeding environment and were randomly divided into two groups according to the weight balance principle, namely a normoxic + solvent group (solvent of the same volume as the liensinine group, i.e. intraperitoneal injection method) and a normoxic + liensinine group (liensinine 60mg/kg/2 days, i.e. intraperitoneal injection method). The experimental group of mice was placed in an oxygen-deficient box for adaptive hypoxia for one week (oxygen partial pressure of 12%), and then randomly divided into 2 groups according to the weight balance principle, namely an oxygen-deficient + solvent group (solvent with the same volume as the liensinine group, i.e. intraperitoneal injection method) and an oxygen-deficient + liensinine group (liensinine 60mg/kg/2 days, i.e. intraperitoneal injection method), and after being placed in the oxygen-deficient box for continuous hypoxia (oxygen partial pressure of 10%) for 21 days, the conditions of fur, diet, activity, death and the like were observed.
The heart and the left lung were taken for 4% fixation of paraformaldehyde, and the remaining lung lobes were frozen. Fixed hearts and lungs were pathologically stained.
3. Results
3.1 liensinine improves survival rates in animals with pulmonary hypertension
24 days after the hypoxic injection, the treatment with liensinine was performed, with this time point taken as 0 day for each group, and the Log-rank (Mantel-Cox) test showed the survival rate of pulmonary hypertension animals on different days after liensinine administration (P0.005).
Through researches, the animals with pulmonary hypertension induced by hypoxia are died in succession along with the increase of the raising time, the mortality rate of the hypoxia + solvent group reaches 58% after 60 days of hypoxia injection, and the mortality rate of the hypoxia + liensinine group (60 mg/kg/day, intraperitoneal injection) is only 33%, which shows that liensinine can improve the survival rate of the animals with pulmonary hypertension, and the results are shown in figure 1.
3.2 liensinine can remarkably improve the quality of life of the rat with pulmonary hypertension
The research shows that the hypoxia induces the pulmonary hypertension of the rats, the rats die in sequence along with the prolonging of the feeding time, the weight of the rats is gradually reduced in the feeding process, and the feeding and water inflow are also gradually reduced. The liensinine treatment can obviously inhibit the weight loss and obviously increase the food intake and water intake of rats, and the result is shown in figure 2.
3.3 liensinine can remarkably improve pulmonary hypertension rat pulmonary vascular remodeling
Hypoxia-induced pulmonary hypertension models can lead to pulmonary vascular remodeling. Compared with the hypoxia + solvent group, the pulmonary hypertension rat pulmonary vascular remodeling condition is obviously improved in the hypoxia + liensinine group, and the result is shown in fig. 3.
3.4 liensinine can effectively reduce the pressure of the right ventricle of the rat with pulmonary hypertension
A significant increase in right ventricular pressure was seen in the hypoxia-induced pulmonary hypertension model. The increased pressure in the right ventricle was significantly reduced in the hypoxic + liensinine group compared to the hypoxic + solvent group, with the results shown in fig. 4.
3.5 liensinine can remarkably reduce the hypertrophy of the right ventricle of the rat with pulmonary hypertension
The study finds that the hypoxia-induced pulmonary hypertension rats gradually die, the dead rats are subjected to material taking, and the result shows that the phenotype of the animals subjected to material taking is remarkable in right ventricular hypertrophy, the right ventricular hypertrophy index (right heart weight/left heart weight + ventricular septum) is remarkably increased, and the increased right ventricular hypertrophy index after the liensinine medication is remarkably inhibited, and the result is shown in fig. 5. The liensinine can obviously relieve the right ventricular hypertrophy of the pulmonary hypertension rat and correct right heart failure.
Claims (2)
1. The application of Liensinine (Liensinine, 4- [ [ (1R) -6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl ] methyl ] -2- [ [ (1R) -1- [ (4-hydroxyphenyl) methyl ] -6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl ] oxy ] phenol) in preparing the medicine for treating pulmonary hypertension is shown as the formula I:
2. the use of claim 1, wherein: the liensinine can treat pulmonary hypertension by relieving pulmonary vascular remodeling of patients with pulmonary hypertension and relieving right ventricular hypertrophy and right heart failure of patients with pulmonary hypertension.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111655826.8A CN114099511B (en) | 2021-12-30 | 2021-12-30 | Application of liensinine in preparation of medicines for treating pulmonary arterial hypertension |
| ZA2022/11282A ZA202211282B (en) | 2021-12-30 | 2022-10-14 | Application of liensinine in preparation of drugs for treating pulmonary arterial hypertension |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111655826.8A CN114099511B (en) | 2021-12-30 | 2021-12-30 | Application of liensinine in preparation of medicines for treating pulmonary arterial hypertension |
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| CN114099511A true CN114099511A (en) | 2022-03-01 |
| CN114099511B CN114099511B (en) | 2023-04-25 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105434335A (en) * | 2016-01-15 | 2016-03-30 | 武汉大学 | Liensinine suppository and preparation method and purpose thereof |
| CN107029002A (en) * | 2016-02-04 | 2017-08-11 | 南京生道源医药科技有限公司 | The preparation method and new application of Chinese lobelia extract |
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2021
- 2021-12-30 CN CN202111655826.8A patent/CN114099511B/en active Active
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- 2022-10-14 ZA ZA2022/11282A patent/ZA202211282B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105434335A (en) * | 2016-01-15 | 2016-03-30 | 武汉大学 | Liensinine suppository and preparation method and purpose thereof |
| CN107029002A (en) * | 2016-02-04 | 2017-08-11 | 南京生道源医药科技有限公司 | The preparation method and new application of Chinese lobelia extract |
Non-Patent Citations (3)
| Title |
|---|
| LI Q.等: "Alkaloids from Nelumbinis Plumula (AFNP) ameliorate aortic remodeling via RhoA/ROCK pathway" * |
| 李琼瑜: "基于RhoA/Rock通路探讨连心总碱抗高血压及抑制主动脉重构的机制研究" * |
| 陆曙等: "莲心碱与莲心季铵碱对肾性高血压大鼠左室肥厚逆转作用的比较" * |
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| ZA202211282B (en) | 2023-02-22 |
| CN114099511B (en) | 2023-04-25 |
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