JP6818486B2 - Composition for promoting atrial natriuretic peptide secretion - Google Patents

Description

The present invention relates to a composition for promoting atrial natriuretic peptide secretion.

Atrial natriuretic peptide (ANP) is a cardiac hormone that is mainly synthesized and stored in the atrium and is secreted from the heart into the blood. Atrial natriuretic peptide may have various actions such as natriuretic, suppression of secretion of renin and aldosterone, suppression of cardiac hypertrophy, suppression of cardiac fibrosis, promotion of angiogenesis, promotion of fat cell decomposition, and suppression of sympathetic nerve. It is known, and it can be said that the bioprotective function is maintained and improved via the heart, blood vessels, central nerves, kidneys, adrenal glands, etc. (Non-Patent Documents 1 to 3). Thus, atrial natriuretic peptide plays an important role in vivo.

Conventionally, carperitide (trade name: Hump) has been put on the market as an atrial natriuretic polypeptide preparation and used for acute heart failure, but it also has contraindications and side effects.

Toshio Nishikimi et al., Discovery and pharmacological action of Na diuretic peptide, Fluid Management Renaissance Vol.4 No.3, 43-49, 2014 Koichiro Kuwahara et al., Cardiovascular protective effects of atrial and brain natriuretic peptides, Fluid Management Renaissance Vol.4 No.3, 50-56, 2014 Michihiro Yoshimura, Exploring the Possibility of Natriuretic Peptides, Angiotensin Research Vol.12 No.3, 158-161, 2015

An object of the present invention is to provide a novel composition capable of promoting the secretion of atrial natriuretic peptide.

As a result of diligent studies in view of the above problems, the present inventors have found that a compound having an iridoid skeleton can promote the secretion of atrial natriuretic peptide. The present invention has been completed as a result of further studies based on the findings, and is as follows.
Item 1. A composition for promoting atrial natriuretic peptide secretion containing a compound having an iridoid skeleton.
Item 2. The composition according to Item 1, which contains 15 to 500 mg of a compound having an iridoid skeleton per daily dose.
Item 3. Item 2. The composition according to Item 1 or 2, which is a food composition, a pharmaceutical composition or a feed composition.
Item 4. Item 6. The composition according to any one of Items 1 to 3, wherein the compound having an iridoid skeleton is geniposidic acid.
Item 5. Item 4. The composition according to any one of Items 1 to 4, which is used for the purpose of preventing or ameliorating hypertension, arteriosclerosis, heart failure, ischemic heart disease, chronic kidney disease, obesity, cancer or osteoporosis.

According to the composition containing the compound having an iridoid skeleton of the present invention, the secretion of atrial natriuretic peptide can be promoted. According to the present invention, various useful actions based on the promotion of secretion of atrial natriuretic peptide can be obtained, and therefore, hypertension, arteriosclerosis, heart failure, ischemic heart disease, chronic kidney disease, obesity, and cancer based on the actions can be obtained. , Various diseases such as osteoporosis can be prevented or ameliorated.

FIG. 1 shows that the plasma ANP concentration was increased in the geniposidic acid-administered group as compared with the control group.

Hereinafter, the present invention will be described.

The present invention relates to a composition for promoting atrial natriuretic peptide secretion containing a compound having an iridoid skeleton.

Compounds having an iridoid skeleton include geniposidic acid, asperuloside, asperuloside acid, oakbin, deacetylasperuloside acid, scandecid 10-O-acetate, eucomiol, 1-deoxyoicomiol, epioicomiol, eucomicid A, and eucomicide. B, eucomicide C and the like are exemplified, preferably geniposidic acid, asperuloside, asperuloside acid and oakbin are exemplified, and more preferably geniposidic acid and asperuloside are exemplified.

These components may be derived from natural products or chemically synthesized, and their origin is not limited. How to obtain these is also known.

For example, as natural products containing compounds having an iridoid skeleton, Eucommia ulmoides (Eucommia ulmoides, Eucommia ulmoides), Noni (Morinda), Noni (Aoki Yaeyama: Morinda citrifolia, Morinda citrifolia, Morinda, Noni), usually " Plants such as "Noni") can be mentioned. The site of these plants to be used is not particularly limited as long as it contains a compound having an iridoid skeleton, and whole plants, flowers, fruits, leaves, branches, bark, rhizomes, and seeds can be used. These may be used individually by 1 type, and may be used in combination of 2 or more type. Methods for obtaining the various components from these natural products are known.

Although not limiting the present invention, from this point of view, the compound having the above-mentioned iridoid skeleton is preferably exemplified by the compound having the iridoid skeleton derived from the plant, and more preferably the compound having the iridoid skeleton derived from Tochu. Illustrated, more preferably a compound having an iridoid skeleton derived from Tochu leaf.

These ingredients are also commercially available. Although not limiting the present invention, for example, a commercially available product of geniposidic acid can be purchased from Wako Pure Chemical Industries, Ltd.

These may be used individually by 1 type, and may be used in combination of 2 or more type.

In the composition for promoting atrial natriuretic peptide secretion of the present invention, the content of the compound having an iridoid skeleton is not limited, and the physique, age, symptom, degree of atrial natriuretic peptide secretion of the subject (target animal), It may be appropriately set according to the application form, purpose of use, and the like. The content of the compound having an iridoid skeleton in the composition does not limit the present invention, but the total amount of the compound having an iridoid skeleton is preferably 15 to 15 to the daily dose based on an adult having a body weight of 60 kg. About 500 mg, more preferably 30 to 300 mg, still more preferably 50 to 150 mg are exemplified. The composition of the present invention may be administered once or multiple times per day.

By administering (ingesting) a compound having an iridoid skeleton with such a range as a guide, the secretion of atrial natriuretic peptide can be promoted more efficiently.

The form of the composition of the present invention is also not limited, and may be appropriately set according to the intended purpose. The forms of the composition of the present invention include liquid forms such as liquids, emulsions, suspensions, syrups, extracts, alcoholic preparations, and elixirs, powders, granules, fine granules, tablets, rounds, and capsules ( Semi-solid or solid forms such as hard capsules (including hard capsules and soft capsules), troches, chewables, gels, creams, pastes, mousses, and liquid lyophilized products, and various other forms such as aerosols are exemplified. ..

Further, for example, when the composition of the present invention is in a solid form, it may be mixed with water or the like and used, or the composition of the present invention may be in a sustained-release dosage form.

Further, the mode of use of the composition of the present invention is not limited, and it may be appropriately set according to the purpose. The composition of the present invention is used as a food composition (including beverages, health functional foods (including specified health foods, nutritional functional foods, supplements, etc.), sick foods), pharmaceutical compositions, and feeds. It can be used as an additive to a composition, a food composition, a pharmaceutical composition, a feed, or the like.

The composition of the present invention may be produced according to a conventionally known conventional procedure in the above-mentioned various forms, usage modes, etc., and if necessary, may be mixed with any component such as a pharmaceutically acceptable component and an edible component. It may be manufactured by mixing or the like. Excipients, disintegrants, diluents, lubricants, fragrances, colorants, sweeteners, flavoring agents, suspending agents, wetting agents, emulsifiers, solubilizers, dispersants, buffers, etc. Binders, penetration promoters, stabilizers, bulking agents, preservatives, thickeners, pH adjusters, surfactants, coating agents, absorption promoters, adsorbents, fillers, antioxidants, anti-inflammatory agents, refreshers Examples thereof include agents, film forming agents, gelling agents, amino acids, vitamins, enzymes, and various nutritional components. These may be used individually by 1 type, and may be used in combination of 2 or more type.

The compositions of the present invention are administered orally. The target person (target animal) is also not limited, but humans and mammals other than humans are exemplified. Examples of mammals other than humans include animals in which atrial sodium diuretic peptides maintain and improve the bioprotective function, such as mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, pigs, cows, and horses. Animals, preferably animals such as mice, rats, guinea pigs, rabbits, dogs, monkeys and the like are exemplified.

Atrial natriuretic peptide is a peptide hormone consisting of 28 amino acids produced and secreted from atrial tissue, and is widely known in this field including its sequence (Non-Patent Document 1).

According to the composition of the present invention, atrial natriuretic peptide secretion can be significantly promoted by using a compound having an iridoid skeleton as an active ingredient. From this, it can be said that the present invention provides a method for producing a composition for promoting atrial natriuretic peptide secretion, which is characterized by using a compound having an iridoid skeleton. Further, it can be said that the present invention provides a method for promoting atrial natriuretic peptide secretion, which is characterized by using a compound having an iridoid skeleton.

Thus, according to the composition of the present invention, atrial natriuretic peptide secretion can be significantly promoted. From this, according to the present invention, it is possible to enhance the useful action based on the secretion of atrial natriuretic peptide, and it is possible to prevent or improve various symptoms based on the promotion of secretion of atrial natriuretic peptide. Although not limiting the present invention, as an example, according to the promotion of atrial natriuretic peptide secretion, suppression of myocardial cell hypertrophy, suppression of cardiofibrillation, promotion of angiogenesis, suppression of sympathetic nerves, regulation of water / salt intake, sodium Promotion of diuresis, suppression of renin secretion, suppression of aldosterone secretion, promotion of lipolysis, promotion of endochondral ossification, suppression of cancer metastasis, vasodilation, regulation of vascular endothelial permeability, regulation of vascular endothelial barrier function, suppression of vascular fibrosis, vascular smooth muscle proliferation Various effects such as suppression of hypertrophy can be obtained. From this, the composition of the present invention is useful for the prevention and / or amelioration of hypertension, arteriosclerosis, heart failure, ischemic heart disease, chronic kidney disease, obesity, cancer and osteoporosis. Therefore, the composition of the present invention can also be used as an antihypertensive agent, an arteriosclerosis agent, and the like.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to the examples.

Test example
(1) Preparation of geniposidic acid (GEA) Sodium hydroxide was added to purified water so as to have a concentration of 48% by weight, and the temperature was raised to 50 ° C. Geniposide (purchased from Sichuan Dicotyledon Biotechnology Co., Ltd.) was added over 6 minutes, and the mixture was stirred at 50 ° C. for 2 hours. After visually confirming the disappearance of the raw material, the mixture was cooled to around 25 ° C. and neutralized with 4N hydrochloric acid to obtain a crude geniposidic acid solution. The crude geniposidic acid solution was adjusted to pH 3.5 with dilute hydrochloric acid and adsorbed on ODS (Daisogel SP-120-40 / 60 ODS-B, manufactured by Daiso Corporation) equilibrated with water. Then, it was washed with purified water for desalting and eluted with a 50% by volume aqueous methanol solution to obtain high-purity geniposidic acid (purity of 99.5% or more).

(2) Administration of geniposidic acid Geniposidic acid was administered to rats, and the blood natriuretic peptide (ANP) concentration was measured. Specifically, geniposidic acid purified by the above method is mixed with pure water, and the obtained solution is transferred to a male 16-week-old SHR (spontaneous hypertensive rat) after fasting so as to have geniposidic acid 100 mg / kg. A single oral dose was administered (n = 6). As a control, the same amount of pure water as the above solution was orally administered to another male 16-week-old SHR (spontaneous hypertensive rat) in a single dose (n = 6).

Six hours after administration, whole blood was collected from the abdominal aorta of each rat to obtain plasma (about 5 mL / animal). Of the obtained plasma, 300 μL was used for the quantification of ANP.

(3) Evaluation of Atrial Natriuretic Peptide (ANP) Secretion Promotion In quantifying ANP in plasma, the sandwich chemiluminescent enzyme immunoassay (sandwich CLEIA) method, which is a kind of chemiluminescent enzyme immunoassay, was used. Rat / mouse a-ANP (Peptide Institute, Inc.) in which anti-rat / mouse α-ANP polyclonal antibody (pAb # 131-7, provided by National Cardiovascular Research Center) was dissolved in an assay buffer as a standard solution on an immobilized microplate. After performing primary antibody treatment by adding laboratory chemical compound), anti-α-ANP mouse monoclonal antibody (anti-α-ANP mAb, provided by Shionogi Pharmaceutical Co., Ltd.) was placed in a plate and treated with secondary antibody. went. Subsequently, after adding the luminescent substrate (CDP-star plus Emerald II enhancer, Applied Biosystems, USA), the luminescence intensity (relative luminescent units (RLU)) of the standard solution was measured using a plate reader (Molecular Devices, USA). Then, the value obtained by subtracting the background (Non-Specific Binding (NSB)) from the average value was calculated as the measured value (RLU-NSB).

The coefficient of variation of the measured value of the standard solution (n = 2) was 10% or less at all concentrations, and it was confirmed that there was no problem in the measurement results. The calibration curve was created with the natural logarithmic value of the standard solution concentration on the horizontal axis and the natural logarithmic value of the measured value on the vertical axis. The resulting coefficient of determination ^{R 2} value of the straight line is 0.9984, was no problem in linearity.

The ANP concentration in plasma was determined by substituting the natural logarithmic value of the value measured by the plate reader (RLU-NSB) into the standard solution calibration curve formula (external standard method). The coefficient of variation of the plasma measurement value (n = 2) was 10% or less in each individual, and it was confirmed that there was no problem in the measurement result.

The average value of the geniposidic acid administration group and the average value of the control group are shown in FIG. The ANP concentrations of the geniposidic acid-administered group (GEA in the figure) and the control group (control in the figure) were 69.4 ± 5.2 pM and 46.2 ± 5.3 pM, respectively, and the plasma ANP concentration of the geniposidic acid-administered group. Was significantly increased compared to the concentration in the control group (p <0.05, p = 0.0106).

When the results of the above test are converted into human doses based on the "CRC Textbook Training Guidelines for CRC Certified by the Japanese Society of Clinical Pharmacology", geniposidic acid can be said to be 100 mg / body (60 kg) / day. From this, it was found that humans can also exert a secretagogue action of atrial natriuretic peptide.

From this, it was confirmed that geniposidic acid can promote the secretion of atrial natriuretic peptide.

Claims (3)

A composition for promoting the secretion of atrial natriuretic peptide containing geniposidic acid . The composition according to claim 1, which contains 15 to 500 mg of geniposidic acid per daily dose. The composition according to claim 1 or 2, which is a food composition, a pharmaceutical composition or a feed composition.