JP2005350433A - Hypotensive agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a natural matter(highly safe food-based plant)-derived hypotensive agent. <P>SOLUTION: This hypotensive agent as a prostaglandin I<SB>2</SB>synthesis promoter, comprises a Passiflora edulis pericarp extract. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an antihypertensive agent that can be used for the treatment or prevention of diseases such as hypertension.

As antihypertensive drugs, calcium antagonists, angiotensin I converting enzyme inhibitors, angiotensin II receptor antagonists, α receptor blockers, β receptor blockers, diuretics, prostaglandin I _{2 and the} like have been conventionally known. ing. Of these, calcium antagonists inhibit the uptake of calcium (Ca) necessary for vasoconstriction into vascular cells, thereby dilating blood vessels and preventing an increase in blood pressure. An angiotensin I converting enzyme inhibitor suppresses the action of angiotensin I converting enzyme necessary for the conversion of angiotensin I into II, and inhibits the production of angiotensin II that contracts blood vessels. Angiotensin II receptor antagonists exhibit antihypertensive effects by antagonizing the endogenous pressor substance angiotensin II at the receptor level. Alpha receptor blockers suppress sympathetic nerves and widen blood vessels. β-receptor blockers suppress the work of the heart and lower blood pressure. Diuretics act on the renal tubules and collecting ducts of the nephron, which is the functional unit of the kidneys, and promote the excretion of sodium (Na) and water (diuresis) in the body, and lower the blood pressure by reducing the volume of fluid (blood volume). Prostaglandin I ₂ is considered to be effective in pulmonary hypertension, which is considered to be an intractable disease because it has a remarkable physiological activity that causes vasodilation, lowers blood pressure, and suppresses platelet aggregation.

  Antihypertensive substances derived from food ingredients are known, but most of them are peptide angiotensin I converting enzyme inhibitors, and some of them are foods for specified health use that are allowed to be labeled “For those with higher blood pressure” It has been commercialized as. In addition, Tochu tea contains various components called Tochu Naka glycosides. Geniposide acid is a typical component in the nakanaka leaf glycoside and has been confirmed to have a blood pressure lowering effect by stimulating parasympathetic nerves to relax vascular smooth muscles and dilate blood vessels. It is also known that gamma-aminobutyric acid (GABA) contained in germinated brown rice and Gabaron tea has a blood pressure lowering effect. Further, it is known that cumistin (Nekonohige) promotes diuretic action and lowers blood pressure. This is believed to be due to the high amount of potassium contained in cumistin.

  In this way, various foods and plants that have a blood pressure lowering action are known, but each blood pressure lowering action is not so strong, more effective, safer and less expensive to manufacture, and more tasteful. Good materials are needed.

In addition, although the angiotensin converting enzyme inhibitory activity of damselfly is reported (patent document 1), the blood pressure lowering effect | action by animal experiment is not proven. On the other hand, there has been no report on the components and functions of pericarp methanol extract, and it has not been known that the methanol extract component has a blood pressure lowering action or a prostaglandin I ₂ synthesis promoting action.

JP 2001-335494 A

  An object of the present invention is to provide a blood pressure lowering agent derived from a food-based plant with high safety.

As a result of diligent investigation on the blood pressure lowering effect of food-based plant extracts, the present inventors have found that the methanol extract of citrus peel fruit has an action of promoting the synthesis of prostaglandin I ₂ having a blood pressure lowering action and a vasodilating action. As a result, the present invention has been completed. It is said that edible citrus fruit pulp contains various useful ingredients for health such as β-carotene, various vitamins, citric acid, potassium, calcium, iron and polyphenols, but it has blood pressure lowering effect. Has not been experimentally proven.

That is, the present invention includes the following inventions.
(1) An antihypertensive agent comprising an extract of cereals and / or a processed product thereof as an active ingredient,
(2) The antihypertensive agent according to (1), wherein the extract of persimmon is a pericarp extract,
(3) a prostaglandin I ₂ synthesis promoter containing an extract of damselfly and / or a processed product thereof as an active ingredient,
(4) The prostaglandin I ₂ synthesis promoter according to (3), wherein the extract of persimmon is a pericarp extract,
(5) The antihypertensive agent according to (1) or (2) for addition to food,
(6) (3) or (4) prostaglandin I ₂ synthesis promoter for addition to food,
(7) A step of squeezing or pulverizing damselfly, a step of extracting the squeezed product or the pulverized product, and a concentration treatment and / or a purification treatment for the squeezed product or the pulverized product or an extract thereof as necessary. (1) or (2) a method for producing an antihypertensive agent, and (8) a step of squeezing or pulverizing damselfly, a step of extracting the squeezed or pulverized product, and as necessary The method for producing a prostaglandin I ₂ synthesis promoter according to (3) or (4), comprising a step of subjecting the juice or the pulverized product or an extract thereof to a concentration treatment and / or a purification treatment.

  According to the present invention, a blood pressure-lowering agent derived from a food-based plant with high safety is provided.

  Hereinafter, the present invention will be described in detail. However, the scope of the present invention is not limited to these descriptions, and other than the following exemplifications, the present invention can be appropriately implemented without departing from the spirit of the present invention.

  The present invention relates to an antihypertensive agent comprising a fern extract.

  The extract of citrus fruit extract may include an extract of pulp, fruit, leaf, stem, or root, but the higher the ratio of the fruit extract, the better.

  Kudamono Passiflora (also known as Passiflora edulis) is a vine perennial tropical fruit tree native to South America, and is now widely spread throughout the world in tropical and subtropical regions. In Okinawa, production is the largest, but it is also cultivated in the Amami and Ogasawara Islands. There are no particular limitations on the variety and production area of the damselfly used in the present invention.

  As for the extract of citrus peel which can be used in the present invention, the whole plant, pulp, fruit, pericarp, leaf or root juice can be used as it is, but the whole plant, pulp, fruit, pericarp, leaf or root is crushed and ground. You may use what was pulverized by the above. It can also be used as an extract of the juice or the pulverized product or a processed product of the juice or the pulverized product or an extract thereof. Here, the “extract” means that the components contained in the whole plant, pulp, fruit, peel, leaf or root are dissolved in a solvent such as water or ethanol, extracted, and dried as appropriate, usually liquid or solid The “processed product” refers to a material obtained by further subjecting the juice, powder, or extract to a concentration process or a purification process.

  When a plant is used as an extract, the extraction time is preferably about 10 minutes to 1 hour, particularly about 30 minutes, and the amount of solvent used for extraction is 2 to 10 times, especially 5 in weight ratio to the raw material. Double amounts are preferred. The extraction solvent may be any solvent, and for example, one or more of methanol, ethanol, ethyl acetate, other organic solvents, and water can be used. Preferably, a mixed solvent of ethanol and water is used. Moreover, you may add diatomaceous earth in the process of solvent extraction. Further, in some cases, after extraction, the extraction residue can be removed by filtration or centrifugation to obtain an extract.

  Further, the juice, powder or extract can be concentrated. Furthermore, since the juice, powder or extract contains a large amount of sugar and organic acid, it is also preferable to carry out a purification step to remove them. Examples of the purification process include normal phase or reverse phase chromatography, ion exchange chromatography, gel filtration and the like. These methods can also be used in appropriate combination. For example, after crushing the peels of damselfly with a mixer, etc., the mixture can be obtained as a powder by stirring in an extraction solvent, removing insolubles by centrifugation or filtration, and drying the supernatant or filtrate under reduced pressure. . In the present invention, the “fruit skin” means a thick skin part outside the fruit, that is, a part obtained by removing the jelly-like pulp and seeds from the fruit, but generally said fruit part may be attached. The extraction solvent may be any solvent, and for example, one or more of methyl alcohol, ethyl alcohol, ethyl acetate, other organic solvents, and water can be used.

Furthermore, substances derived from damselfly and showing prostaglandin I ₂ synthesis promoting activity can be obtained by known methods, and a composition containing these substances also contains the damselfly extract of the present invention as an active ingredient. Included in prostaglandin I ₂ synthesis promoter.

  The antihypertensive agent comprising the extract of citrus peel of the present invention may be an extract itself or an agent such as a tablet, powder, emulsion, capsule or the like by a commonly used solid or liquid carrier, an emulsifying dispersant, etc. It may be formulated into a form. Examples of the carrier include water, gelatin, starch, magnesium stearate, lactose, and vegetable oil. The antihypertensive agent may contain further components.

  The content of the citrus peel extract in the antihypertensive agent of the present invention can be appropriately changed depending on the administration purpose, administration route, dosage form, etc., for example, the content is 0.1 to 90% by weight.

  The blood pressure lowering agent of the present invention can be used as a pharmaceutical, or added to various foods and used as a food for specified health use or a functional food. Examples of such foods include soft drinks, lactic acid drinks, soups, jams, and confectionery. The antihypertensive agent of the present invention can also be added to pet food, feed, etc. and used for prevention and improvement of hypertension in pets and livestock.

  The usage form of the antihypertensive agent of the present invention may be any form depending on the purpose of use, and examples thereof include oral administration and application to the skin and mucous membranes.

  The dosage of the antihypertensive agent of the present invention is not particularly limited, and can be appropriately determined according to, for example, the age, sex, weight, symptom level, or administration method of hypertensive patients. For example, when an antihypertensive agent comprising an extract of citrus peel fruit peel is orally administered to a patient with mild hypertension, it is preferably 1 mg / kg body weight to 200 mg / kg body weight per day. The number of administrations per day is not limited and may be administered once to several times.

  When the antihypertensive agent of the present invention is added to a food for specified health use or a functional food, an appropriate amount can be added depending on the purpose. An antihypertensive agent comprising an extract of citrus peel fruit peel is added so that the food contains, for example, 10 to 100% by weight.

  Furthermore, the present invention includes a food and drink with a label indicating that it is used for improving blood pressure, characterized in that it contains a fern extract of citrus fruit as an active ingredient and has a blood pressure lowering action. To do.

  EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.

Example 1 Method for producing antihypertensive agent consisting of extract of Kudamonodiaceutium peel After peeling the peel (150 g) from 3 Kudamonodiatomaceous fruit with a mixer, 200 ml of methanol was added and stirred with an electromagnetic stirrer at 400 rpm for 60 minutes. did. Next, filtration through a filter paper (Advantech Toyo filter paper, No. 2, diameter 30 cm) was performed to recover the filtrate from which insolubles were removed. The filtrate was concentrated with a rotary evaporator and further dried under reduced pressure with a vacuum pump to obtain 3.6 g of a purple powder.

Example 2 Measurement of blood pressure lowering effect Male spontaneously hypertensive rats (SHR, purchased from Charles River) were used as experimental animals as 6 animals per group. The SHR was normally reared, and the experiment was performed when the systolic blood pressure reached about 200 mmHg at 14 weeks of age or older. The citrus peel extract was dissolved in distilled water, and was orally administered once using a stomach tube so that the dose would be 10 mg / kg body weight and 50 mg / kg body weight. Blood pressure immediately before administration and 1, 3, 5, 7 and 24 hours after administration was measured using tail-cuff (Tail-Cuff) using a non-invasive blood pressure monitor MK-2000 (Muromachi Kikai Co., Ltd.) Measured by the method. As a control, distilled water was similarly administered to SHR, and blood pressure was measured.

  The time-dependent change of the measured systolic blood pressure is shown in FIG. The systolic blood pressure was significantly different as a result of two-sample t-test, and the extract of pearl millet peel showed a significant blood pressure lowering effect 1 hour after administration.

Example 3 Promoting Prostaglandin I ₂ Synthesis in Bovine Aortic Endothelial Cells Bovine aortic endothelial cells (passage number ^2, 25 cm ^{2 in a} culture flask, purchased from Dainippon Pharmaceutical Co., Ltd. (Cell Systems)) in CS-C medium (D- MEM medium and Ham F12 medium are mixed in a 1: 1 equimolar ratio medium and dispersed in 10% fetal bovine serum, 15 mM HEPES, Acidic FGF, heparin-added medium (purchased from Cell Systems) and coated with collagen It was added to one plate with 24 holes (1 cm ² cm ² ) and cultured at 37 ° C. for 3 days in the presence of 5% CO ₂ . Next, the medium in each well of the plate is discarded, and 1 ml of Krebs-Ringer bicarbonate (KRB) buffer (NaCl 129 mM, NaHCO ₃ 5 mM, KCl 4.8 mM, KH ₂ PO ₄ 1.2 mM, CaCl ₂ 1.0 mM, MgSO ₄ 1.2 mM) Each well was washed twice with Glucose 2.8 mM, Bovine serum albumin 0.1%, HEPES 10 mM, pH 7.4). Then add 400 μl of a solution containing 40 μl of sample (1-8 mg / ml citrus peel extract, 10 μM calcium ionophore A23187 as a positive control, or distilled water as a control) to 360 μl KRB buffer. And left at 37 ° C. for 30 minutes in the presence of 5% CO ₂ . The number of cells at the time of sample addition is 2.2 × 10 ⁵ per well. Thereafter, 300 μl of the supernatant was recovered, and the contaminated cells were removed by centrifugation. 6,9 epoxide structure of prostaglandin I ₂ is unstable, because it is converted into a stable 6-keto prostaglandin F _{l [alpha],} the concentration of the supernatant of 6-keto prostaglandin F _{l [alpha],} 6 -Measured by enzyme immunoassay using ketoprostaglandin F _1α ELISA system (purchased from Amersham Biosciences). The results are shown in Table 1.

Table 1 shows a comparison between the amount of 6-ketoprostaglandin F _1α released into the solution during 30 minutes and the amount of 6-keto prostaglandin F _1α (control) when distilled water was added (control) ( The average value of n = 3). A prostaglandin I ₂ synthesis promoting effect was observed in the citrus peel extract.

  Next, when the effect of citrus peel extract on cell proliferation was examined using the Roche MTT (3- [4,5-dimethylthiazole-2-yl] -2,5-diphenyl tetrazolium bromid) kit, It was confirmed that there was no effect on cell proliferation in the concentration range.

It is a figure which shows the change of the blood pressure by the single oral administration of the Kudamono-diame skin extract to a spontaneous hypertensive rat.

Claims (8)

  An antihypertensive agent comprising an extract of cereals and / or a processed product thereof as an active ingredient.   The antihypertensive agent according to claim 1, wherein the extract of cereals is a pericarp extract. A prostaglandin I ₂ synthesis promoter containing an extract of cereals and / or a processed product thereof as an active ingredient. Kuda prostaglandin I ₂ synthesis promoter according to claim 3, wherein the mono passion flower extract is a skin extract.   The antihypertensive agent according to claim 1 or 2 for addition to food. The prostaglandin I ₂ synthesis promoter according to claim 3 or 4 for addition to food.   A step of squeezing or pulverizing damselfly, a step of extracting the squeezed or pulverized product, and a step of concentrating and / or purifying the squeezed or pulverized product or its extract as necessary The manufacturing method of the blood pressure lowering agent of Claim 1 or 2 containing. A step of squeezing or pulverizing damselfly, a step of extracting the squeezed or pulverized product, and a step of concentrating and / or purifying the squeezed or pulverized product or its extract as necessary including method of prostaglandin I ₂ synthesis promoter according to claim 3 or 4.

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