Blood flow-improving agent

Abstract

To provide a blood flow-improving agent which has a blood flow-improving effect with nitric oxide.SOLUTION: There is provided a nitric oxide-dependent blood flow-improving agent having S-allylcysteine as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a nitric oxide-dependent blood flow improver. The present invention also relates to a food additive, a food or drink, a medicine, a feed, and a pet food, each of which uses the blood flow improver. [Background technology]

[0002] Since ancient times, Allium plants such as garlic and onions have been said to have effects such as relieving fatigue and improving vitality.

[0003] On the other hand, it is known that these Allium plants contain various sulfur-containing amino acids, and in recent years, the various physiological actions of S-allylcysteine, a type of sulfur-containing amino acid, have been attracting attention.

[0004] Examples of agents that utilize the physiological effects of S-allylcysteine ​​include agents for preventing tumor development (see, for example, Patent Document 1), agents for treating liver diseases (see, for example, Patent Document 2), agents for suppressing organ fibrosis (see, for example, Patent Document 3), and agents for suppressing sperm function decline (see, for example, Patent Document 4).

[0005] However, the amount of S-allylcysteine ​​contained in garlic, for example, is very small, and various methods for increasing the amount of S-allylcysteine ​​have been investigated.

[0006] Known methods for increasing the S-allylcysteine ​​content in garlic include immersing raw garlic in an ethanol aqueous solution for about two years to allow sulfur-containing amino acids such as S-allylcysteine ​​to accumulate, and warming raw garlic that has been stored at low temperature to between 45°C and 65°C to allow sulfur-containing amino acids to accumulate (see, for example, Patent Document 5).

[0007] Furthermore, Non-Patent Document 1 suggests that S-allylcysteine ​​promotes new blood vessel formation in ischemic conditions. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 2828471 [Patent Document 2] Special Publication No. 5-60447 [Patent Document 3] JP 2007-77116 A [Patent Document 4] JP 2012-17295 A [Patent Document 5] JP 2005-278635 A [Patent Document 6] JP 2007-186435 A [Non-patent literature]

[0009] [Non-Patent Document 1] Cell Transplantation 2017, Vol. 26(10) 1636-1647 Summary of the Invention [Problem to be solved by the invention]

[0010] As mentioned above, Patent Documents 1 to 4 describe various physiological effects of S-allylcysteine. In addition, Non-Patent Document 1 suggests that S-allylcysteine ​​has an effect of promoting new blood vessel formation in ischemic conditions. However, it has not been known that S-allylcysteine ​​can improve blood flow in healthy individuals.

[0011] In addition, a mechanism for improving blood flow is known that utilizes the production of nitric oxide in vascular endothelial cells. Nitric oxide (NO) produced in vascular endothelial cells relaxes the smooth muscle of blood vessels, thereby causing the vessels to expand and increasing the blood flow passing through the vessels. For example, Patent Document 6 describes that nicotinamide derivatives promote the production of nitric oxide by vascular endothelial cells and exert a blood flow improving effect.

[0012] The main object of the present invention is to provide a blood flow improver having a blood flow improving effect by nitric oxide. Another object of the present invention is to provide a food and drink, a medicine, a feed, and a pet food that utilize the blood flow improver. [Means for solving the problem]

[0013] As mentioned above, Allium plants are known to contain various sulfur-containing amino acids, and in recent years, S-allylcysteine, a type of sulfur-containing amino acid, has been reported to have effects such as preventing tumor development, treating liver disease, inhibiting organ fibrosis, and inhibiting decline in sperm function.

[0014] Under such circumstances, the present inventors have conducted extensive research and found that S-allylcysteine ​​has a nitric oxide-dependent blood flow improving effect. Furthermore, the present inventors have found that the blood flow improving effect of S-allylcysteine ​​is not only nitric oxide-dependent, but also nitric oxide-independent. The present invention has been completed based on these findings and further research.

[0015] That is, the present invention provides the following aspects. Item 1. A nitric oxide-dependent blood flow improver whose active ingredient is S-allylcysteine. Item 2. The blood flow improver according to Item 1, which has both nitric oxide-dependent and nitric oxide-independent blood flow improving effects. Item 3. The nitric oxide-dependent blood flow improver according to Item 1 or 2, wherein the content of S-allylcysteine ​​is 0.01 g / 100 g or more. Item 4. A food or drink for improving blood flow, comprising the blood flow improver according to any one of items 1 to 3. Item 5. A pharmaceutical for improving blood flow, comprising the blood flow improver according to any one of items 1 to 3. Item 6. A food or drink for recovering from fatigue and / or reducing a feeling of fatigue, comprising the blood flow improver according to any one of items 1 to 3. Effect of the Invention

[0016] According to the present invention, it is possible to provide a blood flow improver having a blood flow improving effect by nitric oxide. Furthermore, the present invention can provide foods and beverages, medicines, feeds, and pet foods that utilize the blood flow improver. [Brief description of the drawings]

[0017] [Figure 1] 1 is a graph showing the relationship between the time (minutes) elapsed after administration of a blood flow-improving agent and the rate of change (%) in blood flow in the tail vein of rats. [Diagram 2] 1 is a graph showing the relationship between the time (minutes) elapsed after administration of a blood flow-improving agent and the rate of change (%) in blood flow in the tail vein of rats. [Diagram 3] 1 is a graph showing the relationship between the time (minutes) elapsed after administration of a blood flow-improving agent and the rate of change (%) in plantar blood flow in rats. [Figure 4] This shows the relationship between the time (minutes) after administration of the blood flow improving agent and an image showing the state of blood flow in the rat plantar (the capillary blood flow is imaged by measuring the blood flow in the rat's foot pad, and the blood flow rate increases as the color changes from blue to red). [Diagram 5] FIG. 13 is a diagram illustrating the effect of S-allylcysteine ​​on pVASP expression in the thoracic aorta in Example 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The blood flow improver of the present invention is characterized by having S-allylcysteine ​​as an active ingredient and exhibiting a nitric oxide-dependent blood flow improving effect. The blood flow improver of the present invention can effectively improve blood flow (i.e., increase blood flow rate). More specifically, the blood flow improver of the present invention can suitably improve blood flow in healthy subjects.

[0019] Furthermore, the blood flow improver of the present invention can exhibit a nitric oxide-independent blood flow improving effect in addition to the nitric oxide-dependent effect. That is, the blood flow improver of the present invention can have both nitric oxide-dependent and nitric oxide-independent blood flow improving effects. Therefore, even if the blood flow improving effect dependent on one of them does not function effectively, the blood flow improver of the present invention can effectively improve blood flow by the blood flow improving effect dependent on the other. For example, even if the blood flow improving effect dependent on nitric oxide does not function effectively, the blood flow improver of the present invention can effectively improve blood flow by the blood flow improving effect independent of nitric oxide.

[0020] The blood flow improving agent of the present invention will be described below.

[0021] As mentioned above, it has long been known that Allium plants such as garlic have fatigue recovery and energy-boosting effects, but the amount of S-allylcysteine ​​contained in Allium plants such as garlic is very small. In contrast, the blood flow improver of the present invention contains S-allylcysteine ​​as an active ingredient and exerts an excellent effect of improving blood flow.

[0022] S-allyl cysteine Natural S-allylcysteine ​​generally has a structure represented by the following general formula: [ka]

[0023] The S-allylcysteine ​​contained in the blood flow improving agent of the present invention may be S-allylcysteine ​​having the above structure, or an optical isomer thereof, or a mixture of the optical isomers.

[0024] The S-allylcysteine ​​contained in the blood flow improving agent of the present invention may be derived from a plant of the Allium genus or the like, or may be chemically synthesized.

[0025] Plants of the Allium genus are not particularly limited, but due to their high content of sulfur-containing amino acids such as alliin, which is a raw material for S-allylcysteine, examples include garlic, onion, wild garlic, Chinese chive, Chinese chive, Chinese chive, Japanese itorakkyo, Japanese scallion, Nobiru, Japanese scallion, asatsuki, Siberian leek, Himezo leek, Shibutsuasatsuki, Shiroumasatsuki, Izusatsuki, tree onion, green onion, scallion, leek, scallion, Shimarakkyo, shallot, shallot, green onion, chive, Yagura leek, and white onion. Among these, from the viewpoint of containing sulfur-containing amino acids such as alliin at high concentrations, garlic (Allium sativum L.), onion (Allium cepa L.), chives (Allium schoenoprasum L.), scallions (Allium chinense G.Don), wild garlic (Allium victorialis subsp. platyphyllum), etc. are preferred, and garlic (Allium sativum L.) is more preferred. S-allylcysteine ​​may be derived from a single type of Allium plant, or may be derived from two or more types of Allium plants.

[0026] As mentioned above, Allium plants themselves contain very little S-allylcysteine, so Allium plants that have not been treated to increase S-allylcysteine ​​cannot be used as the blood flow improver of the present invention.

[0027] The method for increasing the content of S-allylcysteine ​​contained in Allium plants is not particularly limited, and known methods can be adopted. From the viewpoint of efficiently increasing the content of S-allylcysteine ​​contained in Allium plants to obtain an excellent blood flow improver having S-allylcysteine ​​as an active ingredient, a method of inactivating alliinase present in Allium plants (step 1) and then placing the Allium plants in an environment at a temperature of 20°C to 75°C for 1 hour or more (step 2) can be mentioned. An Allium plant having an increased content of S-allylcysteine ​​by such a method can be an excellent blood flow improver having S-allylcysteine ​​as an active ingredient. An Allium plant treated in this way not only contains S-allylcysteine ​​as an active ingredient, but also contains various ingredients (for example, various sulfur-containing amino acids) derived from Allium plants, and can therefore exhibit an excellent blood flow improving effect. In other words, the blood flow improvement agent of the present invention preferably contains an Allium plant treated by a method comprising steps 1 and 2, and it is preferable that S-allylcysteine ​​as an active ingredient is derived from an Allium plant treated by the method.

[0028] The step of inactivating alliinase present in plants of the genus Allium (step 1) can be carried out, for example, as follows.

[0029] When S-allylcysteine ​​is derived from a plant of the Allium genus, it is necessary to first inactivate the alliinase present in the plant of the Allium genus. The plant of the Allium genus contains alliin, which is the raw material of S-allylcysteine, as well as an enzyme (alliinase) that converts alliin to allicin (odor component). When alliin is converted to allicin by alliinase, the amount of alliin, which is the raw material of S-allylcysteine, decreases, so that the amount of the target S-allylcysteine ​​produced decreases. Therefore, in the present invention, when S-allylcysteine ​​is derived from a plant of the Allium genus, first, the endogenous alliinase is inactivated to suppress the decrease of alliin. By suppressing the production of allicin, it is also possible to suppress the generation of the odor derived from allicin in the blood flow improver of the present invention, which contains S-allylcysteine ​​as an active ingredient.

[0030] The method for inactivating alliinase present in Allium plants is not particularly limited, and may be, for example, a method of raising the internal temperature of the material to 60° C. or higher. Specific examples of inactivation treatment methods include hot water heating treatment, steam heating treatment, microwave heating treatment, etc. In addition, a method of inactivating the alliinase present in the plant by acid treatment or alkali treatment may also be mentioned.

[0031] The Allium plant in which alliinase has been inactivated may be directly subjected to step 2 described below, or may be cut, crushed, ground, powdered, etc., of the plant for the purpose of promoting the production of S-allylcysteine, etc., and then subjected to step 2. The Allium plant cut, crushed, ground, powdered, etc. can be obtained, for example, by cutting, crushing, grinding, and powdering the plant using a crusher, mixer, food processor, pulper fisher, etc. In addition, the juice of the Allium plant can be prepared, for example, using a filter press, juicer mixer, etc. The juice can also be prepared by filtering the ground product using a filter cloth, etc. The Allium plant cut, crushed, ground, and juice may be diluted or concentrated. Examples of the diluted product include cut, crushed, ground, and juice of the plant diluted about 1 to 50 times with water. Examples of the concentrate include cut, crushed, ground, and squeezed juice of the plant, which are concentrated 1 to 100 times by freeze concentration, vacuum concentration, and the like. The cut, crushed, ground, and squeezed juice of the Allium plant may be frozen. The extract of the Allium plant can be obtained by extracting the Allium plant or the cut, etc., with a solvent such as water.

[0032] By placing the Allium plant with inactivated alliinase in an environment with a temperature of 20°C to 75°C for more than one hour (step 2), the conversion reaction from alliin to S-allylcysteine ​​can be promoted, thereby increasing the content of S-allylcysteine.

[0033] In step 2, the pH is preferably 2 to 12, and more preferably 2.5 to 10, from the viewpoint of further improving the production of S-allylcysteine.

[0034] The method for setting the pH in the range of about 2 to 12 is not particularly limited, and may be, for example, a method of adding an acid component or an alkali component to an Allium plant in which alliinase has been inactivated. The acid component is not particularly limited, and may be hydrochloric acid. The alkali component is not particularly limited, and may be sodium hydroxide, potassium hydroxide, etc. The acid component and the alkali component may each be used alone or in combination of two or more.

[0035] The temperature in step 2 is preferably about 20°C to 75°C, more preferably about 25°C to 65°C, and even more preferably about 30°C to 60°C. The time for placing in the environment in step 2 varies depending on the type and amount of the raw material used, but is preferably about 1 hour to 48 hours, more preferably about 6 hours to 48 hours. S-allylcysteine ​​may be produced by stirring the Allium plant in which alliinase has been inactivated, or by leaving it to stand. The stirring method is not particularly limited, and examples thereof include a method of stirring using a stirring blade, a mixer, a stirrer, etc.

[0036] Furthermore, in step 2, an enzyme or an additive that promotes the production of S-allylcysteine ​​may be mixed.

[0037] The enzyme is not particularly limited as long as it promotes the production of S-allylcysteine, and preferably includes enzymes having protease activity, lactase activity, peptidase activity, maceration activity, glutaminase activity, and γ-glutamyltranspeptidase activity. Among these, enzymes whose main activity is glutaminase activity or γ-glutamyltranspeptidase activity are preferred because they are particularly effective in promoting the production of S-allylcysteine.

[0038] Specific examples of enzymes include Amano Enzyme's "Biolacta FN5", "Biolacta N5", "Proleather FG-F", "Protin SD-PC10F", "Protin SD-AY10", "Protin SD-NY10", "Protease M", "Peptidase R", "Pectinase A", "Neurase F3G", "Pancreatin F", "Protease A", "Lipase R", "Lipase A", "Protease P", "Protease N", "Protease S", "Protin AC10F", and "Glutaminase", as well as Kikkoman's "Pectolyase", Kyowa Kasei's "Cellulase TP2 Kyowa", and Godo Shu Seizo's "GODO AGI-EC, Mitsubishi Chemical Foods' "Kokurase", SiberHegner's "Rapidase", Shinnihon Chemical Industry's "Sumiteam AGS-L", "Sumiteam AC-L", "Sumiteam CTS", "Sumiteam CM-G", "Sumiteam KDC", "Sumiteam C6000", "Sumiteam AP", "Sumiteam FP", "Sumiteam LPL", "Sumiteam LP50", "Sumiteam BGT", "Sumiteam RP", "Sumiteam GML", "Sumiteam TG", HBI's "Orienter Examples of the enzyme include "Cellulose 22BF", "Cellulose AC40", "Cellulose HC100", "Cellulose TP25", "Cellulose HC", "Orientase 20A", "Orientase 5BL", "Natto Bacillus Culture Extract NSK-SD" manufactured by Japan Bioscience Laboratories Co., Ltd., "Gamanase" manufactured by Novozymes, "WSCDHCL" manufactured by Peptide Institute, "Pectinase HL", "Cellulase Y-NC", "Cellulase Onozuka RS", "Cellulase Onozuka R-10", and "Macerozyme R-10" manufactured by Yakult Pharmaceutical Co., Ltd. One type of enzyme may be used alone, or two or more types may be used in combination.

[0039] The additive is not particularly limited as long as it has the activity of reducing alliin present in garlic, and preferable examples thereof include cysteine, cystine, glutathione, etc.

[0040] Cysteine ​​may be cysteine ​​(L-form), its optical isomer (D-form), or a mixture of the optical isomers. In addition, cysteine ​​may be chemically synthesized cysteine, a material containing cysteine, an extract or purified product of cysteine ​​extracted from a material containing cysteine, or reduced cystine, which will be described later.

[0041] Of the above cysteines, from the viewpoint of easy availability, it is preferable to use purified cysteine ​​that is commercially available as a reagent, pharmaceutical ingredient, food ingredient, etc. The material containing cysteine ​​is not particularly limited as long as it contains cysteine, and examples thereof include oats, wheat germ, Brussels sprouts, and broccoli.

[0042] In addition, since cystine has a structure in which two molecules of cysteine ​​are linked via a disulfide bond (-SS-) formed by oxidation of a thiol group (-SH), cysteine ​​obtained by reducing said cystine may be used. In addition, cystine may be cystine (L-form), or an optical isomer (D-form) thereof, or a mixture of the optical isomers.

[0043] Glutathione is a tripeptide consisting of three amino acids, glutamic acid, cysteine, and glycine. Foods that contain a large amount of glutathione include beef liver, pork belly, milk, oysters, sardines, Pacific cod, salmon, ark shell, tomato, spinach, broccoli, peas, Brussels sprouts, raw cabbage, kiwi fruit, avocado, rice germ, wheat flour, baker's yeast, yeast, etc., and not only glutathione itself but also all of the above foods containing glutathione can be used. Among them, yeast is preferable from the viewpoint of containing glutathione at a high concentration. As for the form of glutathione, a material containing glutathione may be used as it is, or it may be one that has been subjected to processes such as water extraction, hot water extraction, and purification in order to further increase the concentration of glutathione.

[0044] Glutathione exists in reduced and oxidized forms (two reduced glutathione molecules formed by a disulfide bond), and either can be used, but the reduced form is preferred from the standpoint of reactivity.

[0045] When an enzyme or an additive is used, each of them may be used alone or in combination.

[0046] In the present invention, the reaction product in which the S-allylcysteine ​​content has been increased by step 2 can be used as a blood flow improver as it is, or the reaction product can be further subjected to at least one of filtration, centrifugation, concentration, extraction, drying, etc., to further increase the content of S-allylcysteine, and used as a blood flow improver. In addition, in order to increase the purity of S-allylcysteine ​​in the blood flow improver, a purification step of purifying S-allylcysteine ​​by a normal purification operation such as column chromatography or recrystallization can be performed. Furthermore, the reaction product can be dried by a known drying method such as freeze drying or spray drying to form a solid (powder, granules, etc.). The blood flow improver of the present invention can be suitably used as a blood flow improver for drugs, quasi-drugs, foods and beverages, feeds, health foods, etc.

[0047] Furthermore, in the present invention, the blood flow improving agent containing S-allylcysteine ​​as an active ingredient can also be suitably used as a physical function recovery agent containing S-allylcysteine ​​as an active ingredient.

[0048] S-allylcysteine ​​content and dosage The content of S-allylcysteine ​​contained in the blood flow improver of the present invention is preferably 0.01 g / 100 g or more, more preferably 0.03 g / 100 g or more, and even more preferably 0.05 g / 100 g or more, from the viewpoint of exerting an excellent blood flow improving effect dependent on nitric oxide. The upper limit of the content of S-allylcysteine ​​contained in the blood flow improver of the present invention is not particularly limited, but is usually about 30 g / 100 g.

[0049] The application amount of the blood flow improver of the present invention may be appropriately determined depending on the type of product used, its application, expected effects, application form, etc. For example, the daily intake or administration amount of S-allylcysteine ​​for an adult may be set to 0.0001 to 100 g, preferably 0.0005 to 10 g, and more preferably 0.001 to 1 g.

[0050] Uses of blood flow improvers The blood flow improver of the present invention exerts a blood flow improving effect dependent on nitric oxide (can improve (enhance) blood flow) due to the action of S-allylcysteine, and is therefore used for the prevention or treatment of decreased blood flow. More specifically, the blood flow improver of the present invention can suitably improve blood flow in healthy individuals. Therefore, the blood flow improver of the present invention can be suitably used as an improver for diseases caused by decreased blood flow (fatigue, chills, swelling, stiffness, wrinkled skin, sagging skin, rough skin, etc.), i.e., as an improver for fatigue, chills, swelling, stiffness, wrinkled skin, sagging skin, rough skin, etc.

[0051] How blood flow improvers are used The application form of the blood flow improver of the present invention is not particularly limited, and it can be used in any application form, such as oral, transdermal, enteral, transmucosal, intravenous, intraarterial, subcutaneous, or intramuscular. From the viewpoint of more effectively exerting the blood flow improving effect, oral application is preferred.

[0052] The blood flow improver of the present invention can be used in any application form to exert its blood flow improving effect, and therefore can be incorporated into various products such as food and beverages, pharmaceuticals, feed, and pet food.

[0053] In addition, the dosage form of the product containing the blood flow improver of the present invention may be any of solid, semi-solid, liquid, etc., and is appropriately set according to the type and use of the product. The product containing the blood flow improver of the present invention may contain additives such as water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, plant extracts, water-soluble polymers, surfactants, metal soaps, alcohols, polyhydric alcohols, pH adjusters, antioxidants, UV inhibitors, preservatives, fragrances, powders, thickeners, pigments, and chelating agents, depending on the form, etc., within a range that does not impair the effects of the present invention. In addition, the product containing the blood flow improver of the present invention may contain other ingredients depending on the form, use, etc., within a range that does not impair the effects of the present invention. Examples of other ingredients include vitamin C, squalane, niacin, niacinamide, long-chain hyaluronic acid, placenta extract, sorbitol, chitin, chitosan, various plant extracts, etc. The amount of these ingredients is not limited as long as it does not impair the effects of the present invention.

[0054] When the blood flow improver of the present invention is used in food and drink, S-allylcysteine ​​is prepared as it is or in combination with other food materials or additives to obtain a desired form, and the food and drink is provided as a food and drink that exhibits the desired effect. Examples of such food and drink include general food and drink, as well as specific health foods, nutritional supplements, functional foods, and foods for sick people. Food and drink containing the blood flow improver of the present invention can also be used for fatigue recovery or fatigue reduction. The form of these food and drink is not particularly limited, but specific examples include main dishes such as bread and noodles; side dishes such as cheese, ham, sausages, and seafood products; beverages such as fruit juice drinks, carbonated drinks, and lactic acid drinks; luxury items such as cookies, cakes, jellies, ice cream, puddings, candies, and yogurt; and supplements such as tablets, granules, powders, capsules, soft capsules, and nutritional drinks. These food and drink can be used for the above-mentioned purposes. The food and drink for sick people is provided for patients who require prevention or treatment of reduced blood flow.

[0055] When the blood flow improver of the present invention is used in food and beverages, the amount of the blood flow improver to be incorporated into the food and beverage will vary depending on the form of the food and beverage, but may be, for example, in the range of 0.0001 to 50% by mass, preferably 0.001 to 50% by mass, and more preferably 0.01 to 50% by mass of S-allylcysteine.

[0056] Furthermore, when the blood flow improver of the present invention is used in the field of food and beverages, the blood flow improver of the present invention can be provided as a food additive for improving blood flow, either alone or in combination with other ingredients. When the blood flow improver of the present invention is used as a food additive, the content of S-allylcysteine ​​in the food additive, the amount of the food additive added to the food and beverage, etc. may be appropriately set so that the S-allylcysteine ​​content in the food and beverage to which it is added satisfies the above-mentioned content.

[0057] Furthermore, when the blood flow improver of the present invention is used in a pharmaceutical product, the blood flow improver of the present invention is adjusted to a desired form alone or in combination with other pharmacologically active ingredients, pharma- ceutically acceptable bases, additives, etc., and provided as a pharmaceutical product exhibiting the desired effect. The form of such a pharmaceutical product is not particularly limited, and specific examples thereof include oral administration preparations such as tablets, granules, powders, capsules, soft capsules, and syrups; transdermal or transmucosal administration preparations such as liquids, ointments, creams, gels, sprays, patches, inhalants, and suppositories; and injections.

[0058] When the blood flow improver of the present invention is used as a pharmaceutical, the blending ratio of the blood flow improver to the pharmaceutical varies depending on the form of the pharmaceutical, etc., but for example, in the case of an oral administration formulation or an injection, the S-allylcysteine ​​is in a range of 0.0001 to 50 mass%, preferably 0.001 to 50 mass%, and more preferably 0.01 to 50 mass%, and in the case of a transdermal or transmucosal administration formulation, the S-allylcysteine ​​is in a range of 0.0000001 to 10 mass%, preferably 0.00001 to 10 mass%, and more preferably 0.0001 to 10 mass%.

[0059] When the blood flow improver of the present invention is used in feed or pet food, the blood flow improver of the present invention is prepared into a desired form alone or in combination with other feed ingredients, and provided as feed or pet food that exerts the desired effect. Examples of the feed ingredients used in the feed or pet food include cereals such as corn, wheat, barley, rye, etc.; bran, rice bran, etc.; corn gluten meal, corn jam meal, etc.; animal feeds such as skim milk powder, whey, fish meal, bone meal, etc.; yeasts such as brewer's yeast; calcium phosphate, calcium carbonate, etc.; vitamins; amino acids; sugars, etc.

[0060] When the blood flow improver of the present invention is used as feed or pet food, the blending ratio of the blood flow improver to the feed or pet food will vary depending on the form of the feed or pet food, but for example, the range is 0.000001 to 10 mass%, preferably 0.0001 to 10 mass%, and more preferably 0.001 to 10 mass% of S-allylcysteine. EXAMPLES

[0061] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the examples.

[0062] Example 1 Eight-week-old male Wistar rats were anesthetized with Nembutal after three days of free water intake, and the tail blood flow was measured and recorded after keeping the rats at 37°C for more than 30 minutes. S-allylcysteine ​​(SAC) was orally administered at 100 mg / kg body weight using a stomach tube, and blood flow was measured and recorded at 0, 15, 30, 45, 60, and 75 minutes. The percentage change in blood flow (%) is shown in the graph in Figure 1 (SAC 100 mg / kg).

[0063] Similarly, using a stomach tube, drinking water containing 100 mg / kg body weight of S-allylcysteine ​​(SAC) and 2 mM of nitro-L-arginine (LNA), an inhibitor of blood flow improvement by nitric oxide, was orally administered, and blood flow was measured and recorded 0, 15, 30, 45, 60, and 75 minutes later. The percentage change in blood flow is shown in the graph in Figure 1 (LNA+SAC 100 mg / kg).

[0064] Similarly, 0.5% carboxymethylcellulose (CMC) 2mL / kg body weight and nitro-L-arginine (LNA) 2mM were orally administered using a stomach tube, and blood flow was measured and recorded 0, 15, 30, 45, 60, and 75 minutes later. The change in blood flow (%) is shown in the graph in Figure 1 (LNA+CMC).

[0065] Similarly, 0.5% carboxymethylcellulose (CMC) was orally administered at 2 mL / kg body weight to a control group using a stomach tube, and blood flow was measured and recorded 0, 15, 30, 45, 60, and 75 minutes later. The percentage change in blood flow is shown in the graph in Figure 1 (0.5% CMC).

[0066] As is clear from the results shown in Figure 1, there was almost no change in blood flow during the measurement period in the 0.5% CMC-administered group used as the control group. When 100 mg of SAC was administered to these rats, an increase in venous blood flow of nearly 200% was confirmed. On the other hand, in the group in which endogenous NO production was suppressed by administration of LNA (LNA + CMC group), blood flow temporarily decreased but returned to its previous value, indicating that NO is not involved in the control of tail vein blood flow under physiological conditions. Even when 100 mg of SAC was administered to these LNA-administered rats, tail vein blood flow did not increase compared to the SAC alone group, demonstrating the involvement of endogenous NO in the venous blood flow-increasing effect of SAC.

[0067] Example 2 Eight-week-old male Wistar rats were given free access to water for three days, and then anesthetized with Nembutal. After keeping the rats at 37°C for more than 30 minutes, the blood flow rate of the tail was measured and recorded. S-allylcysteine ​​(SAC) was orally administered at 200 mg / kg body weight using a stomach tube, and the blood flow rate was measured and recorded 0, 15, 30, 45, 60, 75, and 90 minutes later. The percentage change in blood flow rate (%) is shown in the graph in Figure 2 (SAC200).

[0068] Similarly, using a stomach tube, drinking water containing 200 mg / kg body weight of S-allylcysteine ​​(SAC), 2 mM nitro-L-arginine (LNA), an inhibitor of blood flow improvement by nitric oxide, and 100 mM L-arginine (ARG) was orally administered, and blood flow was measured and recorded 0, 15, 30, 45, 60, 75, and 90 minutes later. The rate of change in blood flow (%) is shown in the graph in Figure 2 (LNA+ARG+SAC200).

[0069] Similarly, 200 mg / kg body weight of S-allylcysteine ​​(SAC) and 2 mM of nitro-L-arginine (LNA) were orally administered using a stomach tube, and blood flow was measured and recorded 0, 15, 30, 45, 60, 75, and 90 minutes later. The percentage change in blood flow is shown in the graph in Figure 2 (LNA+SAC).

[0070] There was no increase in blood flow with LNA+SAC, and it is believed that the LNA+Arg rats administered excess Arg to the LNA group had restored their endogenous NO production. In the LNA+ARG+SAC200 group, where the rats were administered SAC, the blood flow increase effect of SAC was partially restored, confirming that endothelium-dependent NO is involved in the tail vein blood flow increase effect of SAC.

[0071] Example 3 Eight-week-old male Wistar rats were anesthetized with Nembutal after three days of free water intake, and the rats were kept at 37°C for more than 30 minutes to measure and record the blood flow in the plantar part of the foot. S-allylcysteine ​​(SAC) was orally administered at 200 mg / kg body weight using a stomach tube, and the blood flow (relative amount) was measured and recorded at 0, 15, 30, 45, and 60 minutes. The blood flow measurement results are shown in the graph (SAC 200 mg / kg) in Figure 3 and the image (SAC200) in Figure 4. The plantar blood flow shown in the image in Figure 4 was measured by placing the rat face down on a 37°C plate, with the sole facing up and the heel fixed with tape (capillary blood flow was measured by measuring the blood flow in the rat's footpad (measurement)).

[0072] Similarly, using a stomach tube, drinking water containing 200 mg / kg body weight of S-allylcysteine ​​(SAC) and 1 mM nitro-L-arginine (LNA), an inhibitor of blood flow improvement by nitric oxide, was orally administered, and blood flow (relative amount) was measured and recorded 0, 15, 30, 45, and 60 minutes later. The blood flow measurement results are shown in the graph (LNA+SAC200) in Figure 3 and the image (LNA+SAC200) in Figure 4. The plantar blood flow shown in the image in Figure 4 was measured by placing the rat face down on a 37°C plate with the sole facing up and the heel fixed with tape (capillary blood flow was measured by measuring blood flow in the rat's footpad (measurement)).

[0073] Similarly, 2 mL / kg body weight of 0.5% carboxymethylcellulose (CMC) was orally administered to a control group using a stomach tube, and blood flow (relative amount) was measured and recorded 0, 15, 30, 45, and 60 minutes later. The blood flow measurement results are shown in the graph (Control (CMC)) in Figure 3 and the image (CMC) in Figure 4. The plantar blood flow shown in the image in Figure 4 was measured by placing the rat face down on a 37°C plate with the sole facing up and the heel fixed with tape (capillary blood flow was measured by measuring blood flow in the rat's footpad (measurement)).

[0074] From Example 3, it was confirmed that SAC administration increased capillary blood flow by about 30-40%. This increase in blood flow disappeared by LNA treatment (i.e., inhibition of endogenous NO production), indicating that endogenous NO is important for the action of SAC.

[0075] Example 4 After administering tap water, nitro-L-Arginine (1mM), or L-Arginine (100mM) to 8-week-old male Wistar rats in drinking water for 3 days, 0.5% CMC or SAC 200mg / kg was orally administered at 1ml / 250g body weight. 60 minutes later, the thoracic aorta was harvested and the bands were analyzed by Western blotting using anti-Vasodilator-Stimulated Phosphoprotein (VASP) and eNOS (NOS3) antibodies. The following antibody types were used at 5,000-fold dilution. β-actin was used as an internal standard protein. As a result, pVASP showed a tendency to increase in the SAC-administered group despite administration of the NO synthesis inhibitor LNA, suggesting that pVASP is expressed in an NO-independent manner. eNOS did not change in any group (see Figure 5). eNOS(140kDa);BD Biosciences,610296 VASP(46-50kDa);Calbiochem,676600 β-actin (42 kDa); sigma, A5441

Claims

1. A nitric oxide-dependent blood flow improver whose active ingredient is S-allylcysteine.

2. 2. The blood flow improver according to claim 1, which has both nitric oxide-dependent and nitric oxide-independent blood flow improving effects.

3. 3. The nitric oxide-dependent blood flow improver according to claim 1, wherein the content of the S-allylcysteine ​​is 0.01 g / 100 g or more.

4. A food or drink for improving blood flow, comprising the blood flow improver according to any one of claims 1 to 3.

5. A pharmaceutical for improving blood flow, comprising the blood flow improver according to any one of claims 1 to 3.

6. A food or drink for recovering from fatigue and / or reducing fatigue, comprising the blood flow improver according to any one of claims 1 to 3.

Images