JPH0638708A - Sodium absorption inhibitor, sodium, absorption inhibitor-containing food for preventing hypertension and therapeutic agent for hypertension - Google Patents

Abstract

PURPOSE:To obtain a sodium absorption inhibitor useful for hypertension, kidney disease, adult disease, etc., moderating restriction of salt, reducing side effects, having excellent treating effects, comprising arginine (derivative), etc. CONSTITUTION:The inhibitor comprises (A) one or more of arginine (derivative) such as L-arginine hydrochloride and preferably (B) a potassium salt. The amount of the component B added is preferably 1/2-1/1 based on the component A and a dose of the component A is preferably 0.5-1g per time by oral administration.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sodium absorption inhibitor, a food product for preventing hypertension and a therapeutic agent for hypertension using the same, and particularly for the treatment of swelling diseases such as kidney disease and heart disease, and hypertension. Medicines and their diseases,
The present invention relates to a sodium absorption inhibitor for humans or animals that can be used in a food for preventing hypertension suitable for a reduced salt diet for the treatment / prevention of hypertension and the application thereof.

[0002]

2. Description of the Related Art The development of antihypertensive agents, which are therapeutic agents for hypertension, has progressed remarkably, and it has become relatively easy to treat severe hypertension such as malignant hypertension, which has been difficult to control blood pressure. However, in essential hypertension etc., when the use of antihypertensive drug is stopped, the blood pressure immediately returns to its original value, and conventionally used antihypertensive agents such as antihypertensive drug
Generally, it does not have a curative effect like a therapeutic agent for other diseases.

It is widely known that reducing the intake of salt in hypertensive patients is extremely effective in lowering blood pressure, and a salt-reducing diet is often used in combination with the use of antihypertensive agents. Further, in the case of mild hypertension, it is often the case that only salt-reduced diet therapy is used instead of drug therapy. Several therapeutic trials have confirmed that even mild salt restriction can provide effective antihypertensive effects. For example, according to a double-blind report, the blood pressure was significantly lowered (mean blood pressure value was 7.7 mmHg) even with a salt reduction of about 5 g. Therefore, in the case of hypertension, it is common sense to eat a diet that limits the intake of salt.

However, regarding the effect of the salt-reducing diet, there is a problem of "salt sensitivity" on the side of the living body receiving salt reduction, and for example, even in severe salt-reducing therapy with a salt amount of 0.5 g or less per day,
Although it was effective in about 2/3 of patients, there is also a report that no blood pressure reduction was observed in the remaining 1/3 of patients. Among the same patients with essential hypertension, there are some people whose blood pressure is susceptible to changes in salt intake and those who are not. In susceptible individuals, the ability of the kidneys to excrete sodium has decreased, and it is thought that blood pressure increases as a result of water and Na being stored in the body due to salt loading.

As described above, since the low salt diet is effective for people with hypertension, hypertension patients are instructed on low salt diet. Because of the reduced salt diet, it is difficult to cook simply by reducing the amount of salt added when cooking, so there is a reduced salt soy sauce and reduced salt butter and a reduced salt food is commercially available for convenience of cooking. There is. In addition, it is known that potassium has a hypotensive action, and its mechanism of action is not clear yet, but natriuretic action, vasodilator action, diminished pressor responsiveness, sympathetic nerve inhibitory action, renin secretion inhibitory action, etc. It is supposed to be due to. When potassium is administered, it has a hypotensive effect in the low salt diet. However, it is said that the administration of potassium drugs may cause gastric ulcer and intestinal perforation, and it is said that patients with renal failure are at risk of hyperkalemia. There is a constraint that it can be decided by the patient, and the effect is not sufficient.

[0006] On the other hand, many pet animals bred at home such as dogs and cats do not have a sweat line, and therefore these animals are required to regulate the in vivo concentration of sodium.
Depends on urine or fecal excretion. In addition, these animals generally have a low required intake of sodium, and the required intake per body weight (per kg) is, for example, 11 mg for dogs and 25 mg for cats, which is about one tenth of that for humans. It is said that the intake of is preferred. However, foods that are given to these animals on a daily basis, such as pet foods and drinks for pets, which are generally called pet foods, that can be given as they are without any processing, are usually necessary. It is in the form that various nutrients are ingested, in which case salt (sodium ion etc.)
The concentration of is also adjusted to an appropriate amount. However, pet animals that are given the same foods as humans, or foods and drinks for pets that are mixed with conventional food, cannot eat excretion from the above-mentioned required intake because they eat foods with high salt concentration. It is supposed that such an amount of sodium ions will be ingested, and for that reason, those exhibiting symptoms such as hypertension have come to be seen in recent years.

[0007]

However, it is not easy to obtain seasoned foods and various foods with reduced salt as described above, while processed foods such as ham, cheese, kamaboko and snacks have a high salt content. Since many such processed foods are on the market and there are many opportunities to take them out by eating out, it is very difficult to keep the salt intake as low as possible. Also, it is difficult to tolerate the salt content of foods in daily diets to a considerably low level due to the taste, and the severe salt-reduced diet of 0.5 g or less per day is continued for a long time. That is extremely difficult in practice.

Therefore, as long-term hypertension treatment, 5 times a day
The diuretics are administered only when the salt is moderately reduced to ˜6 g and the blood pressure is not sufficient. Also,
As described above, in drug therapy using antihypertensive agents, when a large amount of antihypertensive diuretics is administered for a long period of time, side effects such as hypokalemia, impaired glucose tolerance, and hyperuricemia may be observed. It is preferable to administer Considering the problems of salt-reducing diet therapy and drug therapy in patients with hypertension, a drug or the like that does not reduce salt in the diet and does not require the administration of antihypertensive drugs, which have side effects. Is highly desirable for hypertensive patients.

From this point of view, the present invention is to provide a drug or a food containing the same which does not require a hypotensive drug which does not significantly reduce salt in the diet and yet has side effects. The purpose is. Another object of the present invention is to prevent pet animals that are given the same foods as humans from absorbing sodium ions more than necessary, and not to cause the same pathological symptoms as humans such as hypertension. It is what

[0010]

Means for Solving the Problems The present invention provides means for reducing the intake of conventional salt which is a factor of hypertension, and for administering a blood pressure-lowering agent such as a vasodilator or a sympathetic nerve inhibitor to the human body. Therefore, it is a new means that has never been considered before. Sodium ions, which is a factor that raises blood pressure in the human body, is prevented from entering the human body (blood), thereby substantially reducing salt. It was completed by inventing that it could give the same effect as, and finding out that there is arginine as such a substance. In pet animals as well, it is also considered that preventing sodium ions from entering the body of pet animals in the same manner as described above prevents the same hypertensive symptoms as in humans, and has the same effect. It was completed by finding out.

[0011] Conventionally, arginine is one of the basic amino acids and is widely known to exist in proteins, and its properties are also relatively well known. L-arginine hydrochloride is mainly used as a pituitary function test drug. In addition, arginine is an essential amino acid in infants, and it is known that arginine stimulates the pituitary gland to secrete growth hormone. Since arginine is a constituent factor in the final stage of the ornithine cycle that produces urea, it is said to promote urea production and detoxify ammonia. In Europe, arginine promotes liver function and treats hepatic coma due to ammonia poisoning. It is used. Furthermore, even in Japan, 4 g for hyperammonemia due to hepatic coma and liver damage, and 12 to 20 g for severe hepatitis are dissolved in glucose or Ringer's solution and intravenously infused gradually, It is used as it is injected.

However, since arginine has an action of inhibiting absorption of sodium ion in the human body (in blood), it is effective in treating and preventing hypertension.
It was first discovered by the present inventor (hereinafter, for simplicity, the above-mentioned "inhibiting the absorption of sodium ions" may be referred to as "sodium absorption inhibition").

That is, the present invention has achieved the above object by the following means. (1) A sodium absorption inhibitor characterized by containing at least one or more of arginine and / or a derivative thereof and a physiologically acceptable salt thereof. (2) The sodium absorption inhibitor according to (1) above, which is used in combination with a potassium salt. (3) A food product for preventing hypertension, comprising the sodium absorption inhibitor according to (1) above. (4) A food product for preventing hypertension, which comprises the sodium absorption inhibitor according to (1) above in combination with a potassium salt. (5) A therapeutic agent for hypertension comprising at least one blood pressure-lowering active ingredient, arginine and / or a derivative thereof, and at least one physiologically acceptable salt thereof. (6) A food or drink for pet animals, comprising the sodium absorption inhibitor according to (1) above.

In the present invention, as arginine for a sodium absorption inhibitor, its isomers, derivatives, and physiologically acceptable salts thereof (hereinafter referred to as "arginine and / or its derivatives and their physiological An "acceptable salt" may simply be referred to as "arginine"). As the isomer, the L-form is preferable. Examples of the physiologically acceptable salts mentioned above include L-arginine hydrochloride.
The arginine used in the present invention is naturally present as described above, but as a large content, protamine, crupain, and salmine of fish milts, in which 80% or more of total nitrogen is arginine, and various other Highly contained in seeds, squid and garlic. It can be purified from these and used. Commercial products of arginine include L-arginine, L-arginine hydrochloride and L-arginine.
There are three types of arginine L-glutamate, which are easily available.

When the sodium absorption inhibitor of the present invention is used in combination with a potassium salt, the sodium absorption inhibitory effect can be further enhanced. It is well known that potassium has an antihypertensive effect, as described above,
When this potassium salt is used together, the sodium absorption inhibitory action of arginine can be further promoted. As the potassium salt, potassium chloride or the like is preferably used. The potassium salt may be added in an amount of about 1:10 to 10: 1, particularly about 1: 2 to 1: 1 with respect to arginine. Also, caffeine is
Since it has the effect of inhibiting the absorption of sodium ions,
You may use together with said arginine etc. The amount of caffeine blended is, for example, 1/2 to 1/20 of L-arginine hydrochloride.
It is preferable that

Further, the sodium absorption inhibitor of the present invention comprises
By coexisting with a substance having a monovalent cation (excluding sodium ion and potassium ion),
The sodium absorption inhibitory action can be promoted. The dose of this sodium absorption inhibitor is usually L-
0.5 to 1 g of arginine hydrochloride is orally administered once, and especially when a large amount of salty food is taken, 2 g is orally administered once. The dose can be appropriately changed depending on the symptoms.

As mentioned above, an example of blending arginine with a potassium salt or the like is shown below.・ Normal adult oral administration; L-arginine hydrochloride 1000 mg KCl 500 mg (caffeine 50 mg) ・ Adult oral administration especially when salted food is eaten; L-arginine hydrochloride 2000 mg KCl 1000 mg (caffeine 50 mg) Sodium absorption The inhibitor can be used as a drug. When arginine is administered, it may be in the form of a formulation or a liquid form. For example, it may be tablets, granules, or liquids. At that time, if necessary, excipients and other additives used for forming a dosage form can be added.

The sodium absorption inhibitor of the present invention can be made into a food for preventing hypertension by including it in a food and providing it with a meal. By doing so, the sodium absorption inhibitor of the present invention can be easily taken. Since arginine is widely contained in proteins, it can be contained in foods in good harmony with foods. The food to be contained may be any food, but protein foods are suitable, and examples thereof include tofu, dairy products (dairy drinks), and drinks.
In particular, it is preferable to take it regularly every day, for example, dairy drinks and the like are preferable. The content of the sodium absorption inhibitor in this food should be set so that the required amount corresponding to the intake of sodium in view of the intake of food is administered, but it may be set within the maximum compounding amount range. it can. In that case, it is natural that the taste is not changed by containing the sodium absorption inhibitor.

When this food for preventing hypertension is used in combination with potassium salt, its effect can be synergistically increased. As mentioned above, potassium is added as a potassium salt, for example, potassium chloride, but its content in the food is preferably in the range of about 1:10 to 10: 1 with respect to arginine, and particularly about 1: 2. preferable. In the present invention, the sodium absorption inhibitor is blended with at least one antihypertensive component (hypotensive agent),
It can be an extremely effective therapeutic agent for hypertension. As the antihypertensive agent to be blended, any one conventionally approved as this type of agent can be used as long as it does not adversely affect the antihypertensive action or another side effect.
Arginine itself is one of the amino acids and is widely present in proteins, so it usually does not give a harmful effect when used in combination with an antihypertensive agent.

The sodium absorption inhibitor of the present invention can be added to conventional animal foods or animal drinks in the same manner as the above-mentioned foods for preventing hypertension to prevent harm caused by excessive salt intake. It can be used as food and drink. The food and drink for pet animals of the present invention also include a sodium absorption inhibitor alone or a sprinkle for animals in which only the flavor and / or seasoning is added to the sodium absorption inhibitor. In use, the pet food and drink of the present invention and other pet foods or beverages for pets that contain excessive salt for the pets to be ingested can be used as a mixture, for example, human foods for pets concerned. By adding foods and drinks and using them for pet animals, it is possible to suppress the absorption of an excessive sodium content into the living body in pet animals, which is an appropriate amount for humans. And as pet animals, dogs, cats,
In addition to pets such as rabbits and mice (guinea pigs, hamsters, etc.), domestic animals such as horses and sheep are also included. In addition, the food and drink for pets of the present invention, the food that is usually said,
It is used to include pet foods such as dock foods and kit foods, and also includes liquid drinks given to pet animals.

[0021]

In the sodium absorption inhibitor of the present invention, arginine has an effect of inhibiting absorption of sodium ions in the human body and the animal body, and therefore hypertension in which a large amount of salt is ingested, particularly mild hypertension, etc. Is effective for. In addition, it is effective for treating renal diseases and adult diseases. At that time, if a potassium salt or caffeine is used together, the effect is further enhanced. In the combined use, there is a sodium ion excretion action by potassium salt or a diuretic action by caffeine.

This sodium absorption inhibitor has the above-mentioned sodium absorption inhibitory effect when added to foods,
It is useful as a food for preventing hypertension. Since arginine is a kind of amino acid per se and widely present in proteins, it has affinity with foods and can be easily taken. Further, the combination of the sodium absorption inhibitor with the antihypertensive agent has both the sodium absorption inhibitory effect of arginine and the blood pressure lowering effect of the antihypertensive agent, and is therefore extremely effective for the treatment of hypertension.

[0023]

EXAMPLES The present invention will be specifically described below with reference to examples. However, the present invention is not limited to these examples. Example 1 The following experiment was conducted to confirm the sodium absorption inhibitory effect of arginine. (Preparation of small intestine loop) Male Japanese white rabbit (body weight 2.6
~ 3.3 kg) for 24 hours and then pentoparbital Na (trade name Nembutal, 35 mg / kg)
Was anesthetized by intravenous administration and used for the experiment.
An incision of about 10 cm was made along the midline of the abdomen of each of these rabbits, a small intestine (jejunum) having a length of about 12 cm was drawn out from the abdominal cavity, and both ends were joined to form a small intestine loop.

(Preparation of Test Solution) The following aqueous solutions were prepared as test solutions. 0.46M salt solution, (0.46M salt +
0.115M L-arginine) aqueous solution, (0.4
6M sodium chloride + 0.23M L-arginine) aqueous solution,
(0.46M salt + 0.115M L-arginine +
0.23M KCl) aqueous solution, (0.46M salt +
Caffeine) aqueous solution. (Measurement of Sodium Ion Concentration in Blood Collection) These test solutions were separately injected into the rabbit small intestine loop, and every 15 minutes, all blood flowing out from the jejunal vein controlling the small intestine loop was collected, and its sodium concentration was measured. It was measured. The measurement result is shown in FIG. In FIG. 1, the sodium ion absorption amount (mg / ml) on the vertical axis is based on the sodium concentration in the blood of rabbits.

According to FIG. 1, when arginine is present in the saline solution, the amount of sodium ions absorbed through the small intestinal wall is reduced, and arginine has a sodium absorption inhibitory action. The higher the concentration of arginine, the greater the effect. It is also recognized that the coexistence of potassium salt further reduces the absorption amount of sodium ions. From these results, the sodium ion absorption inhibition rate (%) by L-arginine, KCl, and the combination of both after 45 minutes is shown in FIG.
The absorption inhibitory rate, the value obtained by subtracting the sodium absorption M _x of the test solution of sodium absorption amount M ₁ of the test solution M ₁
It is divided by and multiplied by 100.

Example 2 A test was carried out by using a rabbit intestinal loop model as in Example 1. As in Example 1, a 0.46 M sodium chloride solution was used as a reference test solution No. Test liquid No. 10 containing arginine or KCl, and both of them. 11
~ 19 were prepared. The concentration of arginine or KCl is 3 each
It was a kind. In the case of containing both of the above, the compounding ratio was arginine: KCl = 1: 2. Then, the sodium ion absorption suppression rate (%) was calculated from the measurement result. Further, the concentration of each substance when the sodium ion absorption inhibition rate (%) was 50% was determined from the measurement results. 50% Na ion absorption inhibitory concentration (ID ₅₀ ;
M). Table 1 shows the concentrations of these test solutions and the above calculation results. According to Table 1, the test solution No. in which arginine and KCl were used in combination was used. In the cases of 17 to 19, it is recognized that there is a synergistic effect.

[0027]

[Table 1]

Example 3 Rats were divided into 3 groups, and as drinking water, (1) 1.5% saline solution, (2) 1.5% saline solution + 2.5% arginine +
0.5% KCl, (3) 1.5% saline + 5.0% arginine + 0.5% KCl were used, and the daily fecal sodium ion excreted from these rats was measured. After measurement, the excretion rate of sodium ions in the feces under this 1.5% saline load was calculated. This sodium ion excretion rate is {sodium ion excretion (feces)
/ Total intake of sodium ions (food + water)}. The sodium ion excretion rate (%) is shown in FIG.

Example 4 As a pet beverage of the present invention, a beverage comprising the following ingredients was prepared. Ingredients g / 100 ml content Vitamin B group 0.0012 Carnitine hydrochloride 0.05 Calcium chloride 0.1 L-arginine 0.5 Liquid sugar 6.0 Water remaining

[0030]

INDUSTRIAL APPLICABILITY The sodium absorption inhibitor of the present invention has an action of inhibiting absorption of sodium ions in the human body, an action of promoting excretion of sodium ions, and a diuretic action. Even if a person ingests salt, the influence of the salt is small, so it is not necessary to continue a strict salt-reduced diet. For this reason, people with hypertension have a very easy diet. It has an auxiliary effect on the restriction of salt intake in people with hypertension. So this sodium absorption inhibitor
Especially suitable for patients with mild hypertension. In this way, since the effect of sodium ions can be reduced, in the case of patients with mild hypertension, it is not necessary to use an antihypertensive agent, and even if it is not mild, the amount of antihypertensive agent used can be small,
The side effects of it can be eliminated or even suppressed. When the sodium absorption inhibitor is used in combination with a potassium salt or the like, the effect is further increased in combination with the antihypertensive action of the potassium salt and the like. Thus, the sodium absorption inhibitor of the present invention is extremely effective for hypertension, renal diseases, adult diseases and the like.

Since the food for preventing hypertension in which the sodium absorption inhibitor is contained in the food is arginine which is one of the amino acids, it is easily compatible with food and can be easily taken. Since the sodium absorption inhibitory effect described above can be easily achieved, it is effective not only for preventing hypertension but also for treating it. At that time, if a potassium salt is used in combination, the antihypertensive effect and the like can be obtained together. Further, the therapeutic agent for hypertension of the present invention containing a sodium absorption inhibitor and an antihypertensive agent has a remarkable effect on the treatment of hypertension, because the antihypertensive agent has the antihypertensive effect together with the sodium absorption inhibitory effect. Since the amount of conventional antihypertensive agents can be reduced, the side effects of antihypertensive agents can be considerably reduced.

Further, the food and drink for pet animals in which the sodium absorption inhibitor is added to the animal food or the animal drink or only the flavor and / or the seasoning is added to the sodium absorption inhibitor are the above-mentioned foods for preventing hypertension. Similarly, it can be easily ingested by pet animals, and it is possible to prevent adverse effects due to excessive salt intake in these pet animals, for example, hypertension symptoms.

[Brief description of drawings]

FIG. 1 is a graph showing the time course of sodium ion absorption from the small intestine in a rabbit small intestine loop model.

Fig. 2 Arginine and K for inhibition rate of sodium ion absorption from small intestine after 45 minutes in rabbit small intestine model
The graph which shows the combined effect of Cl is shown.

FIG. 3 is a graph showing the sodium ion excretion rate in rat feces.

Claims (6)

[Claims] 1. A sodium absorption inhibitor comprising at least one or more of arginine and / or a derivative thereof and a physiologically acceptable salt thereof. 2. The sodium absorption inhibitor according to claim 1, which is used in combination with a potassium salt. 3. A food for preventing hypertension, comprising the sodium absorption inhibitor according to claim 1. 4. A food for preventing hypertension, which comprises the sodium absorption inhibitor according to claim 1 in combination with a potassium salt. 5. At least one blood pressure lowering active ingredient,
An antihypertensive agent comprising arginine and / or a derivative thereof and at least one physiologically acceptable salt thereof. 6. A food or drink for pet animals, which comprises the sodium absorption inhibitor according to claim 1.