JPH0656674A - Food additive substance for depression of blood pressure and antihypertensive - Google Patents

Abstract

PURPOSE:To provide the subject novel substance containing chitosan as an active ingredient and useful for preventing and treating hypertension because of inhibiting the absorption of Cl<-> in living bodies, where the Cl<-> has an action to activate angiotensin I converting enzyme having a hypertensive action. CONSTITUTION:This additive substance for stimulating the excretion of chlorine in foods contains chitosan as an active ingredient. The chitosan is usually obtained by deacetylating chitin contained in the shells of crustaceans such as shrimps and crabs. The chitosan is usually used at a daily dose of 5-6g for an adult male essential hypertension patient weighing 70kg and taking daily 12g of salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel food additive and antihypertensive agent for promoting the excretion of chlorine in foods and for lowering blood pressure.

[0002]

2. Description of the Related Art To date, hypertension as an adult disease,
In particular, much research and development has been conducted on the etiology of essential hypertension (hypertension without other underlying diseases), and it has been clarified that this is due to the complex establishment of complex blood pressure control mechanisms. ing. These factors include
Renal pressor factor: Renin is a proteolytic enzyme produced in juxtaglomerular cells. It is released in response to changes in the internal pressure of the juxtaglomerular apparatus and is the substrate of angiotensinogen in α ₂ globulin. The Leu-Leu (Leu-Val in humans) bond is specifically hydrolyzed to yield angiotensin I (decapeptide). This loses two amino acids by the action of angiotensin I converting enzyme and becomes angiotensin II (octapeptide). This angiotensin II directly contracts the smooth muscle of peripheral blood vessels and causes a strong pressor activation effect.Adrenal cortex: Angiotensin II acts on the cortical glandular layer of the adrenal cortex, prominently increasing the secretion of aldosterone, The pressor action of the renin-angiotensin system is said to be mediated by aldosterone (usually, in hypertension in which the renin-angiotensin system is abnormally elevated, renovascular hypertension and malignant hypertension, and rarely due to renin-producing tumors) Hypertension, essential hypertension is also said to be involved in the renin-angiotensin system), neural and neurohumoral factors: those thought to be involved in the sympathetic nervous system (confirmation at present is not obtained), Blood circulation factor: due to vascular reactivity and vascular smooth muscle contraction mechanism, other genetic factors,
Factors related to sodium metabolism are included. Antihypertensive agents are widely used because they are used for the treatment of essential hypertension.

This drug affects blood pressure control mechanism and lowers blood pressure, and there are many drugs having different action mechanisms. As such substances, (1) they directly act on vascular smooth muscle to cause vasodilation. (2) Drugs that suppress sympathetic nervous system activity somewhere in the pathway from the central to peripheral vascular receptors (central sympathetic depressants, drugs that suppress both centrally and peripherally, ganglion block) Drug, adrenergic neuron blocker, alpha receptor blocker), (3) diuretic,
(4) Angiotensin antagonist (Angiotensin II
, An angiotensin I-converting enzyme inhibitor) and the like are used.

However, all of these drugs are used as therapeutic agents for patients with essential hypertension, and they need to be properly prescribed by a doctor for proper diagnosis. Therefore, it is desirable to be able to prevent the essential hypertension by diet therapy and the like without using such a therapeutic agent. Therefore, it is possible to prevent or suppress the essential hypertension by controlling the intake of salt. It has been confirmed by subsequent research on preventive medicine.

That is, it has been confirmed that excessive intake of sodium chloride (sodium chloride) has a great influence on the blood pressure control mechanism relating to the cause of essential hypertension, resulting in hypertension. This means that in rats, aldosterone (sodium ion from kidney (hereinafter,
A hormone that suppresses excretion of Na ⁺ ) is administered, and sodium chloride (hereinafter also simply referred to as NaCl) is administered.
It was confirmed that hypertension was caused under the condition that the Na ⁺ concentration in blood was increased by the administration of. From this, it is considered that Na ^{+ in} NaCl is further involved in hypertension. Therefore, plant dietary fibers such as alginic acid contained in vegetables and seaweeds that are easily adsorbed with Na ⁺ generally adsorbs harmful components to non-nutrient dietary fibers and promotes fecal excretion. Since much attention has been paid to this, much research and development has been made.

[0006] However, in the experiment using the above-mentioned rat, it was carried out under the condition that the elevation of Na ^{+ in} the blood was caused in advance.
There is no underlying disorder that causes elevated a ⁺ (ie, a disorder with excessive secretion of aldosterone),
The fact is that it has not been concluded whether Na ⁺ or Cl ⁻ causes the blood pressure-increasing effect due to excessive intake of NaCl.

[0007] Among these, chloride ion to date in NaCl (hereinafter, simply Cl ^- also referred to) and not reported any way for a causal relationship between essential hypertension, therefore, Cl ^- relative adsorption Similarly, no report has been made on physiological effects such as a causal relationship between essential dietary fiber such as chitosan and essential hypertension, and as a preventive factor for hypertension, chitosan has angiotensin antagonism,
In particular, it has never been used as a food additive for lowering blood pressure or an antihypertensive agent which has an action of suppressing angiotensin I converting enzyme.

The above chitosan is a huge polymer of amino sugar (glucomisan) prepared by the deacetylation reaction of chitin contained in the epidermis of crustaceans such as shrimp and crab, and has an amino group. Ion exchangers, a wide range of heavy metal adsorbents, removal agents for various acidic substances (nucleic acids, endotoxins, etc.), as a cation-based activated sludge flocculant for industrial water filters, etc. It is used as a material for recovering protein inside.

Regarding the physiological effect of chitosan, it has been reported that it is decomposed and absorbed in the living body by enzymes such as lysozyme, and attention is paid to it as a biodegradable and absorbable natural polymer for surgical materials. Development has been actively carried out, and from these circumstances, surgical sutures, wound dressings, artificial skin and the like have been put to practical use as biocompatible materials. However, as described above, no report has been made on physiological effects such as influence on essential hypertension.

[0010]

Absorption into in vivo ^- OBJECTS OF THE INVENTION It is therefore an object of the present invention, Cl with activating effect of angiotensin I converting enzyme that is causing the hypertensive effects in essential hypertension It is intended to provide a novel food additive substance for lowering blood pressure that can be suppressed.

Another object of the present invention is to provide a novel antihypertensive agent.

[0012]

[Means for Solving the Problems] In order to achieve the above-mentioned various objects, the present inventors have diligently studied a novel food additive and an antihypertensive agent for lowering blood pressure, which act to suppress angiotensin I converting enzyme activity. As a result, it was found that the activity of angiotensin I-converting enzyme, which is one of the causes of hypertension, is increased by Cl ^{− in} NaCl ingested in the body, and obtained as animal dietary fiber which is easily adsorbed with Cl ^−. By mainly orally administering to humans or animals in the form of a food as a food additive containing a cationic chitosan or a formulation as an antihypertensive agent, the salt in the body ingested together with the food etc. Cl ^-
The chitosan adsorbs in the intestinal tract, suppresses the absorption of Cl ^-into the blood, and excretes it in the feces as it is, so that it is possible to suppress a remarkable increase in the Cl ^- concentration in the body (in the blood) and angiotensin I exchange The present inventors have completed the present invention by finding that the activity of the enzyme can be suppressed and, as a result, the increase in blood pressure can be suppressed, and that it is optimal for promoting the decrease in hypertension.

Therefore, the object of the present invention is achieved by a food additive containing chitosan as an active ingredient for promoting excretion of chlorine in food.

The object of the present invention is also achieved by a food additive for lowering blood pressure which contains chitosan as an active ingredient.

Further, the object of the present invention is achieved by an antihypertensive agent containing chitosan as an active ingredient.

[0016]

The effect of chitosan contained in the food additive and the antihypertensive agent (including antihypertensive agent) of the present invention is one of the causes of essential hypertension by administering an effective amount thereof to humans or animals. By adsorbing chloride ions involved in the activity of angiotensin I-converting enzyme, which is a renal pressor factor, which is one of the two factors, it inhibits absorption of the chloride ions in the body (intestinal tract) into blood and excreted in feces. It is possible to suppress the pressurizing action by increasing.

Therefore, the chitosan used in the present invention is usually a large polymer of amino sugar (glucomisan) prepared by deacetylation reaction of chitin contained in the epidermis of crustaceans such as shrimp and crab. Well, the molecular weight is usually a high molecular weight polymer of about 1,000,000.

The antihypertensive agent used in the present invention is mainly orally administered in the form of tablets, capsules, powders, granules, tablets, fluids, gel preparations and the like. Similarly, the food additive substance of the present invention may be added to foods (including beverages) in the form of powder, granules, tablets, fluids, gels, etc., and can appropriately act in the body (intestinal tract). It may be pre-coated with a retarder or the like.

Further, the tablets and capsules for oral administration of the antihypertensive agent used in the present invention preferably carry one dose each, for example, as a binder drug for syrup, acacia or sorbitol. Those containing conventional excipients, such as lactose, sugar or fillers such as corn-starch.

Oral liquid preparations are those in the form of suspensions, solutions, emulsions, syrups or elixirs containing water or oil, and water or other suitable excipients before use. It may be a dry product which can be added with an agent and returned to a liquid state. Such oral liquid formulations include suspensions such as sorbitol, syrup or gelatin,
Emulsifiers such as acacia and lecithin, coconut oil, non-aqueous excipients such as oily esters (propylene glycol, etc.), other preservatives and additives used as usual chemicals, and seasonings and colorants as necessary. Alternatively, vitamin supplements are used. Further, the addition amount (or dose) of the chitosan in the food additive or antihypertensive agent of the present invention
Depends on the intake of salt, the degree of hypertension, the weight,
It varies depending on age, sex, etc., and it is desirable to determine an appropriate amount for use according to the patient, but when the daily intake of salt is 12 g, 70 kg of essential hypertension ( 5 to 6 g for adult male patients with other underlying diseases (hypertension)
The / day range will be a good guideline for the treatment.

[0021]

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

Example 1 Normal rat and spontaneously high
Animal Experiments on Blood Pressure Rats (1) Evaluation test for activating effects of Cl ⁻ and Na ⁺ on angiotensin I-exchange enzyme One of the causes of hypertension is angiotensin II in blood.
The angiotensin II is produced by the action of angiotensin I to angiotensin I converting enzyme (hereinafter, also simply referred to as ACE) which has no blood pressure raising action. That is, by inhibiting the activity of the ACE, the increase of angiotensin II is suppressed and the blood pressure is not increased. On the contrary, the A
If the activity of CE is promoted, angiotensin II
Is increased and causes an increase in blood pressure. Therefore, changes in the activity of the ACE with respect to Na ⁺ and Cl ⁻ were investigated, and based on this result, it was inferred whether the cause of hypertension was caused by Na ⁺ or Cl ⁻ .

FIG. 1 shows that each rat serum contained NaC.
1 shows the change in the activity of serum ACE by adding 1, 1, potassium chloride (hereinafter, simply referred to as KCl) and sodium acetate (hereinafter, also simply referred to as CH ₃ COONa).

From FIG. 1, both NaCl and KCl increase the ACE activity, but CH ₃ COONa has no such action. From these results, NaCl and K
It was confirmed that Cl ⁻ in Cl has an action of enhancing ACE, and Na ⁺ has no such action. From the above, it could be inferred that Cl ⁻ causes hypertension.

(2) Test for confirming the Cl ⁻ excretion promoting effect in the body by chitosan Next, in order to confirm the Cl ⁻ excretion promoting effect in the body by chitosan, chitosan was added to normal rats (Intact Rat). The amount of chlorine in feces was measured when the diets prepared according to the dietary composition containing alginic acid and the dietary composition containing alginic acid were administered while varying the content of NaCl. The results are shown in Table 1.

[0026]

[Table 1]

From these results, a low NaCl diet and high Na
It was confirmed that chitosan markedly increased the amount of chlorine in feces in any of the Cl diets. From this, it was confirmed that chitosan was bound to Cl ⁻ in the food and excreted in feces.

(3) Confirmation test of blood pressure lowering effect on in vivo administration of chitosan Finally, the blood pressure lowering effect on in vivo administration of chitosan was confirmed from the results of the evaluation test of (1) and the confirmation test of (2). In order to do so, two kinds of dietary fiber were prepared. One, Cl ^- and chitosan prepared by deacetylation of chitin contained in such shell crab having the function of adsorbing and one is included in the hump has a function of adsorbing Na + Alginic acid which is a dietary fiber was used. The food composition containing the chitosan and alginic acid contains Na
The diet prepared by containing Cl is shown in Table 2.

[0029]

[Table 2]

FIG. 2 is a graph showing the systolic blood pressure of a normal rat (Intact Rat) and a rat susceptible to hypertension (SHR), which were respectively administered with a chitosan diet and an alginate diet containing NaCl having the composition shown in Table 2. Is.

As is clear from FIG. 2, normal rats (Intact Rat) and rats susceptible to hypertension (SH
In any of R), it was confirmed that the blood pressure in the chitosan diet-administered group was significantly lower than that in the alginic acid diet-administered group.

From the above-mentioned animal experiments, it has hitherto been observed that excessive intake of salt causes an increase in blood pressure, but simultaneous ingestion of animal fiber chitosan causes a remarkable hypotensive effect in normal rats and rats susceptible to hypertension (spontaneous Was observed in hypertensive rats). From this, it was revealed that chitosan promotes fecal excretion of chlorine contained in sodium chloride, reduces blood chlorine concentration, and as a result, decreases blood ACE activity, thereby suppressing an increase in blood pressure. It was

Example 2 Human Clinical Experiment Based on the results of the animal experiment of Example 1 above,
The mechanism of blood pressure increase when high salt was ingested in human and the blood pressure lowering effect when chitosan was simultaneously ingested were confirmed.

First, seven healthy male subjects aged 20 to 50 were served as a breakfast with a high salt diet (1100 kca) according to the menu shown in Table 3.
1, salt 13 g / meal), and the systolic blood pressure was measured and blood was collected before eating, 1 hour after eating and 3 hours after eating, respectively, and sodium, potassium, bicarbonate and Chlorine concentration, and A
CE activity was measured.

[0035]

[Table 3]

Furthermore, immediately after eating the high salt diet at the same time after one week, 5 g of chitosan was ingested, the systolic blood pressure was measured and blood was collected at the same time, and the same content was measured. It was

The obtained results are shown in Table 4, changes in systolic blood pressure, Table 5 in changes in blood sodium concentration, and Table 6, respectively.
Shows changes in potassium concentration in blood.

[0038]

[Table 4]

[0039]

[Table 5]

[0040]

[Table 6]

Next, the obtained results were statistically processed by a two-way analysis of variance with respect to the effects of chitosan and changes with time due to high salt diet intake, and the presence or absence of interaction was examined. Further, multiple comparison was performed according to the method of Tukey. Note that all of these analyzes were performed using the SAS statistical package PC version (version 6.03).

First, FIG. 3 is a graph showing the effect of chitosan on the systolic blood pressure when the high salt diet is taken.

From Table 4 and FIG. 3 above, a significant increase in blood pressure was observed in all the subjects 1 hour after the intake of high salt. However, it was confirmed that simultaneous ingestion of chitosan at the same time after one week suppressed the increase in blood pressure due to this high salt diet.

Next, FIG. 4 shows the effect of chitosan on blood sodium concentration when a high salt diet was taken, and FIG.
FIG. 4 is a graph showing the effect of chitosan on blood potassium concentration when a high salt diet is ingested.

From the above Tables 5 and 6 and FIGS. 4 and 5, it was confirmed that there is no significant increase due to the intake of the high salt diet and there is no effect due to the intake of chitosan.

FIG. 6 shows the effect of chitosan on blood bicarbonate concentration when a high salt diet was taken, and FIGS. 7 and 8 show the blood chlorine concentration by chitosan when a high salt diet was taken. 3 is a graph showing the influence of

From FIG. 6, the blood bicarbonate concentration was significantly decreased by the intake of the high salt diet, and conversely, FIGS.
The blood chlorine concentration was increased by the intake of high salt diet. However, it was confirmed that the increase and decrease in the concentration of bicarbonate and chlorine disappeared by the intake of chitosan.

Further, FIGS. 9 and 10 are graphs showing the influence of chitosan on blood ACE activity when a high salt diet was ingested.

From FIGS. 9 and 10, the ACE activity, which is an important enzyme for blood pressure regulation, was increased by the intake of the high salt diet, but its effect was suppressed by the simultaneous intake of chitosan.

Although the hypotensive effect of chitosan was demonstrated in animal experiments in Example 1 above, it was confirmed from Example 2 that humans also have a hypotensive effect by ingesting chitosan.

In addition, clinical experiments with chitosan have confirmed that chlorine, out of sodium, has a stronger effect of increasing blood pressure than sodium.

[0052]

INDUSTRIAL APPLICABILITY The food additive and antihypertensive agent comprising chitosan of the present invention are administered in vivo to appropriately adsorb Cl ⁻ in NaCl ingested together with food, It suppresses the absorption of chlorine ions in the intestinal tract and has an excellent function of promoting excretion in feces, which can suppress an increase in the chlorine concentration in blood in the body, and as a result, it directly affects the pressor action. Since it can suppress the activating action of the involved angiotensin I converting enzyme, it can be used for both prevention and treatment of hypertension.

Further, it is not necessary to limit and control the amount of salt intake, and it is possible to season food as well as that of a healthy person (animal). It is not necessary to bother to make a low-salt diet and the taste is salty. Salt that presents (the salty taste is perceived as the total taste of Na ⁺ and Cl ⁻ , which are salt)
It can be used as a food additive and an antihypertensive agent which is excellent in that it does not become dull in a low salt diet.

[Brief description of drawings]

FIG. 1 is a graph showing changes in serum ACE activity when NaCl, KCl and CH ₃ COONa were added to rat serum.

FIG. 2 is a graph showing systolic blood pressures when a NaCl-containing chitosan diet and an alginate diet were administered to normal rats (Intact Rats) and hypertensive rats (SHRs), respectively.

FIG. 3 is a graph showing the effect of chitosan on the systolic blood pressure when a high salt diet is taken.

FIG. 4 is a graph showing the effect of chitosan on blood sodium concentration when a high salt diet is ingested.

FIG. 5 is a graph showing the effect of chitosan on blood potassium concentration when a high salt diet is ingested.

FIG. 6 is a graph showing the effect of chitosan on blood bicarbonate concentration when a high salt diet is ingested.

FIG. 7 is a graph showing the effect of chitosan on blood chlorine concentration when a high salt diet is ingested.

FIG. 8 is a graph showing the effect of chitosan on blood chlorine concentration when a high salt diet is ingested.

FIG. 9: Blood A by chitosan when a high salt diet was ingested
It is a graph which shows the influence on CE activity.

FIG. 10 is a graph showing the effect of chitosan on blood ACE activity when a high salt diet was ingested.

Claims (3)

[Claims] 1. A food additive containing chitosan as an active ingredient for promoting the excretion of chlorine in food. 2. A food additive substance for lowering blood pressure, which comprises chitosan as an active ingredient. 3. An antihypertensive agent containing chitosan as an active ingredient.