Antihypertensive material found in Japanese traditional food
1, What is “Katsuobushi (dried bonito) Oligopeptide” ?
“Katsuobushi (dried bonito) Oligopeptide” described below is protease digests of Katsuobushi (dried bonito), a Japanese traditional seasoning made of bonito muscle.
Protein made of over one hundred amino acids is converted to amino acids by digestive enzymes, when it is taken into human body. Protein is not completely digested to each amino acid at one time, but is partially hydrolyzed to peptides, consisting of two to ten amino acids, and then gradually decomposed and absorbed through digestive organs into body. During this decomposition process, amino acid sequence less than ten amino acids is called “Oligopeptide”.
2, Katsuobushi (dried bonito) Oligopeptide shows anti-hypertensive activity
||What is Katsuobushi?
Katsuobushi is a Japanese traditional food and has 1500 years of history. Down the ages, Japanese have used it to make soup stock and to season the food.
||This is Katsuobushi oligopeptide derived from Katsuobushi.
Oligopeptides are produced from any food protein taken into human body. Primary structure of the oligopeptide will be changed and are depend on a kind of raw material protein or proteases worked because each protein has its own amino acid sequence and each digestive enzyme has different decomposing activity. In short, in some cases, protein can produce especially useful oligopeptides to human body and others do not.
Recently, “Katsuobushi Oligopeptide” was found with anti-hypertensive activity. Professor Masaaki Yoshikawa, department of Food Science and Technology in Kyoto University, showed that “Katsuobushi Oligopeptide” was obtained from “thermolysin” digest of dried bonito.
3, Katsuobushi (dried bonito) Oligopeptide is converted into active form during digestion
The main component in “Katsuobushi Oligopeptide”, showing anti-hypertensive activity, is a sequence of five amino acids, “LKPNM” (Leu-Lys-Pro-Asn-Met). This amino acid sequence is characteristic of Katsuobushi Oligopeptide. You can not take the same peptide from any other ordinary food or Katsuobushi itself.
LKPNM is converted into “LKP” (Leu-Lys-Pro) and “NM” (Asn-Met) in digestive organs or blood. The converted “LKP”, having anti-hypertensive activity, is called as “Active Form”.
This reaction is important to show the long-lasting and moderate anti-hypertensive activity of Katsuobushi Oligopeptide.
Katsuobushi oligopeptide lowers blood pressure by suppressing blood vessel contraction
1, Inhibitor of “ACE” which has anti-hypertensive activity
Katsuobushi Oligopeptide shows anti-hypertensive activity by inhibiting “Angiotensin I-Converting Enzyme (ACE)”.
Angiotensin I is one of peptides synthesized in human body. Angiotensin I is converted into Angiotensin II by ACE reaction. Angiotensin II has hypertensive activity by contracting blood vessel.
ACE has another activity to degrade Kinin, which lowers blood pressure by relaxing blood vessel. Therefore, ACE elevates blood pressure by both the formation of Angiotensin II and the decomposition of Kinin.
2, Highest inhibitor activity among peptides derived from food proteins
Therefore, inhibition of ACE activity can depress hypertension. In fact, Anti-hypertensive drugs such as Captopril, ACE inhibitors, have been widely used and evaluated to be effective for recent 10 years.
On the other hand, some substances derived from food have been reported as ACE-inhibitors. Some peptides, enzymatic digests of proteins are one group of ACE-inhibitors from foods.
Professor Yoshikawa and his group, described above, has studied to find strong ACE-inhibitory peptide by various combinations of enzymes and over 30 food proteins. Katsuobushi Oligopeptide is the one found in their research.
Eating Katsuobushi itself does not show anti-hypertensive activity
1, Katsuobushi (dried bonito) itself has no anti-hypertensive activity
Katsuobushi (dried bonito) Oligopeptide is food derived from Katsuobushi protein by enzymatic reaction. However, eating Katsuobushi itself does not show any anti-hypertensive activity. The reason is that peptides derived from different enzymes show different biochemical activities even if obtained from the same protein. When you take Katsuobushi itself, it is hydrolyzed by digestive enzymes such as pepsin, trypsin and chymotrypsin, secreted from stomach or intestine. Katsuobushi Oligopeptide, on the other hand, is made by an enzyme called “thermolysin (it is secreted by Bacillus thermoproteolyticus, one of Bacillus natto line)”. Katsuobushi Oligopeptide is never produced in human body because no enzyme, which has the same activity with thermolysin, is available in digestive systems.
Enzymatic digests of Katsuobushi by pepsin, trypsin or chymotrypsin indicated any anti-hypertensive activity in animal experiment (Table 1).
Table 1: Effect of enzymatic digests of Katsuobushi on lowering blood pressure
||Effect of lowering
(digestive enzyme secreted in stomach)
(digestive enzyme secreted in intestine)
(digestive enzyme secreted in intestine)
Thermolysin is a safe enzyme, used for food processing such as meat softening or making seasoning (aspartame).It is allowed to use as a food additive in Japan.
2, Katsuobushi Oligopeptide made from natural bonito (non-dried bonito) does not show
anti-hypertensive activity either
Thermolysin digests of non-dried bonito protein obtained no oligopeptides with anti-hypertensive activity.
The reason is assumed as follows:
During a Katsuobushi (dried bonito) manufacturing process, bonito meat is treated with special fungi for a while. It seems that proteases secreted from the fungi are closely contributed to ACE-inhibitory activity.
Katsuobushi Oligopeptide is gradually converted into active form in human body
As explained previously, the main effective component of “Katsuobushi Oligopeptide” is “LKPNM” consisting of five amino acids. It is converted into “LKP” in digestive tube or blood apart from two amino acids. ACE-inhibitory activity of “LKP” is 8 times higher than “LKPNM”. In other words, “LKP” is substantial peptide, which shows anti-hypertensive activity.
You can easily imagine as follows. If you can take “LKP” directly, the anti-hypertensive activity will appear faster and stronger than “LKPNM” because you can save conversion time from “LKPNM” to “LKP”, and “LKP” will be absorbed faster than “LKPNM”.
However, time lag comes from “LKPNM” decomposition or absorption is thought to have advantage of slow, long lasting activity of “Katsuobushi Oligopeptide”.
Anti-hypertensive activity of Katsuobushi Oligopeptide is nearly same as drugs
As shown in Fig.1, anti-hypertensive activity of “LKP”(1), “LKPNM”(2), and Captopril (ACE-inhibitory drug)(3) were observed eight hours with Spontaneously Hypertensive Rats (SHR). In (1) group fed “LKP”, indicated immediate response, but the blood pressure started to go up after 2 hours. In (2) group fed “LKPNM” (Katsuobushi Oligopeptide), anti-hypertensive effect was obtained almost the same extent as Captopril as time passed. And the activity lasted over 6 hours after administration. By this experiment, “LKPNM” was found to have anti-hypertensive activity nearly equal to anti-hypertensive drugs (Captopril) and to show mild reaction.
Fig.1.Antihypertensive Activity of LKPNM (A), LKP (B), and Captopril(C)
after Oral Administration in SHR
Changes of systolic blood pressure from zero time were expressed
with mean ±S.E. *,** indicate significance against control (*p < 0.05, **p < 0.01, t-test, 5d.f.)
Effectiveness of hypertension treatment from the youth
1, Helps to improve hereditary hypertension
Essential hypertension is closely related to hereditary factor, which may be a cause of hypertension. The constitutions of blood pressure elevation succeed from parents to children, from children to grandchildren. Katsuobushi Oligopeptide was confirmed to be effective to improve essential hypertension of animals as described below:
<< Test method >>
Spontaneously Hypertensive Rats (SHR), having hereditary hypertension, were used in the test. SHR were well known as model animal to study human essential hypertension. The SHR were divided into 4 groups and fed as follows:
<< Results >>
|(1) No.1 group
||No.1 group was fed normal chow diet only.
|(2) No.2 group
||No.2 group was fed normal chow diet containing
0.025% of Katsuobushi Oligopeptide.
|(3) No.3 group
||No.3 group was fed normal chow diet containing
0.05% of Katsuobushi Oligopeptide.
|(4) No.4 group
||No.4 group was fed normal chow diet containing
1.0% of Katsuobushi Oligopeptide.
Average blood pressure of normal rats is about 130 mmHg almost the same with human being. Blood pressure of SHR goes up and finally systolic blood pressure reaches to 200 mmHg (Fig. 2). Blood pressure of No.1 group, fed only normal chow diet, without the peptide gradually increased and went over 210 mmHg at the end of the test period (10.5 weeks). In No.2, No.3 and No.4 groups, fed chow diet containing 0.025% - 1.0% of the peptide, however, significant anti-hypertensive effects of 20 - 30 mmHg were observed dose dependently.
The results mentioned above indicates that daily intake of Katsuobushi Oligopeptide from the youth will be effective to prevent essential hypertension.
Systolic blood pressure of over 60% hypertensive patients “decreased”
1, Clinical tests with hypertensive patients
When hypertensive patients eat Katsuobushi Oligopeptide, how much will be the actual anti-hypertensive activity. The authors studied the effect of Katsuobushi Oligopeptide as follows:
<< Experiment >>
The test was started with 30 hypertensive patients who had blood pressure higher than 130 mmHg as systolic blood pressure and higher than 85 mmHg as diastolic blood pressure. First 4 weeks were observation period to check ordinary blood pressure. They were divided into two groups, and started taking of Katsuobushi Oligopeptide (as LKPNM 5 mg per day) as described below:
|1) No.1 group
||They took Katsuobushi Oligopeptide for first 8 weeks following observation period and stop taking after the 9th week.
|(2) No.2 group
||They did not take Oligopeptide for first 8 weeks following observation period and started taking Oligopeptide after the 9th week.
The average systolic blood pressure of both No.1 and No.2 group in observation period were
about 150 mmHg.
<< Results >>
As shown in Fig. 3, statistically significant anti-hypertensive effect was observed on average systolic blood pressure of No.1 group from the second week of administration. Finally, systolic blood pressure lowered 12.7 mmHg and the diastolic blood pressure went down 7.8 mmHg during the test period. The blood pressure change was evaluated by comparing mean values of the pressure during the test period with those of the observation period. Blood pressure decrease was scored by the degree into four classes; “significantly decreased”, “moderately decreased”, “no change” and “increased”. As a result of this evaluation, the effective ratio (ratio of subjects who were judged to have significant or moderate blood pressure decrease) was 60% in No.1 group. The systolic blood pressure of No.2 group also showed significant decrease after the third week of oral administration of Katsuobushi Oligopeptide, indicating antihypertensive effect of 12.4 mmHg in the systolic blood pressure and 7.7 mmHg in the diastolic blood pressure.
The effective ratio was 66.6% in No.2 group.
[ Judgment of blood pressure change ]
Total effectiveness by oral administration : 63.3%
2, Safety of taking Katsuobushi Oligopeptide
||0/15 ( 0.0%)
||1/15 ( 0.0%)
(Significantly decreased + Moderately decreased)
The blood pressure of both groups slowly went back to the level of observation period after stop taking Katsuobushi Oligopeptide. The recovery was slow. A sudden blood pressure elevation or failure of health may occur when you stop taking anti-hypertensive medicine. No such symptom was observed in this test probably because of mild activity of Katsuobushi Oligopeptide. It was also confirmed that Katsuobushi Oligopeptide was safe food because there was no side effect.
Effective ratio was over 60% even in repeated tests
1, Severe test which is not affected psychologically
We examined the effectiveness of Katsuobushi Oligopeptide again after the last clinical test. In order to obtain more exact results, persons took Katsuobushi Oligopeptide or placebo food, its imitation including same appearance, taste and Katsuobushi flavor.
We carried out the test in this way, because sometimes anti-hypertensive effect was observed on people who took food with no active ingredient if they thought the food works to lower the blood pressure. So, we examined as mentioned above to avoid such psychological effect.
<< Test method >>
The test started with 61 hypertensive patients who had blood pressure exceeding the standard. After two weeks of observation period, subjects were randomly divided into two groups and took Katsuobushi Oligopeptide 1.5 g/day (as LKPNM 5 mg/day) as described below:
<< Results >>
|(1) No.1 group
|No.1 group took food containing Katsuobushi Oligopeptide for 5 weeks from the start of the test. After sixth week, they took placebo food.
|(2) No.2 group
|No.2 group took placebo food for 5 weeks from the start of the test. After sixth week, they took food containing Katsuobushi Oligopeptide.
As show in Fig. 4, both groups indicated blood pressure decrease soon after start taking Katsuobushi Oligopeptide and gave significant anti-hypertensive effect.
The judgment of blood pressure change was done in the same way as the last test. As a result, the effective ratio (ratio of subjects who were judged to have significant or moderate blood pressure decrease) was 62.2% in the overall subjects.
Attractive safety with no side effect
1, Long term medical treatment is needed for hypertension
Medical treatment of essential hypertension must take for a long time. It is impossible to be cured in a day because essential hypertension is due to accumulation of small risk factors in daily life.
When Katsuobushi Oligopeptide is taken for improving hypertension, it is also important to continue taking the peptide for a long time.
Side effect issue will come up in mind when you hear long term administration. Let me explain about it in the following sections.
2, Every drug has side effect
ACE-inhibitory drugs such as Captopril are known to have fewer side effects among antihypertensive drugs. Dry cough can often be observed as side effect of ACE-inhibitory drugs (though anti-hypertensive drugs have been improved recently).
It does not have serious influence on human body, but it may weigh on body or mind because hypertension treatment takes for a long time.
3, Safety of Katsuobushi Oligopeptide
Katsuobushi Oligopeptide having same ACE-inhibitory activity as drugs, was found to have no side effect so far. Neither dry cough nor other side effect was reported during all clinical tests. The peptide only works to lower hypertensive blood pressure. It does not give influence to normal blood pressure nor overreact to give low blood pressure. Katsuobushi Oligopeptide works ideally to human body. The reason may be that the peptide is derived from natural food ingredients.
4, Lowering blood pressure without weighing on body
Katsuobushi Oligopeptide, derived from natural food, have another advantage which cannot be obtained from ACE-inhibitory drugs. It is mild anti-hypertensive activity lasting for a long time.
Anti-hypertensive drugs have satisfactory activity to lower blood pressure immediately, but it may sometimes weigh on body on the contrary. Lowering high blood pressure in a short time decreases blood flow and leads to insufficient blood circulation to every organ, and organs work worse to cause various functional disorders. Special care should be taken when you administrate immediate effect drugs to elderly patients who tend to show blood flow decrease.
Mild antihypertensive effect of Katsuobushi Oligopeptide is very useful to avoid lowering blood flow described above. Slow and long lasting anti-hypertensive effect does not weigh on body. This characteristic function depends on the structure of Katsuobushi Oligopeptide.
These are our FOSHU products for anti-hypertension
which are derived from Katsuobushi Oligopeptide.