ANTIHYPERTENSIVE EFFECT OF THERMOLYSIN DIGEST OF DRIED BONITO IN SPONTANEOUSLY HYPERTENSIVE RAT

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Abstract
Summary: 1. The thermolysin digest of dried bonito, Katsuo‐bushi, showed inhibitory activity (IC50= 29 μg/mL) for angiotensin I‐converting enzyme (ACE) and an antihypertensive effect after a single oral administration in SHR at a dose of 500 μg/kg. In a long‐term feeding experiment, in which 3 week old SHR were fed a standard chow supplemented with the digest for 7 weeks, elevation of the systolic blood pressure was significantly suppressed by 15 μg/kg per day of the digest.2. A digest of dried bonito by gastrointestinal proteases (pepsin–‐trypsin–‐chymotrypsin) failed to lower the blood pressure after a single oral administration (1000 μg/kg) in spite of a fairly strong ACEI activity (IC50= 41 μg/mL).3. The ACEI activity of the thermolysin digest did not change after preincubation with gastrointestinal proteases or ACE. However, that of the pepsin–‐trypsin–‐chymotrypsin digest was reduced after the preincubation with ACE suggesting that the apparent inhibitory activity was due to ACE substrate peptides.4. Eight ACEI peptides were isolated from the thermolysin digest. Most of them were true inhibitors or precursors that are converted into true inhibitors by ACE or gastrointestinal proteases in vivo. The precursor type peptides required a longer time than true inhibitors to show maximal antihypertensive effect after a single oral administration in SHR. Thus, the thermolysin digest of dried bonito is a mixture of a true inhibitor and precursor peptides differing from each other in maximally effective times.