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Abstract
It has been previously documented that the thermolysin-digest of "Katsuo-bushi", a
Japanese traditional food processed from dried bonito possesses potent inhibitory
activity against angiotensin I-converting enzyme (ACE). The present authors isolated
eight kinds of ACE-inhibitory peptides from it. Of these isolated peptides, LKPNM
(IC50 = 2.4 microM) was found to be hydrolyzed by ACE to produce LKP (IC50 = 0.32
microM) with 8-fold higher ACE-inhibitory activity relative to the parent peptide
or LKPNM, suggesting that LKPNM can be regarded as a prodrug-type ACE-inhibitory peptide.
For assessment of relative antihypertensive activities of LKPNM and LKP to that of
captopril, they were orally administered to SHR rats to monitor time-course changes
of blood pressures, whereby it was evidenced that both LKPNM and captopril showed
maximal decrease of blood pressure 4 h after oral administration and their efficacies
lasted until 6 h post-administration. In sharp contrast, however, maximal reduction
of blood pressure occurred as early as 2 h after administration of LKP. Minimum effective
doses of LKPNM, LKP and captopril were 8, 2.25 and 1.25 mg/kg, respectively. When
compared on molar basis, antihypertensive activities of LKPNM and LKP accounted for
66% and 91% relative to that of captopril, respectively, whereas in vitro ACE-inhibitory
activities of LKPNM and LKP were no more than 0.92% and 7.73% compared with that of
captopril (IC50 = 0.022 microM). It is of interest to note that both of these peptides
exert remarkably higher antihypertensive activities in vivo despite weaker in vitro
ACE-inhibitory effects, which was ascertained by using captopril as the reference
drug.