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. 2015 Dec 28:59:29788.
doi: 10.3402/fnr.v59.29788. eCollection 2015.

Kinetics of the inhibition of renin and angiotensin I-converting enzyme by cod (Gadus morhua) protein hydrolysates and their antihypertensive effects in spontaneously hypertensive rats

Abraham T Girgih  1   2 , Ifeanyi D Nwachukwu  1   2 , Fida Hasan  3 , Tayo N Fagbemi  4 , Tom Gill  3 , Rotimi E Aluko  1   5
Affiliations

Kinetics of the inhibition of renin and angiotensin I-converting enzyme by cod (Gadus morhua) protein hydrolysates and their antihypertensive effects in spontaneously hypertensive rats

Abraham T Girgih et al. Food Nutr Res. .

Abstract

Background: Cod muscle has a balanced protein profile that contains potentially bioactive amino acid sequences. However, there is limited information on release of these peptides from the parent proteins and their ability to modulate mammalian blood pressure.

Objective: The aim of this study was to generate cod antihypertensive peptides with potent in vitro inhibitory effects against angiotensin-converting enzyme (ACE) and renin. The most active peptides were then tested for systolic blood pressure (SBP)-reducing ability in spontaneously hypertensive rats (SHRs).

Design: Cod protein hydrolysate (CPH) was produced by subjecting the muscle proteins to proteolysis first by pepsin and followed by trypsin+chymotrypsin combination. In order to enhance peptide activity, the CPH was subjected to reverse-phase (RP)-HPLC separation to yield four fractions (CF1, CF2, CF3, and CF4). The CPH and RP-HPLC fractions were each tested at 1 mg/mL for ability to inhibit in vitro ACE and renin activities. CPH and the most active RP-HPLC fraction (CF3) were then used for enzyme inhibition kinetics assays followed by oral administration (200 and 30 mg/kg body weight for CPH and CF3, respectively) to SHRs and SBP measurements within 24 h.

Results: The CPH, CF3, and CF4 had similar ACE-inhibitory activities of 84, 85, and 87%, which were significantly (p<0.05) higher than the values for CF1 (69%) and CF2 (79%). Conversely, the CF3 had the highest (63%) renin-inhibitory activity (p<0.05) when compared to CPH (43%), CF1 (15%), and CF4 (44%). CPH and CF3 exhibited uncompetitive mode of ACE inhibition, whereas renin inhibition was non-competitive. Even at a 6.7-fold lower dosage, the CF3 significantly (p<0.05) reduced SBP (maximum -40.0 mmHg) better than CPH (maximum -19.1 mmHg).

Conclusions: RP-HPLC fractionation led to enhanced antihypertensive effects of cod peptides, which may be due to a stronger renin-inhibitory activity.

Keywords: IC50; angiotensin I-converting enzyme; cod; enzyme inhibition kinetics; protein hydrolysate; renin; spontaneously hypertensive rats; systolic blood pressure.

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Figures

Fig. 1
Fig. 1
In vitro (a) angiotensin I-converting enzyme (ACE) and (b) renin-inhibitory activities of cod protein hydrolysate (CPH) and its RP-HPLC derived peptide fractions (CF1-CF4).
Fig. 2
Fig. 2
Peptide inhibitory concentrations of cod protein hydrolysate (CPH) and its most active RP-HPLC peptide fraction 3 (CF3) that reduced 50% of enzyme activity (IC50).
Fig. 3
Fig. 3
Lineweaver–Burk plots of angiotensin I-converting enzyme (ACE) inhibition at different peptide concentrations: (a) cod protein hydrolysate (CPH) and (b) most active RP-HPLC peptide fraction 3 (CF3).
Fig. 4
Fig. 4
Lineweaver–Burk plots of human recombinant renin inhibition at different peptide concentrations: (a) cod protein hydrolysate (CPH) and (b) most active RP-HPLC peptide fraction 3 (CF3).
Fig. 5
Fig. 5
Time dependent changes in systolic blood pressure (SBP) of spontaneously hypertensive rats administered cod protein hydrolysate (CPH) and the most active RP-HPLC peptide fraction 3 (CF3).
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