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. 2021 May 17:12:658805.
doi: 10.3389/fphar.2021.658805. eCollection 2021.

Chymase Dependent Pathway of Angiotensin II Generation and Rapeseed Derived Peptides for Antihypertensive Treatment of Spontaneously Hypertensive Rats

Iwona Baranowska  1 , Olga Gawrys  1 , Malwina M Roszkowska-Chojecka  1 , Bozena Badzynska  1 , Dagmara Tymecka  2 , Krzysztof H Olszynski  3 , Elzbieta Kompanowska-Jezierska  1
Affiliations

Chymase Dependent Pathway of Angiotensin II Generation and Rapeseed Derived Peptides for Antihypertensive Treatment of Spontaneously Hypertensive Rats

Iwona Baranowska et al. Front Pharmacol. .

Abstract

The contribution of chymase, one of the enzymes responsible for angiotensin II generation in non-ACE pathway, remains unclear in the development of hypertension. The aim of the study was to investigate chymase inhibition as potential antihypertensive therapy in spontaneously hypertensive rats (SHR). To block chymase we employed chymostatin, a commercial inhibitor, and new analogues of rapeseed-derived peptides, VWIS and RIY. These simple and easy to obtain peptides not only block chymase, but also possess weak activity to inhibit ACE. This is a first attempt to evaluate the impact of chronic administration of selected inhibitors on blood pressure of SHR in two phases of hypertension. Male SHR (6 or 16 weeks old) were treated daily for two weeks with chymostatin (CH; 2 mg/kg/day), the peptides VWIS (12.5 mg/kg/day) or RIY (7.5 mg/kg/day); control groups received chymostatin solvent (0.15% DMSO in saline) or peptide solvent (saline). The substances were administered intravenously to conscious animals via a chronically cannulated femoral vein. Systolic blood pressure (SBP) was measured by telemetry. Metabolic parameters were measured weekly, and tissue samples were harvested after two weeks of treatment. None of the administered chymase inhibitors affected the development of hypertension in young rats. Only RIY exhibited beneficial properties when administered in the established phase of hypertension: SBP decreased from 165 ± 10 to 157 ± 7 mmHg while the excretion of nitric oxide metabolites increased significantly. The glomerulosclerosis index was lower after RIY treatment in both age groups (significant only in young rats 0.29 ± 0.05 vs 0.48 ± 0.04 in the control group; p < 0.05). Hence, it seems that peptide RIY exhibits some positive effect on renal morphology. The results obtained suggest that the peptide RIY may be a useful tool in the treatment of hypertension, especially in cases when ACE inhibitors are not effective.

Keywords: CPPs; RAAS; chymase; chymostatin; rapakinin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Digestion of angiotensin I (ANG I) in human chymase solution. The peptide was incubated with the enzyme for different time periods in the absence or presence of the inhibitory peptides and the remaining ANG I amounts were determined by reversed-phase high performance liquid chromatography. The results were independently repeated in a second experiment and were used to calculate the half-life time of ANG I in absence or presence of inhibitory peptides (GraphPad Prism Software): T1/2 (ANG I) = 16 min; T1/2 (ANG I + VW) = 16 min; T1/2 (ANG I + IY) = 15 min; T1/2 (ANG I + RIY) = 24 min; T1/2 (ANG I + VWIS) = 56 min; the mean values were used for the analysis with the SD. R 2 values ranged from 0.9679 to 0.9972. VW: valine-tryptophan, IY: isoleucine-tyrosine, RIY: arginine-isoleucine-tyrosine, VWIS: valine-tryptophan-isoleucine-serine.
FIGURE 2
FIGURE 2
Mean blood pressure (MBP) reordered in acute experiment in anesthetized spontaneously hypertensive rats (SHR) receiving an hour long infusion of chymostatin (CH, 2 mg/kg, n = 7) or it’s solvent (0.05% DMSO, n = 8); *p ≤ 0.05 vs. baseline value within the same group (multivariate analysis of variance ANOVA with repeated measurements, followed by Duncan’s post-hoc test).
FIGURE 3
FIGURE 3
Systolic blood pressure (SBP) measured on 0, 7th and 14th day in young and adult spontaneously hypertensive rats (SHR) receiving intravenous treatment with (A) chymostatin (CH, 2 mg/kg/day, young: n = 5, adult: n = 8) and its solvent (0.15% DMSO, young: n = 5, adult: n = 5) (B) peptides RIY (7.5 mg/kg/day, young: n = 6, adult: n = 5), VWIS (12.5 mg/kg/day, young: n = 5, adult: n = 6) and their solvent–saline (S, young: n = 5, adult: n = 5); (C) overall change in SBP (ΔSBP between day 0 and 14) in young and (D) adult animals; *p < 0.05 significantly different vs. baseline value on day 0 within the same group; § value in RIY vs. CH group on day 14th (p < 0.05; multivariate analysis of variance ANOVA with repeated measurements, followed by Duncan’s post-hoc test); #p < 0.05 significantly different values between indicated groups (one-way ANOVA, followed by Duncan’s post-hoc test).
FIGURE 4
FIGURE 4
Excretion of nitric oxide metabolites (UNOxV) measured on 0, 7th and 14th day in (A) young and (B) adult spontaneously hypertensive rats (SHR) receiving intravenous treatment with chymostatin (CH, 2 mg/kg/day, young: n = 6, adult: n = 8), its solvent (0.15% DMSO, young: n = 6, adult: n = 5); peptides RIY (7.5 mg/kg/day, young: n = 5, adult: n = 5), VWIS (12.5 mg/kg/day, young: n = 5, adult: n = 5) and their solvent–saline (S, young: n = 5, adult: n = 4); *p < 0.05 significantly different vs. baseline value on day 0 within each group; # significantly different for RIY-treated group vs. values in all other groups on 14 days (p < 0.05; multivariate analysis of variance ANOVA with repeated measurements, followed by Dunnet’s post-hoc test).
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