Exogenous Angiotensin I Metabolism in Aorta Isolated from Streptozotocin Treated Diabetic Rats

P P Wołkow, B Bujak-Giżycka, J Jawień, R Olszanecki, J Madej, J Rutowski, R Korbut, P P Wołkow, B Bujak-Giżycka, J Jawień, R Olszanecki, J Madej, J Rutowski, R Korbut

Abstract

Purpose. Products of angiotensin (ANG) I metabolism may predispose to vascular complications of diabetes mellitus. Methods. Diabetes was induced with streptozotocin (75 mg/kg i.p.). Rat aorta fragments, isolated 4 weeks later, were pretreated with perindoprilat (3 μM), thiorphan (3 μM), or vehicle and incubated for 15 minutes with ANG I (1 μM). Products of ANG I metabolism through classical (ANG II, ANG III, and ANG IV) and alternative (ANG (1-9), ANG (1-7), and ANG (1-5)) pathways were measured in the buffer, using liquid chromatography-mass spectrometry. Results. Incubation with ANG I resulted in higher concentration of ANG II (P = 0.02, vehicle pretreatment) and lower of ANG (1-9) (P = 0.048, perindoprilat pretreatment) in diabetes. Preference for the classical pathway is suggested by higher ANG III/ANG (1-7) ratios in vehicle (P = 0.03), perindoprilat (P = 0.02), and thiorphan pretreated (P = 0.02) diabetic rat. Within the classical pathway, ratios of ANG IV/ANG II (P = 0.01) and of ANG IV/ANG III (P = 0.049), but not of ANG III/ANG II are lower in diabetes. Conclusions. Diabetes in rats led to preference toward deleterious (ANG II, ANG III) over protective (ANG IV, ANG (1-9), and ANG (1-7)) ANG I metabolites.

Figures

Figure 1
Figure 1
Main pathways of ANG I metabolism. ACE: angiotensin converting enzyme; ACE-2: angiotensin converting enzyme type 2; APA: aminopeptidase A; APN: aminopeptidase N; CMA: chymase; NEP: neutral endopeptidase.
Figure 2
Figure 2
Representative chromatogram of angiotensins standards mixture. Insert: chromatograms of extracted monitored ions of each analyzed angiotensin.
Figure 3
Figure 3
Representative chromatograms of products of ANG I conversion by aorta of STZ rats (a) and control rats (b). Left panel: TIC chromatogram (peaks represent relative abundance, 100% = ANG I); right panel: extracted chromatograms for monitored ions of ANG II and ANG I (unified scale).
Figure 4
Figure 4
Concentrations (median, minimum, and maximum) of ANG II and ANG (1–9), produced from exogenously added ANG I, by the aortic rings of STZ and CTRL rats, pretreated with perindoprilat (ANG I + P) or thiorphan (ANG I + T). ∗P < 0.05, ANG II concentration was higher in (ANG I only) group of STZ aorta. #P < 0.05, ANG (1–9) concentration was higher in (ANG I + P) group of CTRL aorta.

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