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Title: Diminazene aceturate uses different pathways to induce relaxation in healthy and atherogenic blood vessels.
Austin Authors: Kate Gadanec, Laura;Qaradakhi, Tawar;Renee McSweeney, Kristen;Matsoukas, John M;Apostolopoulos, Vasso;Burrell, Louise M ;Zulli, Anthony
Affiliation: Australian Institute for Musculoskeletal Science, Melbourne 3021, Victoria, Australia.
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1, Canada; NewDrug PC, Patras Science Park, 26500 Patras, Greece.
Institute for Health and Sport, Victoria University, Melbourne 3030, Victoria, Australia
General Medicine
Issue Date: Feb-2022
Date: 2022
Publication information: Biochemical Pharmacology 2023
Abstract: Diminazene aceturate (DIZE), a putative angiotensin-converting enzyme 2 (ACE2) activator, elicits relaxation in various animal models. This study aimed to determine the relaxing mechanisms in internal iliac arteries utilised by DIZE in healthy and atherogenic rabbit models. Studies were conducted on internal iliac artery rings retrieved from male New Zealand White rabbits fed a 4-week healthy control (n = 24) or atherogenic diet (n = 20). To investigate pathways utilised by DIZE to promote arterial relaxation, a DIZE dose response [10-9.0 M - 10-5.0 M] was performed on pre-contracted rings incubated with pharmaceuticals that target: components of the renin-angiotensin system; endothelial- and vascular smooth muscle-dependent mechanisms; protein kinases; and potassium channels. ACE2 expression was quantified by immunohistochemistry analysis following a 2 hr or 4 hr DIZE incubation. DIZE significantly enhanced vessel relaxation in atherogenic rings at doses [10-5.5 M] (p < 0.01) and [10-5.0 M] (p < 0.0001), when compared to healthy controls. Comprehensive results from functional isometric studies determined that DIZE causes relaxation via different mechanisms depending on pathology. For the first time, we report that in healthy blood vessels DIZE exerts its direct relaxing effect through ACE2/AT2R and NO/sGC pathways; however, in atherogenesis this switches to MasR, arachidonic acid pathway (i.e., COX1/2, EET and DHET), MCLP, Ca2+ activated voltage channels, AMPK and ERK1/2. Moreover, quantitative immunohistochemical analysis demonstrated that DIZE increases artery ACE2 expression in a time dependent manner. We provide a detailed investigation of DIZE's mechanisms and demonstrate for the first time that in healthy and atherogenic arteries DIZE provides beneficial effects through directly inducing relaxation, albeit via different pathways.
DOI: 10.1016/j.bcp.2022.115397
Journal: Biochemical Pharmacology
Start page: 115397
PubMed URL: 36566945
ISSN: 1873-2968
Type: Journal Article
Subjects: Angiotensin-converting enzyme 2
Diminazene aceturate
Renin-angiotensin system
Vascular function
Appears in Collections:Journal articles

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