title: IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model.
abstract: Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine. The abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3mM Hcy to induce vascular dysfunction in vitro for 1h. HFI419 was added 5min prior to assessment of vascular function by cumulative doses of acetylcholine. In some rings, vasoconstriction to acetylcholine was observed in aortic rings after pre-incubation with 3mM homocysteine. Incubation with HFI419 inhibited the vasoconstrictive response to acetylcholine, thus improving, but not normalizing, vascular function (11.5±8.9% relaxation vs 79.2±37% constriction, p<0.05). Similarly, in another group with mild vasoconstriction, HFI419 inhibited this effect (34.9±4.6% relaxation vs 11.1±5.2%, constriction, p<0.05). HFI419 had no effect on control aorta or aorta with mild aortic dysfunction. The present study shows that HFI419 prevents acetylcholine mediated vasoconstriction in dysfunctional blood vessels. HFI419 had no effect on normal vasodilation. Our results indicate a therapeutic potential of HFI419 in reducing coronary artery vasospasm.
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Aisha
authors.initials: A
authors.lastname: El-Hawli
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Tawar
authors.initials: T
authors.lastname: Qaradakhi
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Hayes
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Rybalka
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Smith
authors.affiliation: 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
authors.forename: Martin
authors.initials: M
authors.lastname: Caprnda
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia.
authors.forename: Radka
authors.initials: R
authors.lastname: Opatrilova
authors.affiliation: Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovak Republic; Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovak Republic. Electronic address: katarina.gazdikova@szu.sk.
authors.forename: Katarina
authors.initials: K
authors.lastname: Gazdikova
authors.affiliation: Department of Medical and Clinical Biophysics, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
authors.forename: Maria
authors.initials: M
authors.lastname: Benckova
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia; 2nd Department of Surgery, Center for Vascular Disease, Faculty of Medicine, Masaryk University and St. Annés University Hospital, Brno, Czechia. Electronic address: kruzliakpeter@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Kruzliak
authors.affiliation: Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia. Electronic address: Anthony.Zulli@VU.edu.au.
authors.forename: Anthony
authors.initials: A
authors.lastname: Zulli
mesh_terms: D000109:Acetylcholine / Q000633:toxicity*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology*; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009924:Organ Culture Techniques; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D000109:Acetylcholine
keywords: Endothelial dysfunction; HFI419; Homocysteine; Insulin regulated amino peptidase