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@article{1398262, author = {ElandHawli, A. and Qaradakhi, T. and Hayes, A. and Rybalka, E. and Smith, R. and Caprnda, M. and Opatrilova, R. and Gazdikova, K. and Benckova, M. and Kružliak, Peter and Zulli, A.}, article_location = {PARIS}, article_number = {FEB 2017}, doi = {http://dx.doi.org/10.1016/j.biopha.2016.11.142}, keywords = {Insulin regulated amino peptidase; Endothelial dysfunction; Homocysteine; HFI419}, language = {eng}, issn = {0753-3322}, journal = {BIOMEDICINE & PHARMACOTHERAPY}, title = {IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model}, volume = {86}, year = {2017} }
TY - JOUR ID - 1398262 AU - El-Hawli, A. - Qaradakhi, T. - Hayes, A. - Rybalka, E. - Smith, R. - Caprnda, M. - Opatrilova, R. - Gazdikova, K. - Benckova, M. - Kružliak, Peter - Zulli, A. PY - 2017 TI - IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model JF - BIOMEDICINE & PHARMACOTHERAPY VL - 86 IS - FEB 2017 SP - 23-26 EP - 23-26 PB - ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER SN - 07533322 KW - Insulin regulated amino peptidase KW - Endothelial dysfunction KW - Homocysteine KW - HFI419 N2 - 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 3 mM Hcy to induce vascular dysfunction in vitro for 1 h. HFI419 was added 5 min 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 3 mM 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. (C) 2016 Elsevier Masson SAS. All rights reserved. ER -
EL-HAWLI, A., T. QARADAKHI, A. HAYES, E. RYBALKA, R. SMITH, M. CAPRNDA, R. OPATRILOVA, K. GAZDIKOVA, M. BENCKOVA, Peter KRUŽLIAK and A. ZULLI. IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model. \textit{BIOMEDICINE \&{}amp; PHARMACOTHERAPY}. PARIS: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017, vol.~86, FEB 2017, p.~23-26. ISSN~0753-3322. Available from: https://dx.doi.org/10.1016/j.biopha.2016.11.142.
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