89 NOVEL VASOPROTECTIVE ACTIONS OF NITROXYL (HNO) IN THE VASCULATURE

Abstract

Background: Nitric oxide (NO•) plays a fundamental role as a vascular protectant with its well reported ability to induce vasorelaxation in human vessels and reduce leukocyte to endothelium adhesion, an initiating event of vascular inflammation. Nitroxyl (HNO), the one-electron reduced redox sibling of NO•, has distinct pharmacology to NO• and the effects of HNO in this context are not known. Objective: We aimed to determine the vasodilatory and anti-inflammatory actions of HNO using the HNO donor, Angeli's Salt (AS) compared to the NO• donor, GTN. Methods and Results: Cumulative concentration-response curves (CRCs) to AS or GTN were constructed in radial arteries (RA) and saphenous veins (SV) obtained from patients undergoing coronary artery graft surgery mounted in organ baths. AS induced vasorelaxation of RA (EC50 = 6.5 ± 0.1 M; n = 8) and SV (EC50 = 6.6 ± 0.1 M; n = 9) with similar potency to GTN, and AS-induced vasorelaxation was inhibited by the HNO scavenger L-cysteine (3 mM) but not the NO• scavenger hydroxocobalamin (100 μM). Adhesion of monocytic THP-1 cells to activated HUVECs (with tumour necrosis factor α (TNFα)) was decreased in a concentration-dependent manner by AS and GTN (P<0.05). Furthermore, experiments which allow the visualization of leukocyte-endothelium adhesion in isolated mouse (C57BL/6) aorta, using whole blood, showed that AS (10 μM) and GTN (10 μM) significantly attenuated (5 ± 2 and 3 ± 1 cells/field, respectively, n = 4-5;P<0.05) the TNFα-stimulated increase (16 ± 3 cells/field, n = 5-11) in leukocyte adhesion. Conclusions: This study shows for the first time that HNO can relax human blood vessels and reduce leukocyte-endothelium adhesion which will aid in determining the therapeutic potential of HNO donors.