Abstract 16422: Vasorelaxant and Anti-aggregatory Actions of the Nitroxyl Donor, Isopropylamine NONOate, are Preserved in Hypercholesterolemic Mice
Nitroxyl (HNO) donors are vasoprotective and offer considerable therapeutic advantages over traditional nitrovasodilators, including a lack of tolerance development and the potential for preserved efficacy in disease. We tested the hypothesis that the vasorelaxant and anti-aggregatory properties of HNO are preserved in hypercholesterolemia. Hypercholesterolemia was induced in male apolipoprotein E-deficient (ApoE−/−) mice fed a high fat diet from 5 wks of age for 7 wks. Common carotid arteries and platelets were isolated from male C57Bl6/J (wild-type) and ApoE−/− mice, all on a high fat diet. Endothelial function and basal superoxide (.O2-) production by carotid arteries was measured via the vasoconstrictor response to the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME; 100uM) and using L012 (100uM)-enhanced chemiluminescence, respectively. The ability of the HNO donor, isopropylamine NONOate (IPA/NO), to cause vasorelaxation and inhibit collagen (30ug/ml)-stimulated platelet aggregation was assessed. Hypercholesterolemia was associated with a 7-fold (P<0.01; n=12) increase in plasma total cholesterol levels, an increase in .O2- production (wild-type 14±5 x103 vs ApoE−/− 24±6 x103 counts/mg; P<0.05, n=7) and a decrease in endogenous NO bioavailability (L-NAME contraction: wild-type 56±5% vs ApoE−/− 24±5%; P<0.01, n=10) in isolated carotid arteries. IPA/NO-mediated vasorelaxation was sustained in carotid arteries from ApoE−/− mice (pEC50=5.96±0.08, Rmax=88±3%; n=10) with a small, but significant, 2.5-fold (P<0.01) increase in potency as compared with wild-type mice (pEC50=5.55±0.1; n=7). Vasorelaxant responses to IPA/NO in ApoE−/− mice were attenuated by the HNO scavenger L-cysteine (3mM; P<0.001, n=6) yet unchanged in the presence of the NO. scavenger, carboxy-PTIO (200uM; n=6). The ability of IPA/NO to inhibit collagen-induced platelet aggregation was preserved in hypercholesterolemia with 3uM IPA/NO decreasing total aggregation by 41±11% in wild-type (n=7) vs 52±7% in ApoE−/− mice (n=4). In summary, the vasoprotective actions of HNO are preserved in the face of vascular oxidative stress and a loss of endogenous NO and HNO donors may represent future novel treatments for vascular disease.
- © 2010 by American Heart Association, Inc.