Abstract 15855: Nitric Oxide-Independent Stimulators of Soluble Guanylyl Cyclase Circumvent Platelet Nitric Oxide Resistance in Hypercholesterolemic Mice
Objective: NO donors have a potential clinical role as anti-platelet therapies, yet their effects are diminished in several cardiovascular diseases. Impaired platelet responsiveness to NO (platelet NO resistance) is associated with scavenging of NO by superoxide (O2-) and/or dysfunctional soluble guanylyl cyclase (sGC). We tested the hypothesis that NO-independent sGC stimulators, which are not susceptible to scavenging by O2-, would circumvent platelet NO resistance in hypercholesterolemia.
Methods & Results: The anti-aggregatory properties of the NO donor, sodium nitroprusside (SNP) and the NO-independent sGC stimulators, isopropylamine NONOate (IPA/NO, a nitroxyl donor) and BAY 41-2272 were assessed in washed platelets from 12-week old male C57Bl/6J (WT) and ApoE-/- mice all maintained on a high fat diet (7 weeks). ApoE-/- mice displayed a 4- (n=7-9, P<0.001) and 2-fold (n=7-9, P<0.05) increase in plasma cholesterol levels and platelet O2- production, respectively, whilst total collagen (30μ g/ml)-stimulated aggregation was reduced (Area Under Curve: ApoE-/- 50565±1128 vs WT 60293±3582, arbitrary units, n=25-32, P<0.01). In hypercholesterolemic mice, the anti-aggregatory effects of SNP (10μ mol/L) were attenuated such that total aggregation was inhibited by 14±4% in ApoE-/- versus 46±10% in WT platelets (n=10-13, P<0.001). By contrast, platelet responsiveness to IPA/NO (3μ mol/L; ApoE-/- 29±4% vs WT 39±8%, n=7-9) and BAY 41-2272 (10μ mol/L; ApoE-/- 32±5% vs WT 43±8%, n=5-7) was not significantly reduced. Resistance to the anti-aggregatory actions of SNP in ApoE-/- platelets was not overcome by treatment with the reactive oxygen species scavengers superoxide dismutase-polyethylene glycol and catalase-polyethylene glycol (n=5, P<0.05).
Conclusion: Whilst the mechanisms underlying platelet NO resistance in hypercholesterolemia remain to be fully elucidated, the anti-aggregatory actions of IPA/NO and BAY41-2272 appear to be preserved in this setting. Thus NO-independent sGC stimulators may serve as alternative therapies to NO donors in cardiovascular disorders.
- © 2012 by American Heart Association, Inc.