Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia

Nitroxyl (HNO) displays pharmacological and therapeutic actions distinct from those of its redox sibling nitric oxide (NO(.)). It remains unclear, however, whether the vasoprotective actions of HNO are preserved in disease. The ability of the HNO donor isopropylamine NONOate (IPA/NO) to induce vasorelaxation, its susceptibility to tolerance development and anti-aggregatory actions were compared to those of the clinically-used NO(.) donor, glyceryl trinitrate (GTN), in hypercholesterolemic mice. The vasorelaxant and anti-aggregatory properties of IPA/NO and GTN were examined in isolated carotid arteries and washed platelets, respectively, from male C57BL/6J mice maintained on either a normal (WT-ND) or high fat diet (WT-HFD, 7 weeks) and apolipoprotein E-deficient mice (ApoE(-/-)-HFD, 7 weeks). In WT-ND mice, IPA/NO (0.1-30 mumol/L) induced concentration-dependent vasorelaxation and inhibition of collagen (30 mug/ml)-stimulated platelet aggregation, which was predominantly soluble guanylyl cyclase/cGMP-dependent. Compared to WT-HFD, ApoE(-/-)-HFD mice displayed an increase in total plasma cholesterol levels (P