title: Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia.
abstract: 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 antiaggregatory actions were compared with those of a clinically used NO(•) donor, glyceryl trinitrate (GTN), in hypercholesterolemic mice. The vasorelaxant and antiaggregatory properties of IPA/NO and GTN were examined in isolated carotid arteries and washed platelets, respectively, from male C57BL/6J mice [wild-type (WT)] maintained on either a normal diet (WT-ND) or high fat diet (WT-HFD; 7 wk) as well as apolipoprotein E-deficient mice maintained on a HFD (ApoE(-/-)-HFD; 7 wk). In WT-ND mice, IPA/NO (0.1-30 μmol/l) induced concentration-dependent vasorelaxation and inhibition of collagen (30 μg/ml)-stimulated platelet aggregation, which was predominantly soluble guanylyl cyclase/cGMP dependent. Compared with WT-HFD mice, ApoE(-/-)-HFD mice displayed an increase in total plasma cholesterol levels (P < 0.001), vascular (P < 0.05) and platelet (P < 0.05) superoxide (O(2)(·-)) production, and reduced endogenous NO(•) bioavailability (P < 0.001). Vasorelaxant responses to both IPA/NO and GTN were preserved in hypercholesterolemia, whereas vascular tolerance developed to GTN (P < 0.001) but not to IPA/NO. The ability of IPA/NO (3 μmol/l) to inhibit platelet aggregation was preserved in hypercholesterolemia, whereas the actions of GTN (100 μmol/l) were abolished. In conclusion, the vasoprotective effects of IPA/NO were maintained in hypercholesterolemia and, thus, HNO donors may represent future novel treatments for vascular diseases.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Bullen
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Miller
authors.forename: Janahan
authors.initials: J
authors.lastname: Dharmarajah
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017536:Carotid Artery, Common / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents
chemical_list: C507406:1-isopropyldiazen-1-ium-1,2-diolate; D001057:Apolipoproteins E; D004041:Dietary Fats; D016166:Free Radical Scavengers; D006834:Hydrazines; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D003094:Collagen; D002784:Cholesterol; D005996:Nitroglycerin