ABSTRACT
Chemical oxidation of N-hydroxy-L-arginine (NOHA) and other N-hydroxyguanidines has been previously shown to generate either nitric oxide (NO) or nitroxyl (HNO), depending on the oxidative conditions. Because N-hydroxy-L-arginine has been demonstrated to be a biosynthetic intermediate in the oxidative conversion of arginine to endothelium-derived relaxing factor, the possible formation of HNO through a biological process was considered. This study, therefore, explores the biological activity of HNO as a possible effector molecule, and the results indicate that HNO is capable of eliciting vasorelaxation in both rabbit aorta and bovine intrapulmonary artery by a guanylate cyclase-dependent pathway. The pharmacological properties of HNO were very similar to those of endothelium-derived relaxing factor, and the possible relationship between HNO and endothelium-derived relaxing factor is discussed.
Subject(s)
Nitric Oxide/pharmacology , Nitrogen Oxides/pharmacology , Vasodilator Agents/pharmacology , Animals , Aorta , Cattle , Cyanamide/chemistry , Cyclic GMP/analysis , Endothelium, Vascular/drug effects , Lung/blood supply , Methylene Blue/pharmacology , Nitric Oxide/chemistry , Nitrogen Oxides/chemistry , Oxidation-Reduction , RabbitsABSTRACT
N,O-Diacylated-N-hydroxyarylsulfonamides are capable of slowly releasing nitroxyl (HNO) by simple, non-enzymatic hydrolysis in Krebs solution at 37 degrees C. Release of nitric oxide (NO) was not seen. These compounds were also found to elicit vasorelaxation in rabbit thoracic aorta in vitro, presumably as a result of their ability to release HNO. This effect was enhanced by the addition of superoxide dismutase (SOD). Thus, these results are consistent with previous work indicating that HNO is a potent vasorelaxant.
Subject(s)
Muscle, Smooth/drug effects , Nitrogen Oxides/chemistry , Sulfonamides/pharmacology , Vasodilator Agents/pharmacology , Animals , In Vitro Techniques , Prodrugs/chemistry , Rabbits , Superoxide Dismutase/pharmacology , Vasodilator Agents/chemistryABSTRACT
N omega-Hydroxy-L-arginine was found to cause vasodilation in arginine-depleted rabbit aorta. It is, therefore, likely to be a biosynthetic intermediate in the conversion of arginine to nitric oxide in this tissue. N-Hydroxyalkylguanidine compounds, including N omega-hydroxy-L-arginine were oxidized with various oxidizing agents and examined for their ability to release nitric oxide. All oxidizing agents tested were capable of oxidizing the N-hydroxyguanidine function but only lead tetra-acetate (Pb(OAc)4) and potassium ferricyanide/hydrogen peroxide (K3FeCN6/H2O2) were capable of generating significant amounts of nitric oxide. Oxidation with K3FeCN6, lead oxide (PbO2) and silver carbonate (Ag2CO3) resulted instead in the release of nitrous oxide (N2O) presumably through the initial release of nitroxyl (HNO).
