Nitroxyl anion donor, Angeli's salt, does not develop tolerance in rat isolated aortae

The nitroxyl anion (HNO) is emerging as a novel regulator of cardiovascular function with therapeutic potential in the treatment of diseases such as heart failure. It remains unknown whether tolerance develops to HNO donors, a limitation of currently used nitrovasodilators. The susceptibility of the HNO donor, Angeli's salt (AS), to the development of vascular tolerance was compared with the NO donors, glyceryl trinitrate (GTN) and diethylamine/NONOate (DEA/NO) in rat isolated aortae. Vasorelaxation to AS was attenuated (P < 0.01) by the HNO scavenger L-cysteine, whereas the sensitivity to GTN and DEA/NO was decreased (P < 0.01) by the NO center dot scavenger carboxy-[2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidozoline-1-oxy-3-oxide]. The soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one impaired responses to GTN >= AS >> DEA/NO. Pretreatment with 10, 30, and 100 mu mol/L of GTN for 60 minutes induced a 4- (P < 0.05), 13(P < 0.01), and 48-fold (P < 0.01) decrease in sensitivity to GTN, demonstrating tolerance development. In contrast, pretreatment with AS or DEA/NO (10, 30, and 100 mu mol/L) did not alter their subsequent vasorelaxation. All of the nitrovasodilators (30 mu mol/L) displayed a similar time course of vasorelaxation and cGMP accumulation over a 60-minute period. Unlike vasorelaxation, the magnitude of peak cGMP accumulation differed substantially: DEA/NO >> AS > GTN. GTN did not induce cross-tolerance to either AS or DEA/NO. In contrast, pre-exposure to DEA/NO, but not AS, caused a concentration-dependent attenuation (P < 0.01) of GTN-mediated relaxation, which was negated by the protein kinase G inhibitor guanosine 3', 5'-cyclic monophosphorothioate, 8-(4-chlorophenylthio)-,Rp-isomer, triethylammonium salt. In conclusion, vascular tolerance does not develop to HNO, nor does cross-tolerance between HNO and GTN occur. Thus, HNO donors may have therapeutic advantages over traditional nitrovasodilators.