Nitroxyl donors retain their depressor effects in hypertension

Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli's salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 μg/kg), IPA/NO (10, 50, and 200 μg/kg), and DEA/NO (1, 5, and 20 μg/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P < 0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P < 0.01), yet those to DEA/NO in SHR were significantly (P < 0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.