Redox variants of NO (NO. and HNO) elicit vasorelaxation of resistance arteries via distinct mechanisms

Nitric oxide (NO*) is a well known mediator of vascular tone. What is not so well recognised is that NO* exists in several different redox forms. There is considerable evidence that NO* and its one-electron reduction product, the nitroxyl anion (HNO), have pharmacologically distinct actions which extend into the regulation of the vasculature. The aim of this study was to compare the vasorelaxation mechanisms of HNO and NO*, including an examination of the ability of these redox variants to hyperpolarise and repolarise vascular smooth muscle cells from rat mesenteric arteries. The HNO donor, Angeli s salt (0.1nM-10microM) caused a concentration-dependent hyperpolarisation of vessels at resting tone, and a simultaneous, concentration-dependent vasorelaxation and repolarisation of vessels pre-contracted and depolarised with methoxamine. Both vasorelaxation and repolarisation responses to Angeli s salt were significantly attenuated by both the HNO scavenger L-cysteine (3mM) and the KV channel inhibitor 4-aminopyridine (4-AP, 1mM), and virtually abolished by the sGC inhibitor ODQ (10microM) or 30mM K(+). In contrast, NO* (0.01-1microM) repolarised arteries to a lesser extent than HNO and these responses were resistant to inhibition by ODQ (10microM) and 4-AP (1mM). Blockade of KV channels (1mM 4-AP) also significantly inhibited the repolarisation response to YC-1 (0.1-10 microM), confirming a role for sGC/cGMP in the activation of KV channels in this preparation. We conclude that HNO causes vasorelaxation via a cGMP-dependent activation of KV channels and that there are different profiles of vasorelaxant activity for the redox siblings HNO and NO*. Key words: Nitroxyl anion, hyperpolarisation, soluble guanylate cyclase, K+ channels.