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The nitroxyl anion (NO): a novel regulator of sGC and vascular tone


Traditionally the vascular effects of nitric oxide (NO) have been attributed to the free radical form of NO (NO) yet the reduced form of NO (NO-) is also produced endogenously and vasodilates both large conduit and small resistance-like arteries. Interestingly, NO and NO- have been shown to have distinct mechanisms of action in the cardiovascular system, particularly in the heart. This study aimed to determine if the vasorelaxant effects of NO- differed to those of NO in rat small mesenteric resistance arteries.

Materials and Methods

Mesenteric arteries (~350 μm diameter) were obtained from male Sprague-Dawley rats, mounted in small vessel myographs and isometric force and intracellular membrane potential measured simultaneously. Vessels were precontracted to ~50% of maximum (determined by K+(124 mM)) with methoxamine. Cumulative concentration-response curves to NO (NO gas), the NO- donor, Angeli's salt and the NO-independent soluble guanylate cyclase (sGC) activator, YC-1 were examined.


Vasorelaxation to Angeli's salt (pEC50 = 7.02 ± 0.67 -log M; Rmax = 96.0 ± 2.2%, n = 4) was accompanied by simultaneous vascular smooth muscle cell hyperpolarisation (pEC50 = 6.82 ± 0.32, 10 μM AS -17.8 ± 4.4 mV, n = 4). In contrast, maximal vasorelaxation to NO (pEC50 = 6.82 ± 0.39, 92.1 ± 1.3%) was achieved before a small hyperpolarization response was observed at 1 μM NO (-4.9 ± 2.3 mV, n = 5). Both relaxation and hyperpolarisation responses to Angeli's salt were significantly attenuated (P < 0.05, n = 5) by the NO- scavenger, L-cysteine (3 mM) and abolished by the sGC inhibitor, ODQ (10 μM; P < 0.05, n = 4). The Kv channel inhibitor, 4-aminopyridine (1 mM) caused a 4-fold (P < 0.05, n = 4) decrease in sensitivity to Angeli's salt and abolished the hyperpolarisation response (P < 0.05). In contrast glibenclamide (KATP channel inhibitor) and charybdotoxin (BKCa/IKCa channel inhibitor) were without effect. YC-1 also induced vasorelaxation and hyperpolarisation in rat small mesenteric arteries.


In conclusion, in rat small mesenteric arteries, NO- mediates relaxation in part via cGMP-dependent activation of Kv channels. In contrast, NO-mediated vasorelaxation occurs independently of vascular smooth muscle hyperpolarisation. Thus, the redox siblings NO and NO- have distinct mechanisms of vasorelaxation in resistance-like arteries.

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Correspondence to Barbara Kemp-Harper.

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  • Nitric Oxide
  • Glibenclamide
  • KATP Channel
  • Channel Inhibitor
  • Methoxamine