Proposed interactions between NO and superoxide anions (O₂^•–) in the regulation of endothelium-dependent responses. NO synthase (NOS) produces both NO and superoxide anions. Under normal circumstances, and in most arteries, the production of NO predominates, and NO scavenges the small amounts of superoxide anion formed. In the small mesenteric artery of the mice, the superoxide anions that escape the scavenging by NO are transformed by SOD to H₂O₂, which diffuses to the vascular smooth muscle and causes its hyperpolarization (Hyperpol.) by opening of a K⁺ conductance (K_Ca2+). NO activates soluble guanylate cyclase (sGC) to produce more cGMP. In arteries such as the canine cerebral arteries, or the aortas of hypertensive or diabetic animals, other sources of production of superoxide anions (e.g., NAD(P)H oxidase [NAD(P)H Ox]) or xanthine oxidase (Xant Ox) are activated when the intracellular Ca²⁺ concentration increases. The large quantities of superoxide anions formed scavenge most or all of the NO, leading to the production of peroxynitrite (ONOO^–). In addition, superoxide anions can be transformed to hydroxyl radicals, which diffuse to the vascular smooth muscle and induce the production of vasoconstrictor endoperoxides (PGH₂) and prostanoids (and possibly isoprostanes). The latter activate TP receptors (TP-R) that are coupled positively to the contractile process.