Figure 1.

Schematic for impact of hyperglycaemia on nitric oxide (NO)/soluble guanylate cyclase (sGC) pathways. Under normal physiological conditions, NO is generated mainly from L-arginine under the influence of nitric oxide synthase (NOS), which is negatively regulated by asymmetric dimethylarginine (ADMA). Via activation of sGC/cyclic GMP pathway, NO exerts various physiological effects such as anti-aggregation, anti-oxidation and vasodilation. However, during acute hyperglycaemia (BSL ↑), the excessively generated superoxide “scavenges” NO, contributing to attenuation of tissue responsiveness of NO and formation of peroxynitrite (ONOO^–). Furthermore, increased expression of the pro-inflammatory protein thioredoxin-interacting protein (TXNIP) increases oxidative stress, potentially contributing to dysfunction of sGC. Major sites of resultant impairment of NO effect are: (I) “scavenging” of NO; (II) sGC oxidative dysfunction. BSL, blood sugar level; GMP, guanosine monophosphate.