NO- and non-NO-, non-prostanoid-dependent vasodilatation in rat sciatic nerve during maturation and developing experimental diabetic neuropathy

Abstract

This study examined NO- and non-NO-, non-prostanoid-dependent pathways of agonist-induced vasodilatation in streptozotocin (STZ)-induced diabetic rats and their age-matched controls at 1–2, 8–10 and 18–20 weeks after induction of diabetes. Using laser Doppler flowmetry, vasodilatory responses to acetylcholine (ACh; 0.1 mM) and morpholino-sydnonimine (SIN-1) were determined in the presence of Ringer solution, during inhibition of NO synthase (NOS) and cyclo-oxygenase (COX) with N^ω-nitro-L-arginine (L-NNA; 1 mM) + indomethacin (10⁻⁵ M), and during inhibition of K⁺ channels, NOS and COX with tetraethylammonium (TEA; 10 mM) + L-NNA + indomethacin. Basal NOS activity and nerve conduction velocity were also determined. In age-matched controls, SIN-1-induced vasodilatation in the presence of TEA + L-NNA + indomethacin, basal NOS activity and the initial vasodilatory response to ACh during NOS and COX inhibition all decreased with maturation. In STZ-induced diabetics, SIN-1-induced vasodilatation in the presence of TEA + L-NNA + indomethacin was impaired immediately after induction of diabetes, but not at 18–20 weeks. NOS activity in STZ-induced diabetics displayed a transient 2-fold increase at 8–10 weeks, decreasing to age-matched control levels at 18–20 weeks. At 18–20 weeks of STZ-induced diabetes, ACh-induced vasodilatation during NOS and COX inhibition was prolonged due to increased K⁺ channel activity and experimental diabetic sensory neuropathy (EDN) had developed. Thus, in sciatic nerve microcirculation of STZ-induced diabetic rats: (1) diabetic impairment of vasodilatation in response to exogenous NO was transient; (2) non-NO-, non-prostanoid-dependent vasodilatation and K⁺ channel activity were augmented in STZ-induced diabetes; and (3) alterations in NO bioactivity were not related to the development of EDN.