NO- and non-NO-, non-prostanoid-dependent vasodilatation in rat sciatic nerve during maturation and developing experimental diabetic neuropathy.
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(omega)-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.
Thomsen
Kirsten
K
Department of Medical Physiology, University of Copenhagen and Department of Neurophysiology, Glostrup Hospital, Denmark. kthomsen@mfi.ku.dk
Rubin
Inger
I
Lauritzen
Martin
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology*; D005215:Fasting; D006442:Glycated Hemoglobin / Q000032:analysis; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009046:Motor Neurons / Q000502:physiology; D009431:Neural Conduction; D009475:Neurons, Afferent / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000098:blood supply* / Q000201:enzymology / Q000254:growth & development; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000109:Acetylcholine; D001786:Blood Glucose; D016861:Cyclooxygenase Inhibitors; D006442:Glycated Hemoglobin; D007213:Indomethacin; D008981:Molsidomine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D026902:Potassium Channel Blockers; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D014665:Vasodilator Agents; C002385:linsidomine