ucn-1028-c and Diabetes-Mellitus--Type-1

We hypothesized that chronic hyperglycemia has a detrimental effect on neurovascular coupling in the brain and that this may be linked to protein kinase C (PKC)-mediated phosphorylation. Therefore, in a rat model of streptozotocin-induced chronic type 1 diabetes mellitus (T1DM), and in nondiabetic (ND) controls, we monitored pial arteriole diameter changes during sciatic nerve stimulation and topical applications of the large-conductance Ca(2+)-operated K(+) channel (BK(Ca)) opener, NS-1619, or the K(+) inward rectifier (Kir) channel agonist, K(+). In the T1DM vs. ND rats, the dilatory response associated with sciatic nerve stimulation was decreased by ∼30%, whereas pial arteriolar dilations to NS-1619 and K(+) were largely suppressed. These responses were completely restored by the acute topical application of a PKC antagonist, calphostin C. Moreover, the suffusion of a PKC activator, phorbol 12,13-dibutyrate, in ND rats was able to reproduce the vascular reactivity impairments found in T1DM rats. Assay of PKC activity in brain samples from T1DM vs. ND rats revealed a significant gain in activity only in specimens harvested from the pial and superficial glia limitans tissue, but not in bulk cortical gray matter. Altogether, these findings suggest that the T1DM-associated impairment of neurovascular coupling may be mechanistically linked to a readily reversible PKC-mediated depression of BK(Ca) and Kir channel activity.

Topics: Animals; Arterioles; Benzimidazoles; Cerebrovascular Circulation; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Electric Stimulation; Enzyme Activation; Enzyme Activators; Female; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Naphthalenes; Phorbol 12,13-Dibutyrate; Phosphorylation; Pia Mater; Potassium; Potassium Channels; Potassium Channels, Inwardly Rectifying; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Time Factors; Vasodilation