Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BKCa and Kir channels

Vetri F, Xu H, Paisansathan C, Pelligrino DA. Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BKCa and Kir channels. Am J Physiol Heart Circ Physiol 302: H1274-H1284, 2012. First published January 20, 2012; doi:10.1152/ajpheart.01067.2011.-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 Ca2+-operated K+ channel (BKCa) 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 similar to 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 BKCa and Kir channel activity.