title: Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK(Ca) and Kir channels.
abstract: 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.
authors.affiliation: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois at Chicago, 60612, USA. vetri@uic.edu
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetri
authors.forename: Haoliang
authors.initials: H
authors.lastname: Xu
authors.forename: Chanannait
authors.initials: C
authors.lastname: Paisansathan
authors.forename: Dale A
authors.initials: DA
authors.lastname: Pelligrino
mesh_terms: D000818:Animals; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology; D001562:Benzimidazoles / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D048909:Diabetes Complications / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D004558:Electric Stimulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009281:Naphthalenes / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D010841:Pia Mater / Q000098:blood supply*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000503:physiopathology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D020536:Enzyme Activators; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009281:Naphthalenes; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D047428:Protein Kinase Inhibitors; C086491:NS 1619; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; C058819:calphostin C; D011188:Potassium