title: Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor.
abstract: Streptozotocin (STZ)-induced chronic hyperglycemia has a detrimental effect on neurovascular coupling, linked to increased PKC-mediated phosphorylation and PKC isoform expression changes. Here, we sought to determine whether: 1) selective PKC-α/β/γ inhibitor, GF109203X, could reverse the effects of chronic hyperglycemia on cerebrovascular reactivity; 2) pancreatic islet transplantation could prevent the development of cerebrovascular impairment seen in a rat model of Type 1 Diabetes. We studied the effect of GF109203X in diabetic (DM), non-diabetic (ND), and transplanted (TR) Lewis rats during either sciatic nerve stimulation (SNS) or the topical applications of the large-conductance Ca2+-operated K+(BKCa) channel opener, NS1619, or the K+inward rectifier (Kir) channel agonist, KCl. Pial arteriole diameter changes were monitored using a closed cranial window in vivo microscopy technique. The pial arteriole dilatory response associated with SNS was decreased by ~45%, when comparing DM vs either ND or TR rats. Also, pial arteriolar dilations to topical KCl and NS1619 were largely attenuated in DM rats, but not in ND or TR animals. These responses were completely restored by the acute application of GF109203X to the brain surface. The PKC inhibitor had no effect on vascular responses in normoglycemic and TR animals. In conclusion, DM-associated chronic impairment of neurovascular coupling may be readily reversed by a PKC-α/β/γ inhibitor or prevented via pancreatic islet transplantation. We believe that specific PCK isoforms (α/β/γ) are mechanistically linked to the neurovascular uncoupling seen with hyperglycemia.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W Taylor St, Chicago 60612, IL, USA. Electronic address: vetri@uic.edu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetri
authors.affiliation: Division of Transplantation, Department of Surgery, University of Illinois at Chicago, 1740 W Taylor St, Chicago 60612, IL, USA.
authors.forename: Meirigeng
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W Taylor St, Chicago 60612, IL, USA.
authors.forename: Haoliang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Division of Transplantation, Department of Surgery, University of Illinois at Chicago, 1740 W Taylor St, Chicago 60612, IL, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W Taylor St, Chicago 60612, IL, USA.
authors.forename: Chanannait
authors.initials: C
authors.lastname: Paisansathan
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D001562:Benzimidazoles / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology / Q000628:therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D000069336:Neurovascular Coupling / Q000502:physiology; D010841:Pia Mater / Q000187:drug effects / Q000503:physiopathology; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011917:Rats, Inbred Lew; D054340:Receptors, KIR / Q000819:agonists / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology
chemical_list: D001562:Benzimidazoles; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D008301:Maleimides; D018377:Neurotransmitter Agents; D054340:Receptors, KIR; C086491:NS 1619; D011189:Potassium Chloride; D011493:Protein Kinase C; C070515:bisindolylmaleimide I
keywords: BKCa, large-conductance Ca2+-operated K+ channel; DM, diabetic; Diabetes mellitus type 1; GF109203X; Kir, K+ inward rectifier channel; ND, non-diabetic; NVC, neurovascular coupling; Neurovascular coupling; PKC; PKC, protein kinase C; Pancreatic islet transplantation; Potassium channels; SEPs, somatosensory evoked potentials; STZ, streptozotocin; TR, transplanted rats; aCSF, artificial cerebrospinal fluid