title: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.
abstract: The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of approximately 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.
authors.affiliation: Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ishii
authors.forename: M R
authors.initials: MR
authors.lastname: Jirousek
authors.forename: D
authors.initials: D
authors.lastname: Koya
authors.forename: C
authors.initials: C
authors.lastname: Takagi
authors.forename: P
authors.initials: P
authors.lastname: Xia
authors.forename: A
authors.initials: A
authors.lastname: Clermont
authors.forename: S E
authors.initials: SE
authors.lastname: Bursell
authors.forename: T S
authors.initials: TS
authors.lastname: Kern
authors.forename: L M
authors.initials: LM
authors.lastname: Ballas
authors.forename: W F
authors.initials: WF
authors.lastname: Heath
authors.forename: L E
authors.initials: LE
authors.lastname: Stramm
authors.forename: E P
authors.initials: EP
authors.lastname: Feener
authors.forename: G L
authors.initials: GL
authors.lastname: King
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D004075:Diglycerides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D017595:Renal Plasma Flow / Q000187:drug effects; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000503:physiopathology; D013379:Substrate Specificity
chemical_list: D004075:Diglycerides; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta