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.
Publication types
-
Comment
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Administration, Oral
-
Albuminuria / prevention & control
-
Animals
-
Diabetes Mellitus, Experimental / complications*
-
Diabetes Mellitus, Experimental / enzymology
-
Diabetes Mellitus, Experimental / physiopathology
-
Diabetic Angiopathies / enzymology
-
Diabetic Angiopathies / etiology
-
Diabetic Angiopathies / prevention & control*
-
Diglycerides / metabolism
-
Dose-Response Relationship, Drug
-
Enzyme Activation
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Glomerular Filtration Rate / drug effects
-
Humans
-
Indoles / administration & dosage
-
Indoles / chemistry
-
Indoles / pharmacology*
-
Isoenzymes / antagonists & inhibitors*
-
Isoenzymes / metabolism
-
Kidney Glomerulus / metabolism
-
Male
-
Maleimides / administration & dosage
-
Maleimides / chemistry
-
Maleimides / pharmacology*
-
Muscle, Smooth, Vascular / enzymology
-
Phosphorylation / drug effects
-
Protein Kinase C / antagonists & inhibitors*
-
Protein Kinase C / metabolism
-
Protein Kinase C beta
-
Rats
-
Rats, Sprague-Dawley
-
Regional Blood Flow / drug effects
-
Renal Plasma Flow / drug effects
-
Retina / metabolism
-
Retinal Vessels / physiopathology
-
Substrate Specificity
Substances
-
Diglycerides
-
Enzyme Inhibitors
-
Indoles
-
Isoenzymes
-
Maleimides
-
ruboxistaurin
-
Protein Kinase C
-
Protein Kinase C beta