Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.
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.
Ishii
H
H
Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Jirousek
M R
MR
Koya
D
D
Takagi
C
C
Xia
P
P
Clermont
A
A
Bursell
S E
SE
Kern
T S
TS
Ballas
L M
LM
Heath
W F
WF
Stramm
L E
LE
Feener
E P
EP
King
G L
GL
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
D004075:Diglycerides; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta