AMELIORATION OF VASCULAR DYSFUNCTIONS IN DIABETIC RATS BY AN ORAL PKC-BETA INHIBITOR

The vascular complications of diabetes mellitus have been correlated w ith enhanced activation of protein kinase C (PKC). LY333531, a specifi c 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), w ith a half-maximal inhibitory constant of similar to 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth o f that for non-PKC kinases. When administered orally, LY333531 amelior ated the glomerular filtration rate, albumin excretion rate, and retin al circulation in diabetic rats in a dose-responsive manner, in parall el with its inhibition of PKC activities.