Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced beta II PKC activation

beta II protein kinase C (beta PKC) is activated during acute and chronic h yperglycemia and may alter endothelial cell function. We determined whether blockade of bPKC protected in vivo endothelial formation of NO, as measure d with NO-sensitive microelectrodes in the rat intestinal vasculature. NaCl hyperosmolarity, a specific endothelial stimulus to increase NO formation, caused similar to 20% arteriolar vasodilation and similar to 30% increase in NO concentration ([ NO]). After topical 300 mg/dl hyperglycemia for 45 m in, both responses were all but abolished. In comparison, pretreatment with LY-333531, a specific bPKC inhibitor, maintained vasodilation and [NO] res ponses to NaCl hyperosmolarity after hyperglycemia. The bPKC inhibitor alon e had no significant effects on resting diameter or [NO] or their responses to NaCl hyperosmolarity. In separate rats, after topical hyperglycemia had suppressed dilation to ACh, LY-333531 restored similar to 70% of the dilat ory response. These data demonstrated that activation of bPKC during acute hyperglycemia depressed in vivo endothelial formation of NO at rest and dur ing stimulation. This abnormality can be minimized by inhibition of bPKC be fore hyperglycemia and can be substantially reversed by PKC inhibition afte r hyperglycemia-induced abnormalities have occurred.