Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced betaII PKC activation.

betaII protein kinase C (betaPKC) is activated during acute and chronic hyperglycemia and may alter endothelial cell function. We determined whether blockade of betaPKC protected in vivo endothelial formation of NO, as measured with NO-sensitive microelectrodes in the rat intestinal vasculature. NaCl hyperosmolarity, a specific endothelial stimulus to increase NO formation, caused approximately 20% arteriolar vasodilation and approximately 30% increase in NO concentration ([NO]). After topical 300 mg/dl hyperglycemia for 45 min, both responses were all but abolished. In comparison, pretreatment with LY-333531, a specific betaPKC inhibitor, maintained vasodilation and [NO] responses to NaCl hyperosmolarity after hyperglycemia. The betaPKC inhibitor alone 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 approximately 70% of the dilatory response. These data demonstrated that activation of betaPKC during acute hyperglycemia depressed in vivo endothelial formation of NO at rest and during stimulation. This abnormality can be minimized by inhibition of betaPKC before hyperglycemia and can be substantially reversed by PKC inhibition after hyperglycemia-induced abnormalities have occurred.