2-Chloroadenosine reverses hyperglycemia-induced inhibition of phosphoinositide synthesis in cultured human retinal pigment epithelial cells and prevents reduced nerve conduction velocity in diabetic rats

The effect of the adenosine (AD) analog 2-chloroadenosine (C-AD) on glucose -induced inhibition of phosphoinositide synthesis was studied in human reti nal pigment epithelial (RPE) cells by monitoring the level of the phosphati dylinositol (PI) synthase substrate, cytidine diphosphate diglyceride (CDP- DG). In high-aldose reductase (AR)-expressing RPE 91 cells, C-AD decreased CDP-DG at 5 mmol/L glucose and reversed the increase by 20 mmol/L glucose. AD deaminase (ADA), which inactivates endogenously released AD, potentiated the hyperglycemia-induced increase in CDP-DG. Theophylline, an AD-A1 and A D-A2 receptor antagonist, caused an increase in CDP-DG at 20 mmol/L glucose . C-AD did not alter CDP-DG in low-AR-expressing RPE 45 cells, but did decr ease CDP-DG after cells were conditioned in 300 mmol/L glucose for 1 week ( which induces AR). The mechanism by which AD regulates PI synthase in cells with high AR activity is unknown, but it is independent of Gi or Gs protei ns, adenylate cyclase and phospholipase C (PLC) activation, myo-inositol (M I) uptake, or MI efflux. Administration of C-AD to streptozotocin-induced d iabetic rats prevented the slowing of motor nerve conduction velocity (MNCV ). Thus, AD derivatives, which reverse a glucose-induced deficit in phospho inositide metabolism, might serve as a useful pharmacological tool to inter vene in hyperglycemia-induced diabetic complications. Copyright (C) 1999 by W.B. Saunders Company.