BLOCKADE OF CEREBRAL BLOOD-FLOW RESPONSE TO INSULIN-INDUCED HYPOGLYCEMIA BY CAFFEINE AND GLIBENCLAMIDE IN CONSCIOUS RATS

The possibility that adenosine and ATP-sensitive potassium channels (K -ATP) might be involved in the mechanisms of the increases in cerebral blood flow (CBF) that occur in insulin-induced hypoglycemia was exami ned. Cerebral blood flow was measured by the [C-14]iodoantipyrine meth od in conscious rats during insulin-induced, moderate hypoglycemia (2 to 3 mmol/L glucose in arterial plasma) after intravenous injections o f 10 to 20 mg/kg of caffeine, an adenosine receptor antagonist, or int racisternal infusion of 1 to 2 mu mol/L glibenclamide, a K-ATP channel inhibitor. Cerebral blood flow was also measured in corresponding nor moglycemic and drug-free control groups. Cerebral blood flow was 51% h igher in untreated hypoglycemic than in untreated normoglycemic rats ( P < 0.01). Caffeine had a small, statistically insignificant effect on CBF in normoglycemic rats, but reduced the CBF response to hypoglycem ia in a dose-dependent manner, i.e., 27% increase with 10 mg/kg and co mplete elimination with 20 mg/kg. Chemical determinations by HPLC in e xtracts of freeze-blown brains showed significant increases in the lev els of adenosine and its degradation products, inosine and hypoxanthin e, during hypoglycemia (P < 0.05). Intracisternal glibenclamide had li ttle effect on CBF in normoglycemia, but, like caffeine, produced dose -dependent reductions in the magnitude of the increases in CBF during hypoglycemia, i.e., +66% with glibenclamide-free artificial CSF admini stration, +25% with 1 mu mol/L glibenclamide, and almost complete bloc kade (+5%) with 2 mu mol/L glibenclamide. These results suggest that a denosine and K-ATP channels may play a role in the increases in CBF du ring hypoglycemia.