. Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am J Physiol Heart Circ Physiol 280: H821-H829, 2001.-Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N G -nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF. adenosine; nitric oxide; caffeine; 7-nitroindazole; N G -nitro-Larginine NUMEROUS STUDIES HAVE ESTABLISHED that neuronal functional activation is associated with increases in both cerebral energy metabolism and blood flow (CBF) in components of the activated neural pathway (8,18,(30)(31)(32). The increases in energy metabolism evoked by functional activation have been shown to be proportional to the increases in spike frequency in the afferent inputs to the activated areas (13, 32) and to be due mainly to activation of Na ϩ -K ϩ -ATPase activity (21, 32). The mechanisms mediating the increases in CBF during functional activation remain, however, largely undefined. A popular hypothesis proposed by Roy and Sherrington (27) was that CBF is intrinsically regulated by products of energy metabolism to meet the altered metabolic demands associated with functional activity. This hypothesis received support from subsequent findings that CBF is raised by increased CO 2 tension, lowered pH, and decreased oxygen tension, all expected consequences of increased tissue metabolism, and reduced by changes in these chemical factors in the opposite direction, to be expected with decreased metabolism (14). Since then, many other endogenous agents that affect cerebral blood vessels, e.g., nitric oxide (NO), adenosine, adenine nucleotides, K ϩ , prostaglandins, vasoactive intestinal peptide, etc., have been identified and considered as possible candidates, but not one of them, alone or in combination with others, has yet been proven to account fully or even to be essential for the enhancement of CBF by neuronal activation.Inhibition of cerebral glucose utilization by hypo...

The possibility that adenosine and ATP-sensitive potassium channels (KATP) might be involved in the mechanisms of the increases in cerebral blood flow (CBF) that occur in insulin-induced hypoglycemia was examined. Cerebral blood flow was measured by the [14C]iodoantipyrine method in conscious rats during insulin-induced, moderate hypoglycemia (2 to 3 mmol/L glucose in arterial plasma) after intravenous injections of 10 to 20 mg/kg of caffeine, an adenosine receptor antagonist, or intracisternal infusion of 1 to 2 mumol/L glibenclamide, a KATP channel inhibitor. Cerebral blood flow was also measured in corresponding normoglycemic and drug-free control groups. Cerebral blood flow was 51% higher 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 hypoglycemia in a dose-dependent manner, i.e., 27% increase with 10 mg/kg and complete elimination with 20 mg/kg. Chemical determinations by HPLC in extracts of freeze-blown brains showed significant increases in the levels of adenosine and its degradation products, inosine and hypoxanthine, during hypoglycemia (P < 0.05). Intracisternal glibenclamide had little 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 administration, +25% with 1 mumol/L glibenclamide, and almost complete blockade (+5%) with 2 mumol/L glibenclamide. These results suggest that adenosine and KATP channels may play a role in the increases in CBF during hypoglycemia.

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