The effect of acute and chronic administration of three different prostaglandin (PG) synthesis inhibitors–aspirin, indomethacin and naproxen–on the basal and CO2‐stimulated cerebral blood flow (CBF) was studied in healthy subjects, using the N2O wash‐in technique for assessment of CBF. The regional O2 extraction over the brain, the regional production of free fatty acids (FFA)–including the PG precursor arachidonic acid (AA)–and the regional production of two prostacyclin (PGI2) metabolites, were also measured. The efficacy of cyclo‐oxygenase inhibition by these drugs was monitored through AA‐induced platelet aggregation in blood samples taken before and after drug administration. In the basal state there was no detectable release of AA, other FFA or PGI2 metabolites over the brain. Acute administration of aspirin (45 mg/kg) failed to affect CBF, as did chronic administration of this drug (15 mg/kg × 3 daily). Indomethacin (1.5 mg/kg) significantly (p<0.05)reduced CBF after acute administration, but after one week's treatment (0.8 mg/kg × 3 daily) this effect had disappeared. Acute administration of naproxen (4 mg/kg) did not affect O2 extraction over the brain, thus indicating that CBF was unchanged. After chronic administration, naproxen (4 mg/kg × 2 daily) also failed to change CBF. During inhalation of CO2, no release of AA, other FFA or PGI2 metabolites occurred in untreated subjects. In subjects given indomethacin there was a small but significant release of AA during inhalation of CO2. Both acute and chronic administration of aspirin failed to affect the CO2‐induced elevation of CBF, whereas both forms of indomethacin administration significantly reduced this rise. Chronic administration of naproxen did not affect the CO2‐induced increase in CBF. We conclude that in healthy subjects: 1) local PGI2 production does not appear to be involved in the regulation of cerebral blood flow: 2) indomethacin reduces basal and CO2‐stimulated CBF, an effect not shared by the other structurally unrelated cyclo‐oxygenase inhibitors: 3) the mechanism(s) of indomethacin‐induced reduction of CBF does not appear to be related to inhibition of PG‐synthesis and remains to be determined.

1. L-Leucine was given to healthy, post-absorptive subjects as a continuous intravenous infusion (300 mumol/min) during 2 1/2 h. Arterial blood concentrations and regional exchange amino acids were measured across the splanchnic region, the brain and a leg, by the catheter technique. Renal clearance of amino acids was also determined. 2. During the infusion of leucine its concentration rose four- to six-folds, while the concentrations of several other amino acids declined continually, the effect being most pronounced for isoleucine (-55% of initial value), methionine (-55%), valine (-40%), tyrosine (-35%) and phenylalanine (-35%). 3. The infused leucine was taken up by muscle tissue (55%), by the splanchnic region (25%) and by the brain (10%). Neither leg-muscle release nor splanchnic uptake of aromatic amino acids was affected. Renal clearance and tubular reabsorption of amino acids were uninfluenced by leucine infusion. The uptake of isoleucine and methionine by the brain, seen in the basal state, was inhibited during leucine infusion. 4. The marked reduction in the concentrations of the aromatic amino acids, the uptake of leucine by the brain and the inhibition of brain methionine uptake, which accompany leucine infusion in healthy subjects, may be of relevance for the treatment of patients with portal-systemic encephalopathy.

Summary. Cerebral blood flow (CBF) was measured using the nitrous oxide technique in the basal state and following inhalation of CO2 in eight, healthy, awake male volunteers, before and during inhibition of prostaglandin synthesis with indomethacin. Arterial and jugular venous oxygen contents and pCO2 were also analysed. Indomethacin reduced the basal CBF by 35%, from 43 ± 2 to 28 ± 2 ml/100 ml tissue per min, but did not affect the calculated cerebral metabolic rate of oxygen (CMRO2). The reduced CBF was accompanied by an elevation of jugular venous pCO2. Inhalation of 6–7% CO2 increased CBF to 98 ± 17 ml/100 ml tissue per min before indomethacin, compared with only 42 ± 4 ml/100 ml tissue per min after indomethacin. This difference in the hypercapnia induced increase in CBF before and after indomethacin was reflected also by the data on arterio‐venous differences in pCO2. We conclude that indomethacin inhibits both basal and hypercapnia stimulated CBF in man and suggest that this effect of the drug is due to inhibition of prostaglandin formation. If so, cerebral vascular PG formation plays an important role not only in the maintenance of CBF during normocapnia, but also in the cerebral vasodilation associated with elevated arterial pCO2.

Changes in brain amino acid uptake and metabolism have been proposed as a possible etiological factor in hepatic encephalopathy. By use of a brain dialysis technique (a thin tube implanted in the brain of the living animal), the extracellular amino acid concentrations in the striatum of portacaval (PC)-shunted and sham-operated rats were measured. Leucine, phenylalanine, methionine, and glutamine were increased two- to sixfold in the PC-shunted rats, whilst no changes were seen for GABA, valine, glutamate, or isoleucine, confirming previous reports. Aspartate levels were 350% higher in the PC-shunted rats, and this rise, as well as that of phenylalanine, was significantly correlated with the lower motor activity observed in the PC-shunted rats, suggesting a possible importance of these amino acids in the etiology of hepatic encephalopathy. The amino acid concentrations measured in whole blood demonstrated the well-known pattern of low levels of branched-chain amino acids and increased concentrations of phenylalanine, glutamine, and histidine.