Effect of prostaglandin synthesis inhibitors on basal and carbon dioxide stimulated cerebral blood flow in man

Abstract

The effect of acute and chronic administration of 3 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 2 prostacyclin (PGI2) metabolites, were also measured. The efficacy of cyclooxygenase 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 times daily). Indomethacin (1.5 mg/kg) significantly (P < 0.05) reduced CBF after acute administration, but after 1 wk treatment (0.8 mg/kg 3 times daily) this effect had disappeared. Acute administration of naproxen (4 mg/kg) did not affect O2 extraction over the brain, indicating that CBF was unchanged. After chronic administration, naproxen (4 mg/kg 2 times 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. Evidently, in healthy subjects: local PGI2 production does not appear to be involved in the regulation of cerebral blood flow, indomethacin reduces basal and CO2-stimulated CBF, an effect not shared by the other structurally unrelated cyclooxygenase inhibitors: and 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.