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 three different prostaglandin (PG) synthesis inhibitors–aspirin, indomethacin and naproxen–on the basal and CO 2 ‐stimulated cerebral blood flow (CBF) was studied in healthy subjects, using the N 2 O wash‐in technique for assessment of CBF. The regional O 2 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 (PGI 2 ) 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 PGI 2 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 O 2 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 CO 2 , no release of AA, other FFA or PGI 2 metabolites occurred in untreated subjects. In subjects given indomethacin there was a small but significant release of AA during inhalation of CO 2 . Both acute and chronic administration of aspirin failed to affect the CO 2 ‐induced elevation of CBF, whereas both forms of indomethacin administration significantly reduced this rise. Chronic administration of naproxen did not affect the CO 2 ‐induced increase in CBF. We conclude that in healthy subjects: 1) local PGI 2 production does not appear to be involved in the regulation of cerebral blood flow: 2) indomethacin reduces basal and CO 2 ‐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.