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 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.

Indomethacin lowers optic nerve oxygen tension and reduces the effect of carbonic anhydrase inhibition and carbon dioxide breathing

“…21 25 Also diclofenac does not decrease the cerebral blood flow in rats while ibuprofen does. 11 Ibuprofen decreases pial vessel diameter in newborn pigs but does not affect the CO 2 reactivity of these vessels.…”

Indomethacin Abolishes Cerebral Blood Flow Increase in Response to Acetazolamide-Induced Extracellular Acidosis: A Mechanism for its Effect on Hypercapnia?

“…The substance almost completely blocks the increase in CBF caused by hypercapnia in several species including rat (Sakabe and Siesj6, 1979;Dahlgren et al, 1981;Quintana et al, 1988). How ever, experimental evidence argues against a pros taglandin-mediated mechanism since several other inhibitors of cyclic oxygenase, including diclofenac, do not duplicate the effects of indomethacin (Pick ard et al, 1977;Amano and Meyer, 1981;Eriksson et al, 1983;Quintana et al, 1988), and since hyper capnia is not associated with altered prostaglandin production (Ellis et al, 1982;Eriksson et al, 1983;McCalden et al, 1984). The mechanism of the strik- Abbreviation used: Az, acetazolamide.…”

Is Indomethacin Harmful in Spinal Cord Injury Treatment?

“…Experimental [44, 49, 50]and clinical [55]studies show that IND causes reduction of cerebral blood flow while cerebral metabolism remains unchanged, and that it reduces the formation of cerebral edema. The inhibition of oxygen radical generation by IND may be exerting its beneficial effect either via the prevention of vascular damage which leads to edema or other forms of permeability change [46, 47, 48, 52, 56, 57, 58, 59, 60]. Some authors suggested that cell damage following ischemia or SCI was induced by free-radical reaction and lipid peroxidation [54, 61, 62, 63].…”