Differential effect of three cyclooxygenase inhibitors on human cerebral blood flow velocity and carbon dioxide reactivity.

Abstract

Prostaglandins are believed to play an important role in maintenance of cerebral blood flow and possibly in the vasodilatory response to carbon dioxide. Therefore, the nonsteroidal anti-inflammatory drugs and aspirin, which inhibit cyclooxygenase, might be expected to reduce cerebral blood flow and the response to hypercapnia. This could induce cerebral ischemia in patients with a hemodynamically critical circulation. It would also interfere with the measurement of cerebrovascular reserve using carbon dioxide. The effect of a single dose of indomethacin and of two other cyclooxygenase inhibitors (aspirin and sulindac) on the cerebral circulation was measured using transcranial Doppler ultrasonography of the middle cerebral artery. Seven normal adults were studied in each drug group. Resting blood flow velocity and the responses to hypercapnia and to hyperventilation were measured. Indomethacin resulted in a fall in basal middle cerebral artery flow velocity from a mean of 48.9 cm/s to 34.0 cm/s (P < .002). It also reduced the vasoconstrictor response to hypocapnia (induced by hyperventilation) from 37.5% to 20.7% (P < .003). There was a nonsignificant reduction in the vasodilatory response to 8% carbon dioxide (mean: predrug, 87.7%; postdrug, 61.0%), with marked intersubject variability. In contrast, basal middle cerebral artery velocity and vasoconstrictor and vasodilatory responses to changes in carbon dioxide were unchanged after aspirin or sulindac administration. The lack of effect of aspirin on basal cerebral blood flow velocity and on vasodilatory reserve is reassuring; aspirin will not reduce cerebral blood flow or the response to a reduced perfusion pressure in patients with critically impaired cerebral hemodynamics. However, indomethacin should be avoided in such patients.

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.…”

“…The blood flow decreasing effect of indomethacin lasts for at least 150 minutes in the human brain. 21 Systemic administration of indomethacin also decreases cerebral blood flow in rabbits, 1 rats, 22 newborn pigs, 23 24 and humans. 21 25 However, Cuypers et al did not find this effect in the rabbits they examined.…”

COX-1 and COX-2 Contributions to Basal and IL-1β-Stimulated Prostanoid Synthesis in Human Neonatal Cerebral Microvascular Endothelial Cells

“…Data on adult humans, as infants, is very limited, but with regard to effects of COX inhibitors, responses are similar to those from juvenile pigs (and adult rats). Thus, indomethacin typically reduces cerebral hyperemia in response to hypercapnia by 50% or less, much less than in newborns (30,31). Overall, constitutive expression of COX-2 appears to be a specific characteristic of human tissues.…”

Mode of Administration-Dependent Brain Uptake of Indomethacin: Sustained Systemic Input Increases Brain Influx

“…A well known and documented adverse effect of indomethacin is the contraction of blood vessels supplying blood into the brain, resulting in hypoperfusion to brain tissue (McCulloch et al, 1982;Markus et al, 1994). Hence, high blood levels of the drug can induce this brain hypoperfusion, resulting in decrease in the transport of indomethacin from the blood into the brain.…”