The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tensions

Abstract

The effect of the fatty acid cyclo-oxygenase inhibitor indomethacin on cerebral blood flow (CBF) and the metabolic rate for oxygen (CMRO2) was studied in paralyzed and artificially ventilated rats. In normocapnic animals, the drug (10 mg.kg-1i.v.) reduced CBF to 50% of control without a measurable effect on CMRO2. During hypercapnia (PaCO2 70-80 mmHg) the increase in CBF was reduced by about 80% but CMRO2 remained unchanged. Autoradiographic evaluation of local CBF in 20 brain structures indicated that the reduction in CBF was relatively uniform throughout the brain. Dose response curves showed that an effect on CBF was evident already at an indomethacin dose of 1 mg.kg-1 and maximal effects were obtained with 3-5 mg.kg-1. Following i.v. injection of the drug reduction in CBF was observed already after 10 s and the full response occurred after 1-2 min. It is concluded that metabolites of arachidonic acid, possibly mainly prostacyclin, are powerful modulators of normal cerebrovascular tone, and help to mediate the CBF response to increased CO2 tensions. However, since indomethacin does not modify the circulatory response in other conditions with increased CBF these substances do not qualify as general coupling factors controlling CBF in physiological or pathological states.

Effects of Indomethacin on Cerebral Blood Flow and Oxygen Consumption in Barbiturate-Anesthetized Normocapnic and Hypercapnic Rats

“…As stated, all studies have shown that indomethacin reduces CBF at constant CMR02. However, in spection of the present data, and those reported by Dahlgren et al (1981), shows that in all groups studied (normo-and hypercapnic animals), the mean value for CMR02 was lower in indomethacin treated animals. In order to test the possibility that a true decrease in CMR02 remained undetected due to the small groups studied, we calculated all individ- The second and controversial issue referred to concerns the effect of hypercapnia on CMROz.…”

“…A similar reduction in CO2 sensitivity has been noted in the baboon, in which chloralose anesthesia (as compared to Sernylan anesthesia) reduced both CMR02 and the CO2 responsiveness (Sandor et aL, 1977). It is clear that the CO2 responsiveness, so calculated, is reduced by indomethacin, although the drug does not decrease CMR02 significantly (Pickard and MacKenzie, 1973;Sakabe and Siesj6, 1979;Dahlgren et aL, 1981).…”

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

“…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.…”

Cerebral Metabolic Response to Low Blood Flow: Possible Role of Cytochrome Oxidase Inhibition

“…Previous animal studies of the effects of indomethacin on CMR O 2 gave conflicting results of no change (Dahlgren et al, 1981;Pickard and MacKenzie, 1973) or reduction (Nowicki et al, 1987). The only tomographic study on living animals (Schumann et al, 1996), found no change of the global CMR O 2 but interestingly (see below) a small and significant increase of CMR O 2 in thalamus and pons.…”