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

Abstract

Summary: Indomethacin is known to attenuate quite markedly the increase in CBF during hypercapnia. Hy percapnia is, in all likelihood, mediated by the acid shift at the level of the smooth muscle cells of the cerebral arterioles. We therefore investigated the effect of indo methacin on the CBF increase caused by acetazolamide (Az) , a drug that induces brain extracellular acidosis, which triggers its effect on CBF. We compared the results to the inhibitory effect of indomethacin on the CBF in crease during hypercapnia. Indomethacin but not di clofenac, another potent cyclooxygenase inhibitor, wasThe effect of indomethacin, an inhibitor of cyclo oxygenase, on hypercapnic cerebral vasodilation has been intensively investigated over the last de cade. 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. 724found to block almost completely the CBF increase caused by Az-induced extracellular acidosis or by CO2, but it did not influence the CBF increase produced by sodium nitroprusside or papaverine. The results suggest that indomethacin exerts its action on CO2 reactivity by a nonprostaglandin-mediated mechanism that directly in terferes with the regulation of cerebrovascular tone me diated by extracellular pH.

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. 24 Indomethacin may therefore change the vessel reactivity through affecting other processes than the prostaglandin synthesis, 27 but it may also be a more potent drug in inhibiting cyclo-oxygenase.…”

“…A similar effect of indomethacin on CAI reactivity has been reported in rat cerebral vessels. 11 Since indomethacin reduced the ONPO 2 increase induced by both CO 2 breathing and carbonic anhydrase inhibition and since both of these manipulations cause CO 2 , accumulation it is likely that the effect of carbonic anhydrase inhibition on ONPO 2 is caused by the effect of CO 2 accumulation.…”

“…The effects of different kinds of NSAIDs have been investigated, and the results have been contradictory. 11 21 24 25 Further investigations are needed to clarify whether other NSAIDs have the same effect as indomethacin and also if the drugs orally or topically administered affect optic nerve oxygen tension.…”

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

“…We then tested the properties of the extended model equation by calculating the magnitude of the equation parameters, which would accurately predict the values of oxygen consumption measured in the course of drug-induced lowering of CBF. We used indomethacin, which lowers blood flow, probably by nonselectively inhibiting cyclooxygenase-1 (COX-1) and -2 (Jensen et al, 1991(Jensen et al, , 1993Dahl et al, 1996;Imberti et al, 1997;Zonta et al, 2003), although other mechanisms have also been proposed (Wang et al, 1993;Parfenova et al, 1995).…”

Acetazolamide Reactivity on 123I-IMP Single Photon Emission Computed Tomography in Patients with Major Cerebral Artery Occlusive Disease: Correlation with Positron Emission Tomography Parameters

“…It was reported that the vasodilatation is mediated by inhibition of carbonic anhydrase, which is localized in the brain and circulating red blood cells (Posner and Plum, 1960;Maren, 1967Maren, , 1977. Acetazolamide induces a local extracellular acidosis in the brain that triggers an increase in CBF as CO 2 does (Wang et al , 1993). Because acetazolamide reactivity does not directly represent the pressure autoregulation, but instead represents chemical vasodilatatory capacity, SPECT studies with an acetazolamide challenge may not be adequate to detect hemodynamic fail ure.…”