Effect of Indomethacin on the Hypercapnia-Associated Vasodilation of the Optic Nerve Head Vessels: An Experimental Study in Miniature Pigs

Abstract

Purpose: To evaluate whether prostaglandins are mediators of the hypercapnia-associated vasodilation of the optic nerve head vessels. Methods: We measured the PO₂ at intervascular areas of the optic disc in 9 anaesthetized miniature pigs using oxygen-sensitive microelectrodes placed at <50 µm from the optic disc. PO₂ was measured continuously under normoxia, hyperoxia (breathing of 100% O₂), carbogen breathing (95% O₂, 5% CO₂), and hypercapnia (40% increase in inhaled CO₂). Similar measurements under these conditions were also done after intravenous administration of the prostaglandin inhibitor indomethacin. Results: Before the injection of indomethacin, we observed a slight increase in the optic disc PO₂ during hypercapnia (ΔPO₂ = 2.0 ± 1.7 mm Hg; p < 0.001; n = 18) or hyperoxia (ΔPO₂ = 3.4 ± 1.6 mm Hg; p < 0.001; n = 23), but a much more important increase during carbogen breathing (ΔPO₂ = 12.0 ± 5.1 mm Hg; p < 0.001; n = 23). After the injection of indomethacin, the increase in the optic disc PO₂ was similar during hyperoxia (ΔPO₂ = 5.6 ± 2.2 mm Hg; p < 0.001; n = 9) or carbogen breathing (ΔPO₂ = 5.8 ± 3.2 mm Hg; p < 0.001; n = 9), while in hypercapnia the variation of the optic disc PO₂ was minimal (ΔPO₂ = 0.5 ± 1.9 mm Hg; p > 0.1; n = 6). Conclusions: Indomethacin inhibits the vasodilatory effect of increased systemic PaCO₂ on the optic nerve head vessels, leading to a similar moderate increase in the optic disc PO₂ during carbogen breathing as in hyperoxia. Indomethacin also inhibits the increase in the optic disc PO₂ seen during hypercapnia. Those results indicate that prostaglandins are mediators of the hypercapnia-associated vasodilation of the optic nerve head vessels.

Retinal Oxygen Metabolism During Normoxia and Hyperoxia in Healthy Subjects

“…[3][4][5][6] Although several animal studies 3,4 were directed toward oxygen metabolism in different species, little is known about the situation in humans. Most of the available techniques such as microelectrodes [7][8][9][10][11][12] and phosphorescence quenching 13 cannot be applied in humans because of their invasive character.…”

Indomethacin decreases optic nerve oxygen tension by a mechanism other than cyclo-oxygenase inhibition

“…Through its effect on the COX enzyme, indomethacin is a powerful inhibitor of the synthesis of prostanoids, and the drug is widely used experimentally as a typical COX inhibitor 5 13 14. Prostanoids, among them 6-ketoprostaglandin F1 α , are important vasodilators that have been implicated in the cerebral and ocular vascular response to CO 2 and carbonic anhydrase inhibition.…”

Effect of Systemic Nitric Oxide Synthase Inhibition on Optic Disc Oxygen Partial Pressure in Normoxia and in Hypercapnia

“…Under systemic normoxia (PaO 2 ϭ 103.6 Ϯ 17.9 mm Hg; PaCO 2 ϭ 35.4 Ϯ 2.4 mm Hg; pH ϭ 7.47 Ϯ 0.04; n ϭ 12), mean optic disc PO 2 recorded in intervascular areas of 12 eyes was 18.3 Ϯ 4.0 mm Hg, a level similar to those described previously in minipigs. 10,11,17,21 Measurements under Systemic Hyperoxia (100% O 2 ). The inhalation of 100% O 2 induced a mean increase in optic disc PO 2 of ⌬PO 2 ϭ 3.9 Ϯ 1.6 mm Hg, or 22% (n ϭ 11; Fig.…”

“…As a result, inhalation of CO 2 increases preretinal 16 and optic disc PO 2 . 17 In addition, inhalation of carbogen (95% O 2 , 5% CO 2 ), which increases both PaO 2 and PaCO 2 , also increases preretinal, 18,19 inner retinal, 20 and optic disc PO 2 , 21 since the vasodilatory effect of elevated PaCO 2 partially counterbalances the vasoconstriction induced by elevated PaO 2 . Elevated PaCO 2 increases tissue PO 2 through a dual mechanism: a rightward shift of the oxyhemoglobin dissociation curve, 22 which enhances oxygen release from hemoglobin (the Bohr effect), as well as a CO 2induced arteriolar vasodilation.…”

“…13 Thus, a CO 2 -induced PO 2 increase has been demonstrated at the level of the ONH. 17,21 Nitric oxide (NO) has been reported to control CO 2 -induced vasodilation in the cerebral 23 and the retinal circulation. 24 NO is constitutively synthesized from L-arginine by two isoforms of NO synthase (NOS): endothelial NOS, expressed in vascular endothelial cells 25 and in some neurons, 26 and neuronal NOS, expressed only in neurons.…”