Kurt Bang

Optic nerve oxygenation.

The oxygen tension of the optic nerve is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The oxygen tension is autoregulated and moderate changes in intraocular pressure or blood pressure do not affect the optic nerve oxygen tension. If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. A disturbance in oxidative metabolism in the cytochromes of the optic nerve can be seen at similar levels of perfusion pressure. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. The risk for progressive optic nerve atrophy in human glaucoma patients is six times higher at a perfusion pressure of 30 mmHg, which corresponds to a level where the optic nerve is hypoxic in experimental animals, as compared to perfusion pressure levels above 50 mmHg where the optic nerve is normoxic. Medical intervention can affect optic nerve oxygen tension. Lowering the intraocular pressure tends to increase the optic nerve oxygen tension, even though this effect may be masked by the autoregulation when the optic nerve oxygen tension and perfusion pressure is in the normal range. Carbonic anhydrase inhibitors increase the optic nerve oxygen tension through a mechanism of vasodilatation and lowering of the intraocular pressure. Carbonic anhydrase inhibition reduces the removal of CO2 from the tissue and the CO2 accumulation induces vasodilatation resulting in increased blood flow and improved oxygen supply. This effect is inhibited by the cyclo-oxygenase inhibitor, indomethacin, which indicates that prostaglandin metabolism plays a role. Laboratory studies suggest that carbonic anhydrase inhibitors might be useful for medical treatment of optic nerve and retinal ischemia, potentially in diseases such as glaucoma and diabetic retinopathy. However, clinical trials and needed to test this hypotheses.

Optic nerve oxygen tension: effects of intraocular pressure and dorzolamide

AIM To investigate the influence of acute changes in intraocular pressure on the oxygen tension in the vicinity of the optic nerve head under control conditions and after intravenous administration of 500 mg of the carbonic anhydrase inhibitor dorzolamide. METHODS Domestic pigs were used as experimental animals. Oxygen tension was measured by means of a polarographic electrode in the vitreous 0.5 mm anterior to the optic disc. This entity is called the optic nerve oxygen tension. Intraocular pressure was controlled by a hypodermic needle inserted into the anterior chamber and connected to a saline reservoir. RESULTS When the intraocular pressure was clamped at 20 cm H2O optic nerve oxygen tension was 20 (5) mm Hg (n=8). Intravenous administration of dorzolamide caused an increase in optic nerve oxygen tension of 43 (8)% (n=6). Both before and after administration of dorzolamide optic nerve oxygen tension was unaffected by changes in intraocular pressure, as long as this pressure remained below 60 cm H2O. At intraocular pressures of 60 cm H2O and below, dorzolamide significantly increased optic nerve oxygen tension. CONCLUSION Intravenous administration of 500 mg dorzolamide increases the oxygen tension at the optic nerve head during acute increases in intraocular pressure.

Dorzolamide Increases Retinal Oxygen Tension after Branch Retinal Vein Occlusion

PURPOSE To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs. METHODS Experimental BRVO was induced by diathermy close to the optic disc. RPO(2) was measured with an oxygen-sensitive electrode 0.5 mm above the BRVO-affected area, which was compared to the retinal areas not affected by BRVO. In one group of five pigs, RPO(2) was measured at baseline, 1 and 3 hours after BRVO, and after intravenous injection of 500 mg dorzolamide. In a second group of five pigs, RPO(2) was measured 1 week after the BRVO, both before and after intravenous injection of 500 mg dorzolamide. RESULTS The average baseline RPO(2) was 2.64 +/- 0.09 kPa (mean +/- SD). In the BRVO-affected areas, RPO(2) decreased significantly (by 0.67 +/- 0.29 and 0.94 +/- 0.13 kPa) at 1 hour and 3 hours after BRVO induction. In the non-BRVO areas RPO(2) increased significantly (by 0.51 +/- 0.14 kPa) 1 hour after BRVO induction, but subsequently decreased and reached baseline 3 hours after BRVO induction. One week after BRVO induction, RPO(2) was 0.67 +/- 0.29 kPa lower in affected areas when compared with the non-BRVO areas. In the BRVO-affected areas, dorzolamide increased RPO(2) significantly (by 0.36 +/- 0.21 kPa at 3 to 4 hours and by 0.67 +/- 0.40 kPa) 1 week after BRVO induction. CONCLUSIONS Retinal hypoxia induced by experimental BRVO remained significant 1 week after BRVO. Dorzolamide increased retinal oxygen tension in the BRVO-affected areas both at 4 hours and 1 week after experimental BRVO in pigs.

Optic nerve oxygen tension: the effects of timolol and dorzolamide

Background/aims: The authors have previously reported that carbonic anhydrase inhibitors such as acetazolamide and dorzolamide raise optic nerve oxygen tension (ONPO2) in pigs. The purpose of the present study was to investigate whether timolol, which belongs to another group of glaucoma drugs called β blockers, has a similar effect. In addition, the effect of dorzolamide and timolol in combination was studied. Methods: Polarographic oxygen electrodes were placed transvitreally over the optic disc in anaesthetised pigs and ONPO2 was recorded continually. Drugs were administered intravenously either as 100 mg timolol followed by 500 mg dorzolamide (n = 5), 500 mg dorzolamide followed by 100 mg timolol (n = 5), or 100 mg timolol and 500 mg dorzolamide given simultaneously (n = 5). Arterial blood pressure, blood gasses, and heart rate were recorded. Results: ONPO2 was unaffected by administration of 100 mg timolol as an intravenous injection (n = 5). Administration of 500 mg dorzolamide by itself significantly increased ONPO2 from 2.96 (SD 0.62) kPa to 3.69 (SD 0.88) kPa (n = 4, p = 0.035). The dorzolamide induced ONPO2 increase was not significantly different from the ONPO2 increases were seen when dorzolamide was administered simultaneous with (n = 5) or 35 minutes (n = 5) after 100 mg timolol. Conclusion: Systemic administration of timolol does not affect the optic nerve oxygen tension despite its lowering effect on the intraocular pressure. Additionally, timolol does not affect the ONPO2 increasing effect of dorzolamide.

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

Background/aims: Prostaglandins are important in blood flow regulation. Carbon dioxide (CO2) breathing and carbonic anhydrase inhibition increase the oxygen tension in the retina and optic nerve. To study the mechanism of this effect and the role of cyclo-oxygenase in the regulation of optic nerve oxygen tension (ONPO2), the authors investigated how indomethacin affects ONPO2 and the ONPO2 increases caused by CO2 breathing and carbonic anhydrase inhibition in the pig. Methods: Optic nerve oxygen tension was measured in 11 pigs with a polarographic oxygen electrode. The tip of the electrode was placed 0.5 mm above the optic disc. The effects of indomethacin, CO2 breathing (3%) before and after indomethacin treatment, and carbonic anhydrase inhibition with or without indomethacin treatment were investigated. Results: Administration of 300 mg indomethacin decreased optic nerve oxygen tension significantly. Carbonic anhydrase inhibition and CO2 breathing increased ONPO2 significantly. After indomethacin had been given, the rise in ONPO2 caused by CO2 breathing and carbonic anhydrase inhibition was significantly reduced. Conclusion: Systemic administration of indomethacin decreases the optic nerve oxygen tension; this is probably the result of decreased blood flow through vasoconstriction of vessels in the optic nerve. Additionally, indomethacin diminishes the ONPO2 increasing effect of CO2 breathing and carbonic anhydrase inhibition, thus affecting the reactivity of vessels in the optic nerve.

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

Aims: We investigated the effect of several Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), on the preoptic nerve oxygen tension (ONPo2), as indomethacin previously has demonstrated a strong decreasing effect on ONPo2. We tested whether these NSAIDs, like indomethacin, also reduce the increasing effect of dorzolamide on ONPo2. Methods: ONPo2 was measured 0.5 mm above the optic disc in 23 domestic pigs (26–36 kg) with a polarographic oxygen-sensitive electrode. One of the following NSAIDs was administered intravenously as increasing doses or as one large dose: indomethacin, ibuprofen, diclofenac, ketoprofen, parecyclo-oxygenase-2 inhibitor and lornoxicam. Indomethacin was both tested alone and after preceding administration of the other NSAIDs. Dorzolamide was also tested after preceding administration of NSAIDs different from indomethacin. Results: Indomethacin decreased ONPo2 significantly in a dose-dependent manner. None of the other NSAIDs produced any effect on the ONPo2 (p>>0.05; n = 17). No difference was found between the effect of indomethacin injected alone, and after preceding administration of the other NSAIDs. Intravenous dorzolamide (500 mg) increased ONPo2 by 32 (7)% (n = 7; p<0.001) after preceding administration of several NSAIDs different from indomethacin. Conclusions: Indomethacin decreased ONPo2, while the other NSAIDs showed no effect on ONPo2, and they did not affect the effect of indomethacin. The hypoxic effect of indomethacin must be due to another mechanism than cyclo-oxygenase inhibition. The effect of dorzolamide on ONPo2 is not related to prostaglandin production.