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 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 pH and PO2: the effects of carbonic anhydrase inhibition, and metabolic and respiratory acidosis.

PURPOSE: Earlier studies have demonstrated that carbonic anhydrase inhibitors (CAIs) increase optic nerve oxygen tension (ONPO(2)) in pigs. We hypothesized that the mechanism of this effect was either a CO(2) increase or a pH decrease in tissue and blood. To test this hypothesis we investigated and compared how optic nerve pH (ONpH) and ONPO(2) are affected by: (1) carbonic anhydrase inhibition; (2) respiratory acidosis, and (3) metabolic acidosis. We measured ONpH with a glass pH electrode and ONPO(2) with a polarographic oxygen electrode. One of the electrodes was placed in the vitreous cavity 0.5 mm over the optic nerve in the eyes of domestic pigs. METHODS: We measured ONpH during carbonic anhydrase inhibition and ONpH or ONPO(2) during NH(4)Cl-induced metabolic acidosis and during CO(2) breathing (respiratory acidosis). RESULTS: Baseline ONpH was 0.12 +/- 0.06 lower than arterial pH (mean +/- SD, n = 10, p < 0.001). Optic nerve pH decreased with arterial pH during carbonic anhydrase inhibition, metabolic and respiratory acidosis. Optic nerve oxygen tension was not affected by metabolic acidosis but increased during CO(2) breathing, as it has been shown to do during carbonic anhydrase inhibition. CONCLUSIONS: There is a close correlation between arterial blood pH and intraocular pH. Isolated ONpH changes do not affect ONPO(2), thus the ONPO(2) increase seen with carbonic anhydrase inhibition is probably not only due to pH changes in the blood and optic nerve. Accumulation of CO(2), either alone or in combination with a pH change, is likely to cause the ONPO(2) increase, but a direct vascular effect should also be considered.

Carbonic anhydrase inhibition increases retinal oxygen tension and dilates retinal vessels.

BACKGROUND: Carbonic anhydrase inhibitors (CAIs) increase blood flow in the brain and probably also in the optic nerve and retina. Additionally they elevate the oxygen tension in the optic nerve in the pig. We propose that they also raise the oxygen tension in the retina. We studied the oxygen tension in the pig retina and optic nerve before and after dorzolamide injection. Also the retinal vessel diameters during carbonic anhydrase inhibition were studied. METHODS: A polarographic oxygen electrode was placed transvitreally immediately over the retina or the optic disc in anaesthetised pigs. The oxygen tension was recorded continually and 500 mg dorzolamide was injected intravenously. Retinal vessel diameters were analysed from monochromatic fundus photographs taken before and after injection of dorzolamide. RESULTS: Baseline retinal oxygen tension (RPO2) was 3.34+/-0.50 kPa (mean +/- SD, n=6) and baseline optic nerve oxygen tension (ONPO2) was 3.63+/-1.00 kPa. RPO2 was increased by 0.36+/-0.11 kPa (n=6, P=0.025) and ONPO2 by 0.73+/-0.34 kPa (n=6, P=0.003) 30 min after dorzolamide administration. The retinal arterioles was significantly dilated by 13+/-7% (n=5, P=0.016) and the retinal venules by 12+/-8% (n=5, P=0.030) 30 min after injection of dorzolamide. CONCLUSION: Retinal and optic nerve oxygen tension increased with systemic administration of dorzolamide. The retinal vessels dilated, probably causing increased blood flow inducing the observed increase in RPO2. The increased oxygenation of retina by CAI may offer therapeutic possibilities in ischaemic diseases of the retina and optic nerve.

Dorzolamide induces vasodilatation in isolated pre-contracted bovine retinal arteries.

The effect of the carbonic anhydrase inhibitor dorzolamide on vascular smooth muscle in pre-contracted bovine retinal arteries was examined. Ring segments of retinal arteries were placed in a small vessel myograph for measurement of contractile activity. The arteries were placed in a physiological saline solution. Vasoconstriction was induced by either 124 mM KCl (0.90 +/- 0.46 mN, n=34), 10(-4) M prostaglandin F2alpha (1.72 +/- 0.84 mN, n=10) or 10(-6) M norepinephrine (0.78 +/- 0.47 mN, n=6). Both KCl and prostaglandin F2alpha caused steady repeatable contractions but norepinephrine caused a single phasic contraction. The effect of the carbonic anhydrase inhibitor, dorzolamide on the vasoconstriction was examined. Dorzolamide, if added to the bath when the vasoconstriction had reached a maximum steady level, caused a highly significant relaxation (vasodilatation) of the arteries. This action of dorzolamide occurred irrespective of which agent was used to induce vasoconstriction. Similar results were obtained in experiments were Hepes buffer was used instead of CO2/bicarbonate buffer. The vasodilatation induced by dorzolamide was stable as long as the drug remained in the bath, and was reversible. These results show that dorzolamide causes a vasodilatation of retinal arteries, pre-contracted by three different mechanisms by direct action and presumably independent of changes in extracellular pH.