October 1999
Volume 40, Issue 11
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Physiology and Pharmacology  |   October 1999
Optic Nerve Oxygen Tension in Pigs and the Effect of Carbonic Anhydrase Inhibitors
Author Affiliations
  • Einar Stefánsson
    From the Department of Ophthalmology, University of Iceland; the
  • Peter Koch Jensen
    Eye Department, National University Hospital of Copenhagen, and
  • Thor Eysteinsson
    From the Department of Ophthalmology, University of Iceland; the
  • Kurt Bang
    MSD Glostrup, Denmark.
  • Jens F. Kiilgaard
    Eye Department, National University Hospital of Copenhagen, and
  • Jens Dollerup
    MSD Glostrup, Denmark.
  • Erik Scherfig
    Eye Department, National University Hospital of Copenhagen, and
  • Morten la Cour
    Eye Department, National University Hospital of Copenhagen, and
Investigative Ophthalmology & Visual Science October 1999, Vol.40, 2756-2761. doi:
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      Einar Stefánsson, Peter Koch Jensen, Thor Eysteinsson, Kurt Bang, Jens F. Kiilgaard, Jens Dollerup, Erik Scherfig, Morten la Cour; Optic Nerve Oxygen Tension in Pigs and the Effect of Carbonic Anhydrase Inhibitors. Invest. Ophthalmol. Vis. Sci. 1999;40(11):2756-2761.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. To evaluate how the oxygen tension of the optic nerve (ONPo 2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture.

methods. Polarographic oxygen electrodes were placed in the vitreous humor immediately over the optic disc in 20 anesthetized pigs. Blood gasses and cardiovascular physiology were monitored. ONPo 2 was recorded continuously with breathing gasses of 21% O2-79% N2, 100% O2, 20% O2-80% N2, and 5.19% CO2-19.9% O2-74.9% N2. Acetazolamide (15–1000 mg) and dorzolamide (6–1000 mg) were administered intravenously.

results. The mean (± SD) ONPo 2 was found to be 24.1 ± 11.6 mm Hg when the pigs were breathing room air and 50.7 ± 29.3 mm Hg when they were breathing 100% O2 (n = 15; P < 0.001). In response to breathing 5.19% CO2, ONPo 2 changed from 20.8 ± 5.6 mm Hg (with 20.0% O2) to 28.9 ± 3.6 mm Hg (n = 4; P < 0.001). Intravenous injections of 500 mg dorzolamide increased ONPo 2 from 16.4 ± 6.1 mm Hg to 26.9 ± 12.2 mm Hg, or 52.5% ± 21.2% (n = 5; P = 0.017). A dose-dependent effect on ONPo 2 was seen with intravenous dorzolamide doses of 1000, 500, 250, 125, 63, 27, 15, and 6 mg. Intravenous injections of 500 mg acetazolamide increased ONPo 2 from 23.6 ± 9.5 mm Hg to 30.9 ± 10.0 mm Hg (n = 6; P < 0.001), and a dose-dependent effect was seen with doses of 1000, 500, 250, 125, 31, and 15 mg.

conclusions. ONPo 2 is significantly increased by the carbonic anhydrase inhibition of dorzolamide and acetazolamide, and the effect is dose dependent. These data demonstrate for the first time a direct effect of carbonic anhydrase inhibitors on ONPo 2.

Studies of optic nerve oxygen tension (ONPo 2) go back to Ernest in 1973, 1 and several investigators have reported on ONPo 2 in a number of species. 2 3 4 Novack et al. 5 studied the oxidative metabolism of cytochromes in the optic nerve in the cat and found it to be sensitive to arterial blood pressure, intraocular pressure, and oxygen. Cranstoun et al. 6 reported intra- and extravascular oxygen tension measurements in the pig optic nerve. 
In the brain, systemically administered acetazolamide leads to increased cerebral blood flow. 7 Rassam et al. 8 found that intravenous acetazolamide increased retinal blood flow, whereas Grunwald and Zinn 9 found no effect of oral acetazolamide on macular blood flow evaluated with the blue-field entoptic technique. Harris et al. 10 reported that the application of one drop of 2% dorzolamide decreased arteriovenous transit time and increased the velocity of fluorescent particles in the paramacular and peripapillary microcirculations, whereas no effect was seen on flow velocity in the retrobulbar vessels. In contrast, Grunwald et al. 11 found no significant change in the hemodynamic parameters of the retinal circulation after application of topical dorzolamide. Although the results of blood flow studies are not all in agreement, perhaps because of differences in method, they suggest that blood flow, and consequently oxygen delivery, may be affected in the optic nerve region in association with carbonic anhydrase inhibition. 7 8 9 10 11  
The purpose of this study was to develop an experimental preparation suitable for studying ONPo 2 and to examine how it is affected by drugs such as carbonic anhydrase inhibitors and physiologic conditions such as inspiration of oxygen and carbon dioxide. 
Materials and Methods
Danish agricultural pigs (Landrace), 25 to 33 kg in weight and brought up in a specific pathogen-free environment, were used. Their treatment was supervised by a veterinarian and followed the decrees of the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. All experiments were conducted during daytime. 
Animal Preparation
The pigs were anesthetized with midazolam and ketamine, followed by intravenous application of 250 mg mebumal, with additional dosages as needed throughout the experiment, and 0.5 mg/h fentanylum, and atropine as needed. The pigs were paralyzed using 16 mg an hour pancuron bromide. They were intubated and automatically ventilated (model MCM-801; Dameca, Copenhagen, Denmark). The respiratory frequency and stroke volume were kept constant during the experiments. The right pupil was dilated with 1% tropicamide eye drops and 2.5% phenylephrine eye drops. An arterial catheter was placed in a femoral artery for continuous measurement of blood pressure and intermittent blood gas analysis. A venous catheter was placed in a femoral vein for continuous infusion of the anesthetics and saline as needed and the injection of the study drugs. A rectal thermoprobe provided a continuous reading of body temperature. 
The pig was secured with surgical tape laterally on an operating table, and a speculum was placed between the right eyelids. A conjunctival peritomy was performed and 3-0 silk sutures placed under the rectus muscle tendons to immobilize the eye. A sclerotomy was made 2.5 mm behind the limbus in the superonasal quadrant and a cannula placed, through which the polarographic electrode was advanced into the vitreous cavity. 
Oxygen Measurements
The electrode was held in a micromanipulator (Stoelting, Chicago, IL) and placed in the vitreous humor approximately 0.5 mm (one half the width of the electrode probe) over the optic disc in an area not covered by the large vessels. The entire operation was performed using an operating microscope (Carl Zeiss; Oberkochen, Germany), and the electrode was placed using an indirect ophthalmoscope or the microscope and a flat corneal contact lens. The location of the electrode was checked repeatedly using the indirect ophthalmoscope during the experiment. The placement of the electrodes was found to be stable, and readjustment was rarely necessary. 
A silver-silver chloride reference electrode was placed in the conjunctival sac of the same (right) eye and kept moist with saline. The polarographic oxygen meter consists of a 100-μm platinum-iridium electrode inside a 20-gauge needle (model 761; Diamond Electrotech, Ann Arbor, MI), a silver-silver chloride reference electrode, and a chemical microsensor (model 1251; Diamond Electrotech). The recording system was calibrated before and after each experiment in a calibration cell (Diamond Electrotech) at 37°C in 0.9% saline using 100% N2, 5.0% O2-95% N2, and 20% O2-80% N2 (provided by AGA, Copenhagen, Denmark). 12 The barometric pressure was monitored, and the oxygen tension recordings were adjusted for barometric pressure and expressed as mm Hg. 
The experiments were all run with typical indoor illumination (white fluorescent light tubes (TLM 40W/29RS; Philips, Eindthoven, The Netherlands). The ambient light intensity at the level of the pig’s eye was measured with a digital light meter (Mavolux; Gossen, Ehrlangen, Germany) and found to be 497 lux or 6 W/m2
Arterial blood samples were obtained at regular intervals, and arterial partial oxygen pressure (Po 2), pH, and arterial partial carbon dioxide pressure (Pco 2) were measured with a blood gas analyzer (model 605 Radiometer, ABL, Copenhagen, Denmark) (Table 1) . Arterial blood pressure, electrocardiogram, and rectal temperature were monitored continuously, and it was verified that these values were within normal limits. The output of the Po 2 amplifier, together with continuous recordings of arterial blood pressure and the electrocardiogram, was digitized on-line with an analog-to-digital converter (MacLaboratory 4/e; ADInstruments, Melbourne, Australia). The digitized recordings were fed into a computer (Power Macintosh; Apple; Cupertino, CA). Data were displayed and analyzed with the software provided (Chart ver. 3.5.4/s; ADInstruments) and printed (LaserWriter II; Apple). 
Experimental Protocol
Each experiment was begun with the animal breathing 100% O2. Once a stable ONPo 2 level was obtained, the breathing mixture was changed to air containing 21% O2-79% N2, and a stable level was obtained again. In four experiments the breathing mixture was changed to 20% O2 followed by 5.19% CO2-19.9% O2-74.9% N2, followed by 20% O2-80% N2
The test drug, dorzolamide (MSD, Glostrup, Denmark) (4%, 6–500-mg doses) or acetazolamide (Diamox, Wyeth Lederle Nordiska, Solna, Sweden) (15–500 mg) were injected intravenously into the femoral venous catheter. Dorzolamide was dissolved in 0.1 M sodium citrate buffer (pH 5.6). Acetazolamide was dissolved in saline. In some cases repeated injections of 500 mg dorzolamide and acetazolamide were performed to evaluate the effect of 1000 mg of each drug and whether the effect could be saturated. Intravenous control injections of 20 ml physiological saline and sodium citrate buffer were performed while ONPo 2 was monitored. 
In three experiments the intraocular pressure was fixed at 20 cm saline (15 mm Hg) with a needle in the anterior chamber connected to a saline reservoir, and recorded with a pressure transducer, whereas dorzolamide was injected intravenously and ONPo 2 recorded. Means and SDs were calculated and differences evaluated with a paired Student’s t-test. 
Results
The Effect of Inhaled O2 and CO2
Stable recordings of ONPo 2 could be obtained reliably for up to 8 hours. The mean ONPo 2 was 24.1 ± 11.6 mm Hg when the pigs were breathing air and 50.7 ± 29.3 mm Hg when they were breathing 100% O2 (n = 15; P < 0.001). Figure 1 shows an experiment in which the animal first inhaled 100% O2. When the oxygen content was reduced to 20% O2, there was an immediate reduction in ONPo 2
In response to breathing 5.19% CO2-19.9% O2 (N2 to balance), ONPo 2 changed from 20.8 ± 5.6 mm Hg to 28.9 ± 3.6 mm Hg (n = 4; P < 0.001). An example of this increase in ONPo 2 is illustrated in Figure 1 , which also shows that almost immediately after returning to 20% O2-80% N2, ONPo 2 returned to its value before CO2 was administered. As shown in Table 2 , breathing CO2 significantly lowered arterial pH and also increased arterial Pco 2, but had no significant effect on arterial Po 2
The Effects of Carbonic Anhydrase Inhibition
Intravenous injections of 500 mg dorzolamide increased ONPo 2 from 16.4 ± 6.1 mm Hg to 26.9 ± 12.2 mm Hg, or 52.5% ± 21.2% (n = 5; P = 0.017; Fig. 2 A). As shown in Table 2 , dorzolamide significantly lowered arterial pH, and also increased arterial Pco 2, but had no significant effect on arterial Po 2. The effect of dorzolamide on ONPo 2 was dependent on the dose injected and was seen with dosages of 1000, 500, 250, 125, 63, 27, 15, and 6 mg (Fig. 3) . Most of the effect of dorzolamide was reached at 500 to 1000 mg total dosage, and additional injections of the drug had only a small effect on ONPo 2. Control intravenous injections of 20 ml of the vehicle sodium citrate buffer solution alone had no effect on ONPo 2 in three experiments. 
Intravenous injections of 500 mg acetazolamide increased ONPo 2 from 23.6 ± 9.5 mm Hg to 30.9 ± 10.0 mm Hg (n = 6; P = 0.0008). Figure 2B shows a typical response to intravenous injection of acetazolamide. This effect on ONPo 2 was also seen after injections of 250, 125, 31, and 15 mg acetazolamide and with 1000-mg dosages administered in two equal doses (Fig. 3) . Control intravenous injections of 20 ml saline had no effect on ONPo 2. As indicated in Table 2 , 500 mg acetazolamide significantly lowered arterial pH and also increased arterial Pco 2, but had no significant effect on arterial Po 2. Additional injections of 500 and 1000 mg acetazolamide had little further effect on ONPo 2 after initial administration of 1000 mg acetazolamide, indicating that a maximum effect had been reached by the injections first administered. The effects of acetazolamide and dorzolamide on ONPo 2 were dose dependent, and dorzolamide was more potent, as illustrated in Figure 3 . The effect of dorzolamide injections on ONPo 2 was also present when the intraocular pressure was fixed at 15 mm Hg. 
Discussion
The discovery that the carbonic anhydrase inhibitors dorzolamide and acetazolamide markedly and significantly elevated ONPo 2 offers for the first time clear evidence that these drugs have a direct effect on ONPo 2
The effects of dorzolamide and acetazolamide on ONPo 2 were dose dependent. The effect was seen over a dosage range from 1000 mg down to 6 mg for dorzolamide and 1000 to 15 mg for acetazolamide. Lower doses were not tested. The effects were saturated by injection of 500 to 1000 mg of either drug, probably because these dosages fully inhibited carbonic anhydrase. However, breathing carbon dioxide further increased ONPo 2 after a saturation dose of carbonic anhydrase inhibitor had been applied. 
In Figure 3 the dose–response pattern is shown as the relationship between the dose of drug in millimoles in each pig and ONPo 2 response. Molecule for molecule, dorzolamide has roughly three times the effect of acetazolamide. Sugrue et al. 13 found dorzolamide to be approximately twice as effective as acetazolamide in inhibiting carbonic anhydrase isoenzyme IV and almost 19 times as effective in inhibiting isoenzyme II, whereas acetazolamide is more effective in inhibiting isoenzyme I. This suggests that carbonic anhydrase isoenzyme IV may be involved in this process. 
Our data clearly demonstrate the dose dependency of the oxygen tension effect; we recorded an effect at 6 mg dorzolamide. Maren et al. 14 found an effective daily dose of 2% dorzolamide in both eyes three times a day to be 4 mg, because the red blood cells accumulate the drug over a period of days. Sugrue 15 reported that topically applied dorzolamide reaches the retina in pigmented rabbits and that the retinal concentration is approximately 5 μg/g. In contrast, Conroy 16 suggested that topically applied sulfonamides penetrate poorly into the back of the eye and may reach the retina and optic nerve through blood circulation. 
The effect of dorzolamide on ONPo 2 is independent of the intraocular pressure–lowering effect of the drug. Even when the intraocular pressure is clamped at 15 mm Hg, the oxygen tension effect is still present. Elevated intraocular pressure can lower ONPo 2 in the pig. 17 Carbonic anhydrase inhibitors such as dorzolamide may increase ONPo 2 through a dual mechanism: lowering of intraocular pressure and a direct effect on ONPo 2
The vasculature of the pig optic nerve head has features that are in common with the human, as well as features that are different. 18 The blood supply of the optic nerve head in the pig eye, as in the human eye, is distinct from that of the surrounding fundus. In the pig there is a continuous arterial circle of Zinn–Haller around the optic disc. The laminar regions of the disc are supplied by vessels arising from the circle of Zinn–Haller, as well as branches of the posterior ciliary arteries. As in humans, vessels in the prelaminar region of the optic disc are derived from the choroid, and laminar branches from the Zinn–Haller circle contribute to the blood supply. In the pig, the capillaries in the surface layer of the disc arise from smaller vessels at the disc margin originating from the prelaminar retinal vessels or from the circle of Zinn–Haller, rather than from recurrent branches from circumpapillary vessels, as in humans. The capillary nets supplying the nerve head are clearly trilaminar, and peripapillary zone 1 has four layers, whereas the human angioarchitecture is far less distinctly laminar. 18  
The change in ONPo 2 may be related to a change in optic nerve blood flow and may be the result of blood flow change. Acetazolamide and dorzolamide increase ONPo 2, and previous studies have shown that the carbonic anhydrase inhibitors increase cerebral and retinal blood flow. 7 8 10 Our technique cannot reliably distinguish between the effects from the different vascular beds that involve the optic disc head. The cells in the optic nerve region are affected by their chemical environment and the concentration of oxygen and nutrients, which naturally reflects the regional blood flow and metabolism. Oxygen tension is a more direct measure of the cellular environment than is evaluation of blood flow. 
In the experiments in which the breathing mixture alternated between 21% and 100% O2, ONPo 2 showed a robust and near immediate response. Placing the tip of a polarographic Po 2 electrode 0.5 mm above the optic nerve head is clearly sensitive enough to measure changes in ONPo 2 in response to various physiologic conditions. Our results showing that 100% O2 breathing elevated ONPo 2 is in agreement with Ahmed et al. 2 and Pournaras et al., 3 who also found that systemic hyperoxia increased periarteriolar but not intervascular oxygen tension. 
ONPo 2 increased markedly when pigs breathed carbon dioxide. Breathing carbon dioxide and the carbonic anhydrase inhibitors lowered arterial blood pH and elevated blood Pco 2 (Table 2) . It is tempting to speculate that the oxygen tension effects of the carbonic anhydrase inhibitors may be linked through the influence of pH and Pco 2
Acetazolamide and dorzolamide are commonly used in the treatment of glaucoma, and our data suggest that these drugs may affect the glaucomatous optic nerve through two distinct mechanisms. One is the traditional intraocular pressure–lowering effect, and the other is the direct effect on ONPo 2. Further research is needed to find whether this effect is seen with other glaucoma drugs and to explore the importance of optic nerve oxygen metabolism in the pathophysiology of glaucoma and its treatment. 
 
Table 1.
 
Physiological Parameters in Experimental Pigs
Table 1.
 
Physiological Parameters in Experimental Pigs
Parameter Level
Heart rate (per minute) 113.6 ± 33.2 (65–187)
Blood pressure (mmHg) 100.9 ± 16.2 (75–127)
pH 7.61 ± 0.042 (7.49–7.66)
Pco 2 (kPa) 4.04 ± 0.471 (3.3–5.55)
Po 2 in air (kPa) 13.67 ± 1.46 (10.57–17.43)
Po 2 in 100% O2 (kPa) 70.13 ± 4.85 (61.54–76.45)
Rectal temperature (C) 38.28 ± 1.09 (36.7–40.7)
Electrode drift (% O2/h) 0.033 ± 0.061 (0.006–0.214)
Figure 1.
 
Continuous ONPo 2 recording during changes in breathing mixture. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow on the left, the breathing mixture was changed from 100% O2 to 20% O2. The middle arrow indicates when the breathing mixture was switched to 5.19% CO2-19.9% O2. The arrow on the right indicates when the breathing mixture was returned to 20% oxygen (N2 to balance). Note the increase in ONPo 2 during exposure to CO2.
Figure 1.
 
Continuous ONPo 2 recording during changes in breathing mixture. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow on the left, the breathing mixture was changed from 100% O2 to 20% O2. The middle arrow indicates when the breathing mixture was switched to 5.19% CO2-19.9% O2. The arrow on the right indicates when the breathing mixture was returned to 20% oxygen (N2 to balance). Note the increase in ONPo 2 during exposure to CO2.
Table 2.
 
Effect of Breathing Carbon Dioxide and of Study Drugs on Arterial Blood Gas Pressures and pH
Table 2.
 
Effect of Breathing Carbon Dioxide and of Study Drugs on Arterial Blood Gas Pressures and pH
Arterial pH Arterial PO2 (kPa) Arterial PCO2 (kPa)
Before After Before After Before After
CO2 (n = 4) 7.62 ± 0.05 7.42 ± 0.03* 13.84 ± 1.1 14.13 ± 0.93 3.96 ± 0.46 6.82 ± 0.52*
Acetazolamide, 500 mg (n = 6) 7.62 ± 0.01 7.49 ± 0.03* 14.79 ± 1.67 13.62 ± 1.5 3.84 ± 0.33 5.29 ± 0.57*
Dorzolamide, 500 mg (n = 5) 7.57 ± 0.01 7.43 ± 0.05* 12.96 ± 1.58 12.36 ± 0.7 4.42 ± 0.72 6.02 ± 0.87*
Figure 2.
 
(A) The effect of intravenous dorzolamide on ONPo 2. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow, an intravenous 500-mg injection of dorzolamide was administered. (B) The effect of intravenous acetazolamide on ONPo 2. At the point indicated by the arrow, an intravenous injection of 500 mg acetazolamide was administered. A transient lowering of arterial blood pressure followed the injection and resulted in the transient dip in ONPo 2.
Figure 2.
 
(A) The effect of intravenous dorzolamide on ONPo 2. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow, an intravenous 500-mg injection of dorzolamide was administered. (B) The effect of intravenous acetazolamide on ONPo 2. At the point indicated by the arrow, an intravenous injection of 500 mg acetazolamide was administered. A transient lowering of arterial blood pressure followed the injection and resulted in the transient dip in ONPo 2.
Figure 3.
 
Dose–response relationship between intravenous acetazolamide (•) and dorzolamide (○), expressed in log millimoles, and increase in ONPo 2 (expressed as change in millimeters of mercury).
Figure 3.
 
Dose–response relationship between intravenous acetazolamide (•) and dorzolamide (○), expressed in log millimoles, and increase in ONPo 2 (expressed as change in millimeters of mercury).
The authors thank Letty Klarskov and Mette Olsen, veterinary nurses, for their assistance with the handling of the experimental animals. 
Ernest JT. In vivo measurement of optic disk oxygen tension. Invest Ophthalmol. 1973;12:927–931. [PubMed]
Ahmed J, Linsenmeier RA, Dunn R, Jr. The oxygen distribution in the prelaminar optic nerve head of the cat. Exp Eye Res. 1994;59:457–465. [CrossRef] [PubMed]
Pournaras CJ, Munoz JL, Abdesselem R. Régulation de la PO2 au niveau de la papille du porc miniature en hypoxie. Klin Monatsbl Augenheilkd. 1991;198:404–405. [CrossRef] [PubMed]
Shonat RD, Wilson DF, Riva CE, Cranstoun SD. Effect of acute increases in intraocular pressure on intravascular optic nerve head oxygen tension in cats. Invest Ophthalmol Vis Sci. 1992;33:3174–3180. [PubMed]
Novack RL, Stefansson E, Hatchell DL. Intraocular pressure effects on optic nerve head oxidative metabolism measured in vivo. Graefes Arch Clin Exp Ophthalmol. 1990;228:128–133. [CrossRef] [PubMed]
Cranstoun SD, Riva CE, Munoz JL, Pournaras CJ. Continuous measurements of intra-vascular PO2 in the pig optic nerve head. Klin Monatsbl Augenheilkd. 1997;210:313–315. [CrossRef] [PubMed]
Vorstrup S, Henriksen I, Paulson OB. Effect of acetazolamide on cerebral blood flow and cerebral metabolic rate for oxygen. J Clin Invest. 1984;74:1634–1639. [CrossRef] [PubMed]
Rassam SMB, Patel V, Kohner EM. The effect of acetazolamide on the retinal circulation. Eye. 1993;7:697–701. [CrossRef] [PubMed]
Grunwald JE, Zinn H. The acute effect of oral acetazolamide on macular blood flow. Invest Ophthalmol Vis Sci. 1992;33:504–507. [PubMed]
Harris A, Arend O, Arend S, Martin B. Effects of topical dorzolamide on retinal and retrobulbar hemodynamics. Acta Ophthalmol. 1996;74:569–572.
Grunwald JE, Mathur S, DuPont J. Effects of dorzolamide hydrochloride 2% on the retinal circulation. Acta Ophthalmol Scand. 1997;75:236–238. [PubMed]
Stefansson E, Hatchell DL, Fisher BL, Sutherland FS, Machemer R. Panretinal photocoagulation and retinal oxygenation in normal and diabetic cats. Am J Ophthalmol. 1986;101:657–664. [CrossRef] [PubMed]
Sugrue MF, Waheed A, Sly WS, et al. A study of the in vitro inhibition of human carbonic anhydrase isoenzymes I, II, and IV [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1993;34(4)S930.Abstract nr 1143
Maren TH, Conroy CW, Wynns GC, Levy NS. Ocular absorption, blood levels, and excretion of dorzolamide, a topically active carbonic anhydrase inhibitor. J Ocul Pharmacol Ther. 1997;13:23–30. [CrossRef] [PubMed]
Sugrue MT. The preclinical pharmacology of dorzolamide hydrochloride, a topical carbonic anhydrase inhibitor. J Ocul Pharmacol Ther. 1996;12:363–376. [CrossRef] [PubMed]
Conroy CW. Sulfonamides do not reach the retina in therapeutic amounts after topical application to the cornea. J Ocul Pharmacol Ther. 1997;13:465–472. [CrossRef] [PubMed]
LaCour M, Eysteinsson T, Kiilgaard JF, et al. Optic nerve oxygen tension. The effect of intraocular pressure and carbonic anhydrase inhibition [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1999;40:S491.Abstract nr 2591
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Figure 1.
 
Continuous ONPo 2 recording during changes in breathing mixture. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow on the left, the breathing mixture was changed from 100% O2 to 20% O2. The middle arrow indicates when the breathing mixture was switched to 5.19% CO2-19.9% O2. The arrow on the right indicates when the breathing mixture was returned to 20% oxygen (N2 to balance). Note the increase in ONPo 2 during exposure to CO2.
Figure 1.
 
Continuous ONPo 2 recording during changes in breathing mixture. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow on the left, the breathing mixture was changed from 100% O2 to 20% O2. The middle arrow indicates when the breathing mixture was switched to 5.19% CO2-19.9% O2. The arrow on the right indicates when the breathing mixture was returned to 20% oxygen (N2 to balance). Note the increase in ONPo 2 during exposure to CO2.
Figure 2.
 
(A) The effect of intravenous dorzolamide on ONPo 2. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow, an intravenous 500-mg injection of dorzolamide was administered. (B) The effect of intravenous acetazolamide on ONPo 2. At the point indicated by the arrow, an intravenous injection of 500 mg acetazolamide was administered. A transient lowering of arterial blood pressure followed the injection and resulted in the transient dip in ONPo 2.
Figure 2.
 
(A) The effect of intravenous dorzolamide on ONPo 2. Time from beginning of record is shown (in seconds) on the horizontal axis and oxygen tension (in millimeters of mercury) on the vertical axis. At the point indicated by the arrow, an intravenous 500-mg injection of dorzolamide was administered. (B) The effect of intravenous acetazolamide on ONPo 2. At the point indicated by the arrow, an intravenous injection of 500 mg acetazolamide was administered. A transient lowering of arterial blood pressure followed the injection and resulted in the transient dip in ONPo 2.
Figure 3.
 
Dose–response relationship between intravenous acetazolamide (•) and dorzolamide (○), expressed in log millimoles, and increase in ONPo 2 (expressed as change in millimeters of mercury).
Figure 3.
 
Dose–response relationship between intravenous acetazolamide (•) and dorzolamide (○), expressed in log millimoles, and increase in ONPo 2 (expressed as change in millimeters of mercury).
Table 1.
 
Physiological Parameters in Experimental Pigs
Table 1.
 
Physiological Parameters in Experimental Pigs
Parameter Level
Heart rate (per minute) 113.6 ± 33.2 (65–187)
Blood pressure (mmHg) 100.9 ± 16.2 (75–127)
pH 7.61 ± 0.042 (7.49–7.66)
Pco 2 (kPa) 4.04 ± 0.471 (3.3–5.55)
Po 2 in air (kPa) 13.67 ± 1.46 (10.57–17.43)
Po 2 in 100% O2 (kPa) 70.13 ± 4.85 (61.54–76.45)
Rectal temperature (C) 38.28 ± 1.09 (36.7–40.7)
Electrode drift (% O2/h) 0.033 ± 0.061 (0.006–0.214)
Table 2.
 
Effect of Breathing Carbon Dioxide and of Study Drugs on Arterial Blood Gas Pressures and pH
Table 2.
 
Effect of Breathing Carbon Dioxide and of Study Drugs on Arterial Blood Gas Pressures and pH
Arterial pH Arterial PO2 (kPa) Arterial PCO2 (kPa)
Before After Before After Before After
CO2 (n = 4) 7.62 ± 0.05 7.42 ± 0.03* 13.84 ± 1.1 14.13 ± 0.93 3.96 ± 0.46 6.82 ± 0.52*
Acetazolamide, 500 mg (n = 6) 7.62 ± 0.01 7.49 ± 0.03* 14.79 ± 1.67 13.62 ± 1.5 3.84 ± 0.33 5.29 ± 0.57*
Dorzolamide, 500 mg (n = 5) 7.57 ± 0.01 7.43 ± 0.05* 12.96 ± 1.58 12.36 ± 0.7 4.42 ± 0.72 6.02 ± 0.87*
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