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Ocular Perfusion Pressure and Choroidal Blood Flow in the Rabbit J. W. Kiel and W. A.J. van Heuven Purpose. To compare choroidal blood pressure versus flow relationships obtained by three different methods of changing the ocular perfusion pressure. Methods. Experiments were performed in pentobarbital-anesthetized rabbits with occluders on the aorta and inferior vena cava to control mean arterial pressure (MAP). The central ear artery was cannulated to measure MAP. Two 23-gauge needles were inserted through the pars plana into the vitreous: one connected to a saline-filled syringe to vary the ocular volume and the other to a pressure transducer to measure intraocular pressure (IOP). Choroidal perfusion was measured by laser-Dopplerflowmetrywith the probe in the vitreous over the posterior pole. In group 1 (n = 15), the MAP was varied while holding the IOP at 10, 15, 20, 25 and 30 mm Hg. In group 2 (n = 19), the IOP was increased while holding the MAP at 80, 70, 60, 50, 40, 30 and 20 mm Hg. In group 3 (n = 21), the MAP was varied without controlling the IOP. Results. Group 1 baseline choroidal flows were similar at the five IOPs. When the flow was plotted against MAP, the curves diverged and extrapolated to intersect the pressure axis when the MAP equaled the set IOP. Group 2 baseline flows were similar at MAPs greater than 40 mm Hg. When the flow was plotted against the IOP, the curves diverged and intersected the pressure axis when the IOP equaled the MAP. In both groups, plotting the flow against the perfusion pressure (i.e., MAP minus IOP) collapsed the data points into single curves. Choroidal autoregulation occurred in all three groups; however, the low end of the autoregulatory perfusion pressure range was ==50 mm Hg in group 1, »40 mm Hg in group 2, and ^30 mm Hg in group 3. Conclusions. The results show that the effective choroidal perfusion pressure gradient equals the MAP minus the IOP, and that choroidal autoregulation is most effective when the MAP varies and IOP is not controlled. Invest Ophthalmol Vis Sci. 1995; 36:579-585. A he driving force for the movement of blood through the choroid is the arteriovenous pressure gradient. Because the choroidal venous pressure slightly exceeds the intraocular pressure (IOP) when the IOP is varied across a wide range,'l2 a reasonable approximation of the effective choroidal perfusion pressure is the mean arterial pressure (MAP) in the ophthalmic artery minus the IOP.3'4 If this premise is correct, it Supported by National Institutes of Health grant EY09702 and by an unrestricted research grant from Research to Prevent Blindness Inc., Neiv York, Neto York. JWK is the recipient of a Research to Prevent Blindness Miriam and Benedict Wolf Scholar Award. Proprietary interest category: N. Submitted for publication July 14, 1994; revised September 19, 1994; accepted October 19, 1994. Reprint requests: J. W. Kiel, Department of Ophthalmology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284. follows that raising the IOP at different MAPs should generate a family of pressure-flow curves when the data are plotted against IOP that resolve into a single curve when plotted against perfusion pressure. Similarly, decreasing the MAP at different IOPs should also generate a family of curves when plotted against MAP that form a single curve when plotted against the perfusion pressure. Although these flow responses have been observed in physical models5'6 they have not been demonstrated in the choroid. Thus, one goal of this study is to fill this gap in our knowledge of choroidal blood flow. In contrast to previous studies that found little evidence of choroidal pressure-flow autoregulation,7"9 our recent studies indicate that the choroid is capable of vigorous autoregulation.1011 One possible explanation for these discrepant findings is the differ- Invesligative Ophthalmology & Visual Sci< e, March 1995, Vol. 36, No. 3 Copyright © Association for Research in ' on and Ophthalmology 579 From the Department of Ophthalmology, University of Texas Health Science Center, Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 580 Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No. 3 ence in the methods used to vary the perfusion pressure. Therefore, the second goal of the present study is to compare the choroidal pressure-flow relationships obtained when the perfusion pressure gradient is varied by three different methods. METHODS The animals used in this study were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Animal Preparation Locally obtained New Zealand albino rabbits of both sexes were housed in the institutional animal care facility and given food and water ad libitum for at least 2 days before the experiments. At 8 AM, the animals were anesthetized with pentobarbital sodium (30 mg/ kg, intravenously, supplemented every 30 minutes), intubated through a tracheostomy and respired with room air. Expired PCO2 was monitored (Datex Normocap 200, Tewksbury, MA) and maintained between 40 and 45 mm Hg. A heating pad was used to maintain normal body temperature (38°C to 39°C). The animals were killed with an overdose of anesthetic (100 mg/ kg) at the end of the experiments. Hydraulic occluders were placed around the thoracic descending aorta and inferior vena cava through a right thoracotomy to control ocular MAP. The aortic occluder was used to redirect the cardiac output to the upper half of the body, thus increasing the MAP at the eye. The caval occluder was used to impede venous return, thus lowering cardiac output and reducing MAP throughout the circulation. To estimate ocular MAP, a cannula was inserted into the left central ear artery and connected to a pressure transducer (BLPR, World Precision Instruments, Sarasota, FL) to measure MAP at roughly the same height above the heart as the eye. The animals were then mounted in a stereotaxic head holder. Two 23-gauge needles were inserted into the vitreous through the pars plana to control and measure intraocular pressure. One needle was connected to a saline-filled syringe to change the ocular volume. The second needle was connected to a pressure transducer to measure the IOP. A laser-Doppler flowmeter (PF-2B, Perimed, Stockholm, Sweden) was used to measure two indices of choroidal perfusion: the concentration of moving blood cells (CMBC) and the red blood cell flux.12 In brief, the technique is based on the spectral broadening of laser light in perfused tissue caused by photon interaction with moving blood cells. Two perfusion parameters are continuously derived from the resultant Doppler-broadened spectrum. The mean red cell velocity is determined from the intensity-normalized first moment of the spectrum, and the CMBC is determined from the total power spectral density. The product of these two parameters is the red blood cell flux, which varies linearly with blood flow in a wide variety of tissues.12 The flowmeter used in this study uses a 2 mW HeNe laser light source and a probe (Pf 303, Perimed, Stockholm, Sweden) with three fiber optic light guides, one to transmit the light to the tissue and two to capture the light re-emitted from the tissue. The flowmeter frequency cut-off was set at 12 kHz in group 1 and at 24 kHz in the other two groups. (The higher frequency cut-off was not available on the flowmeter used in group 1.) The time constant was set at 0.2 seconds and the gain at 1. The flowmeter was calibrated by placing the probe in a suspension of latex particles at 22°C and adjusting the internal gain so that the instrument read 250 perfusion units. During the experiments, the "total backscatter" (i.e., the DC voltage at the photodetector) was maintained constant between 2 to 4 volts.10 To measure choroidal perfusion, the probe was advanced through the pars plana with a micromanipulator so that the probe tip was positioned in the vitreous near the retinal surface over the posterior pole. The volume of tissue sampled by the instrument is approximately 1 mm3, which is sufficient to measure perfusion in both the retina and the choriocapillaris and perhaps the conduit vessels in the outer choroid. Because the rabbit retina is largely avascular,13 the flux and CMBC signals in this preparation are measures of choroidal perfusion. Experimental Protocols Three series of experiments were performed. A representative set of tracings from each protocol is shown in Figure 1. In the first series (group 1, n = 15), the perfusion pressure (MAP minus IOP) was varied by changing the MAP while holding the IOP at 10, 15, 20, 25, and 30 mm Hg. In the second series (group 2, n = 19), the perfusion pressure was decreased by progressively increasing the IOP by saline infusion at 0.5 fj\/sec while holding the MAP at 80, 70, 60, 50, 40, 30, and 20 mm Hg. In the third series, (group 3, n = 21), the perfusion pressure was varied by changing the MAP without controlling the IOP after setting it to an initial baseline value of 15 mm Hg. Data Analysis All measured variables were recorded with a MacLab (World Precision Instruments) data acquisition system connected to an Apple Macintosh SE30 computer (Apple, Cupertino, CA). The digitized values for the measured variables were averaged in 5 mm Hg bins of MAP for groups 1 and 3 and of IOP for group 2. Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 581 Ocular Perfusion Pressure and Choroidal Blood Flow Protocol #1 Protocol #2 Protocol #3 Arterial Pressure (mmHg) Intraocular Pressure (mmHg) FIGURE 1. In group 1, the perfusion pressure (MAP minus IOP) was decreased by progressively occluding the vena cava to lower the MAP while holding the IOP at different levels by adjusting the ocular volume. In group 2, the perfusion pressure was decreased by continuous infusion of saline at 0.5 /xl/sec to raise the IOP while holding the MAP constant at different levels by partially occluding the descending aorta or inferior vena cava. In group 3, the .perfusion pressure was decreased by lowering the MAP without controlling the IOP (time in seconds). MAP = mean arterial pressure; IOP = intraocular pressure. The results are expressed as the mean ± the standard error of the mean. RESULTS Immediately upon cannulation of the eye, the average MAP and IOP for all animals were 75.49 ± 1.26 mm Hg and 16.22 ± 0.50 mm Hg, respectively. The pressure-flow results for the three groups are shown in Figure 2. The left column of graphs shows the choroidal flux values plotted against the manipulated pressure, and the right column shows the choroidal flux data replotted against the perfusion pressure gradient. Figure 2A presents the choroidal flow responses when the MAP was decreased at different fixed IOPs (group 1). The actual IOPs were: 9.8 ± 0.1, 14.5 ± 0.1, 20.1 ± 0.3, 24.0 ± 0.4, and 29.8 ± 0.4 mm Hg. The left graph shows that the baseline flux values were similar at all five IOPs, but, as the MAP was decreased, the pressure-flow curves diverged, resulting in a family of curves that extrapolate to intersect the pressure axis when the MAP approximately equals the set IOP. The right graph shows that, when the choroidal flux values are plotted against the perfusion pressure, the individual pressure-flow curves form a common curve with a projected zero intercept. Figure 2B shows the choroidal flow responses when the IOP was increased at different fixed MAPs (group 2). The actual MAPs were: 80.9 ± 0 . 1 , 70.9 ± 0.1, 61.9 ± 0.2, 51.4 ± 0.1, 41.6 ± 0.1, 31.5 ± 0.2, and 20.7 ± 0 . 1 mm Hg. The left graph shows that the baseline flux values were similar at MAPs between 80 and 50 mm Hg and reduced in a pressure-dependent manner at the lower MAPs. As in group 1, the individual curves intersect the pressure axis when the IOP approximately equals the set MAP. The right graph shows the choroidal flux values plotted against the perfusion pressure, and, as in group 1, the individual curves resolve into a common curve intersecting the pressure axis at approximately 0 mm Hg. Figure 2C shows the choroidal flow responses when the MAP was decreased without controlling the IOP (group 3). Under this protocol, the single pressure-flow curve obtained when the choroidal flux values are plotted against the manipulated pressure (left graph) is shifted to the left when plotted against the perfusion pressure (right graph). The right column of graphs in Figure 2 shows that choroidal autoregulation occurred in all three groups. However, the perfusion pressure below which choroidal flow became pressure-dependent varied between groups, occurring at approximately 50 mm Hg in group 1, 40 mm Hg in group 2, and 30 mm Hg in group 3. Figure 3 presents the CMBC data plotted against the perfusion pressure for the three groups. The CMBC parameter is an index of blood volume. Figure 3A shows that the CMBC was relatively constant at perfusion pressures greater than 20 mm Hg when the MAP was decreased at fixed IOPs (group 1). Figure 3B shows that when the IOP was increased at fixed MAPs (group 2), the CMBC increased slightly as the perfusion pressure decreased from 60 to 20 mm Hg, then fell in a pressure-dependent manner. Figure 3C Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 582 Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No. A. 1000 ~ 600 i. 2 400• IOP@10 O IOP@15 I S 200 0 B. 10 20 30 40 50 60 MAP (mmHg) 70 80 -10 0 10 20 30 40 50 MAP - IOP (mmHg) 60 70 1000 II j 800~ 600 1 400Z a 5 200- 20 C. 40 60 IOP (mmHg) 80 • O A A • a * MAP@SO MAP@70 MAP@60 MAP@50 MAP@40 MAP®30 MAP@20 100 -10 0 10 20 30 40 50 60 70 MAP • IOP (mmHg) 80 -10 0 10 1000 -i I 400 H o 5 30 40 50 60 MAP (mmHg) 70 20 30 40 50 MAP-IOP (mmHg) FIGURE 2. Choroidal pressure-flow relationships plotted as a function of the manipulated pressure {left column) and the perfusion pressure {right column). (A) Choroidalfluxresponses to decreasing the MAP at different IOPs. (B) Choroidal flux responses to increasing the IOP at different fixed MAPs. (C) Choroidal flux responses to decreasing the MAP without controlling the IOP. MAP = mean arterial pressure; IOP = intraocular pressure. shows that when the MAP was decreased without controlling the IOP (group 3), the CMBC tended to increase as the perfusion pressure was reduced from 60 to 5 mm Hg. DISCUSSION The goals of this study were twofold: to provide a systematic demonstration of the ocular perfusion pressure gradient and its effect on choroidal blood flow and to determine whether the method used to vary the perfusion pressure alters the efficacy of choroidal autoregulation. Ocular Perfusion Pressure A basic premise of choroidal blood flow studies is that the choroidal perfusion pressure is well approximated by the pressure gradient between the MAP in the ophthalmic artery and the IOP. However, this has never been demonstrated systematically, probably because of the limitations of techniques previously used for measuring choroidal blood flow. For example, the ra- Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 583 Ocular Perfusion Pressure and Choroidal Blood Flow A. 10-1 iu - t*5S? _ 8- f 6- Tj o I1 " A £ U 4- 1 J • O A A • 20-10 B. i , 0 10 20 30 40 50 MAP - IOP (mmHg) IOP@10 IOP@15 IOP@20 IOP@25 IOP@30 60 70 10-, O MAP@80 MAP@70 A MAP@60 Underlying Mechanism A MAP@50 • MAP@40 a MAP@30 • MAP@20 -10 0 10 20 30 40 50 60 70 MAP • IOP (mmHg) C. 10-. 8- u i ••••I, 4- -10 0 10 20 30 40 50 MAP-IOP (mmHg) 60 dioactive microsphere technique is inherently discontinuous and, as validated by Aim et al,14 is limited to one measurement per eye. The various clearance techniques9'15 permit multiple measurements, but they are also discontinuous and require several minutes to complete. Thus, the large number of measurements needed to obtain multiple pressure-flow curves by systematic manipulation of the perfusion pressure have not been feasible. By contrast, laserDoppler flowmetry provides a continuous measurement that makes such a study possible. If the choroidal perfusion pressure equals the MAP minus the IOP, then varying one pressure while holding the other pressure constant at different levels should result in a family of pressure-flow curves when the data are plotted against the manipulated variable and a single common curve when the data are plotted against the perfusion pressure. The results shown in Figure 2 demonstrate this pattern of choroidal flow behavior both when the MAP is the manipulated variable (Fig. 2A) and when the IOP is the manipulated variable (Fig. 2B). Similar results were obtained by Fry et al,16 who analyzed the flow behavior in a collapsible tube passing through a pressurized chamber. 70 FIGURE 3. Choroidal pressure-blood volume relationships. Graphs show the concentration of moving blood cells (CMBC) plotted as a function of the perfusion pressure when the MAP is reduced at fixed IOPs (A), the IOP is increased at fixed MAPs (B), and the MAP is reduced without controlling IOP (C). MAP = mean arterial pressure; IOP = intraocular pressure. Moses5 likened the effect of IOP on the intraocular veins to a Starling resistor whose cross-sectional area is a function of the transmural pressure gradient. In other words, the balance of the pressures inside and outside the veins determines their caliber and resistance to flow. In support of this hypothesis, raising the IOP causes a parallel shift in the blood pressures "upstream" in the choroidal veins1'2 and choriocapillaris2 across a wide range of IOPs. Fry et al6 performed a systematic analysis of the flow behavior in a simple Starling resistor device by varying the tubing pressure gradient at different chamber pressures. At zero chamber pressure, the pressure-flow relationship was linear when plotted against the tubing pressure gradient. At progressively increased chamber pressures, the pressure-flow curves consisted of two linear segments: an initial segment with reduced slopes as the tubing pressure gradient was raised from zero to the prevailing chamber pressure and a second segment where the slopes were parallel to that at zero chamber pressure. The slope change at positive chamber pressures occurred when the tubing geometry changed from a partially collapsed to a fully distended configuration. In this simple passive model, plotting the flow data against the pressure gradient defined as the inlet pressure minus the chamber pressure resulted in a single common function. In the present study, the protocol for group 1, in which the MAP was reduced at set IOPs, most closely Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 584 Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No. 3 replicates the pressure manipulations in the Starling resistor device studied by Fry et al.6 Although the results are remarkably similar, there are several noteworthy differences between the two studies. First, the venous pressure outside the eye was not measured so the vascular pressure gradient analogous to the tubing pressure gradient is unavailable. Instead, the data are plotted against the MAP (Fig. 2), and it is assumed the change in extraocular venous pressure during the MAP manipulation is relatively small as observed in a previous study." Second, it was not possible consistently to lower the MAP below the IOP and, therefore, it is uncertain whether the choroid exhibits an initial reduced slope analogous to that seen when the tubing pressure gradient was less than the chamber pressure. Third, unlike the choroid, the Starling resistor device is inherendy passive and incapable of the pressureflow autoregulation seen at the higher MAPs (Fig. 2). Despite these caveats, the similar flow behavior in the choroid and the Starling resistor device supports the assertion by Moses5 that the choroidal veins function as biologic Starling resistors. The Starling resistor mechanism is also consistent with the CMBC responses shown in Figure 3. As noted earlier, the CMBC is an index of choriocapillaris blood volume. In all three groups, the CMBC either remained constant or increased slightly as the perfusion pressure gradient was decreased from s=»65 to «*20 mm Hg. With further reductions in the perfusion pressure, the CMBC then fell in groups 1 and 2, in which the IOP was controlled, but not in group 3, in which the IOP was not controlled. As predicated by the Starling resistor mechanism, the fall in the CMBC indicates the partial collapse of the vessels under the probe as the extravascular pressure begins to overcome the intravascular pressure. The fact that the IOP was not artificially maintained or elevated in group 3 suggests that the IOP fell sufficiently for the vessels to remain distended. Choroidal Autoregulation Previous choroidal pressure-flow studies differ in their methods used to manipulate the perfusion pressure gradient and in their findings regarding choroidal autoregulation.7""'15 The present results also indicate a link between the method of pressure manipulation and the efficacy of choroidal autoregulation. The right column of graphs in Figure 2 shows that choroidal autoregulation is least evident when the MAP is decreased and the IOP fixed, it is more pronounced when the IOP is increased and the MAP held constant, and it occurs over the widest perfusion pressure range when the MAP is varied without controlling the IOP. Although rarely used in choroidal pressure-flow studies,11 this latter protocol most closely simulates the in vivo situation; hence, it is not surprising that the autoregulatory mechanism is most effective under this condition. It is possible that the arterial baroreflex may have altered the choroidal sympathetic nerve activity and, by changing the intraocular vascular resistance, so altered the pressure-flow relation and the autoregulatory range. However, if the sympathetic tone to the choroid were under baroreflex control, the pressureflow curves for group 2 would not superimpose when plotted against perfusion pressure. Instead, baroreflex withdrawal of sympathetic tone at the higher MAPs would cause vasodilation, whereas baroreflex activation at the lower MAPs would cause vasocontriction. Figure 2B shows that this did not occur. Moreover, if the baroreflex was responsible for the shift in the autoregulatory range, one would expect the range to be the same in groups 1 and 3 because the MAP was manipulated in the same manner in both groups. Instead, the autoregulatory range was smallest in group 1 and largest in group 3. Thus, it does not appear that the baroreflex is responsible for the shift in the autoregulatory range between protocols. The present results indicate that the choice of experimental protocol for varying the perfusion pressure may partly explain the discrepancies in the choroidal autoregulation literature. Differences in blood flow measuring methodologies may also account for the discrepant findings.'' Lastly, anatomic differences between species may be involved. For example, unlike primates, rabbits do not have a retinal circulation,13 and their inner retina relies on anaerobic metabolism.15 Thus, rabbits might require choroidal autoregulation, whereas species with a vascularized retina may not. The problem with this hypodiesis is the underlying assumption that choroidal autoregulation is linked to retinal metabolism. This is unlikely given the long diffusion distance between the inner retina and the choroidal resistance vessels, the negligible choroidal oxygen extraction,4 and the high anaerobic capacity of the rabbit retina.16 An alternative possibility supported by previous studies1011 is that choroidal autoregulation is myogenic and that it functions to prevent large MAP-dependent changes in choroidal blood volume and consequent changes in IOP. Such a protective mechanism would be a beneficial adaptation in rabbits or humans. Clinical Significance Any attempt to extrapolate animal studies to humans must be viewed with caution and, at present, the autoregulatory capacity of the human choroid is unknown. However, the foveal avascular zone and a large portion of the outer human retina are nourished by the choroid4 and susceptible to choroidal ischemia. Given the possibility that the human choroid may have some autoregulatory ability, we offer the following as two Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017 585 Ocular Perfusion Pressure and Choroidal Blood Flow examples of where the present results may be clinically relevant. Hayreh'7 has hypothesized that nocturnal arterial hypotension underlies the development of glaucoma in patients with seemingly normal IOP. This hypothesis can be described graphically using the flow plotted against the perfusion pressure (Fig. 2A, right) by selecting a point on the graph representing a normal daytime MAP and IOP and then moving that point to the left into the pressure-dependent portion of the curve to show the potential for ischemia associated with nocturnal arterial hypotension. However, by also considering the graph of flow plotted against MAP at different IOPs (Fig. 2A, left), it is further appreciated that a nocturnal fall in MAP has a smaller effect on blood flow at an IOP of 10 mm Hg than at 20 mm Hg, although these values bracket the normal range of IOP. Another clinical situation in which this study may have importance is during closed vitrectomy surgery in patients with low blood pressure. This scenario can occur in any patient who may have a hypotensive period resulting from anesthesia, but it is especially apt to occur in very young patients undergoing surgery for stage V retinopathy of prematurity. In such patients, the MAP is often between 30 and 80 mm Hg, whereas the IOP is frequently maintained at 25 to 35 mm Hg and even higher if intraocular hemostasis is desired. During the relatively long and complex procedure, the IOP may not even be known because the ocular infusion bottle is simply hung at an empiric height, which minimizes bleeding. It is interesting to speculate how much the ensuing choroidal ischemia contributes to poor visual results after vitrectomy for retinopathy of prematurity.18 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Key Words arterial pressure, intraocular pressure, choroidal autoregulation, eye, peripheral circulation 15. 16. Acknowledgments The authors thank Leslie McBride for her technical assistance, and A. P. Shepherd, PhD, and R. Whitaker, Jr., MD, for their advice and encouragement. 17. References 1. Bill A. Aspects of the regulation of the uveal venous pressure in rabbits. Exp Eye Res. 1962;1:193-199. 2. Maepea O. Pressures in the anterior ciliary arteries, 18. choroidal veins and choriocapillaris. Exp Eye Res. 1992:54:731-736. Moses RA. Intraocular pressure: Adler's Physiology of the Eye: Clinical Application. St. Louis: C.V. Mosby; 1987:223-245. Bill A. Ocular circulation. Adler's Physiology of the Eye: Clinical Application. St. Louis: C.V. Mosby; 1987:183203. Moses RA. Hydrodynamic model eye. Ophthalmologica. 1963:146:137-142. Fry DL, Thomas LJ, Greenfield JC. Flow in collapsible tubes. Basic Hemodynamics and Its Role in Disease Processes. Baltimore: University Park Press; 1980:407-425. Aim A, Bill A. The oxygen supply to the retina: II: Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats. Ada Physiol. Scand. 1972; 84:306319. Aim A, Bill A. Ocular and optic nerve blood flow at normal and increased intraocular pressure in monkeys (Macaca irus): A study with radioactively labeled microspheres including flow determinations in brain and some other tissues. Exp Eye Res. 1973; 15:15-29. Yu DY, Alder VA, Cringle SJ, Brown MJ. Choroidal blood flow measured in the dog eye in vivo and in vitro by local hydrogen clearance polography: Validation of a technique and response to raised intraocular pressure. Exp Eye Res. 1987;46:289-303. Kiel JW, Shepherd AP. Autoregulation of choroidal blood flow in the rabbit. Invest Ophlhalmol Vis Sri. 1992;33:2399-2410. Kiel JW. Choroidal myogenic autoregulation and intraocular pressure. Exp Eye Res. 1994;58:529-544. Shepherd AP, Oberg PA. Laser-Doppler Blood Fbwmetry. Norwell, MA: Kluwer Academic Publishers; 1990. Ruskell G. The Rabbit in Eye Research. Springfield, IL: Charles C. Thomas; 1964:514-553. Aim A, Tornquist P, Stjerschantz J. Radioactively labeled microspheres in regional ocular blood flow determinations. BiblAnat. 1977; 16:24-29. Friedman E. Choroidal blood flow: Pressure-flow relationships. Arch Ophthalmol. 1970;83:95-99. Lowry OH, Roberts NR, Schulz DW, Clow JE, Clark JR. Quantitative histochemistry of the retina: II: Enzymes of glucose metabolism. / Biol Chevi. 1961;236:2813-2820. Hayreh SS, Zimmerman MB, Podhaisky P, Alward WL. The role of nocturnal hypotension in ocular and optic nerve ischemic disorders. ARVO Abstracts. Invest Ophthalmol Vis Set. 1993; 34:994. Quinn EG, Dobson V, Barr CC, et al. Visual acuity in infants after vitrectomy for severe retinopathy of prematurity. Ophthalmology. 1991;98:5-13. Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933409/ on 05/15/2017