Simultaneous management of blood flow and IOP in glaucoma

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Article

Reference

Simultaneous management of blood flow and IOP in glaucoma

HARRIS, A, et al.

Abstract

Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causation may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis reduce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links ischemia to IOP.

Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.

HARRIS, A, et al . Simultaneous management of blood flow and IOP in glaucoma. Acta Ophthalmologica Scandinavica , 2001, vol. 79, no. 4, p. 336-341

DOI : 10.1034/j.1600-0420.2001.079004336.x PMID : 11453850

Available at:

http://archive-ouverte.unige.ch/unige:154264

Disclaimer: layout of this document may differ from the published version.

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Simultaneous management of

blood flow and IOP in glaucoma

Alon Harris

¹

, Christian Jonescu-Cuypers

¹

, Bruce Martin

²

, Larry Kagemann

¹

, Miriam Zalish

³

and Hannah J. Garzozi

⁴

1Department of Ophthalmology, Indiana University School of Medicine,

Indianapolis, IN, USA,²Medical Sciences Program, Indiana University, Bloomington, IN, USA,³Department of Ophthalmology, Kaplan Medical Center, Rehovot, Israel,

4Department of Ophthalmology, Haemek Medical Center, Afula, Israel

ABSTRACT.

Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causa- tion may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis re- duce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links isch- emia to IOP. Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.

Key words:carbonic anhydrase – intraocular pressure – ischemia – glaucoma.

Acta Ophthalmol. Scand. 2001: 79: 336–341 CopyrightcActa Ophthalmol Scand 2001. ISSN 1395-3907

A

lthough elevation of the intraocular pressure (IOP) is clearly a major risk factor for the development and progression of glaucoma, therapeutic reduction of the IOP provides neither im- proved visual function nor stabilization of the disease process in many patients (Rossetti et al. 1993; Chauhan 1995). The failure of ocular pressure lowering to prevent disease progression, the association of glaucomatous optic nerve head damage with normal pressure in many patients, and racial variations in disease incidence independent of IOP (Tielsch et al.

1991), point to the critical role that other factors must play in the development of this disease (Flammer et al. 1999).

One candidate for an additional glaucoma risk factor, independent from, yet interacting with IOP, is blood flow insufficiency. Ischemia fulfills many of the cri- teria for a causative element for this illness:

1) Ischemic cellular damage mimics pathologic changes seen in glaucoma 2) Glaucoma patients with normal IOP

show signs of ocular and cerebral isch- emia

3) Increases in IOP worsen ischemia, linking the known and hypothetical risk factors, and potentially contribu- ting to the increased risk for glaucoma in persons with elevated IOP

While each of these topics will be ad- dressed in turn, the third point is the primary topic for this review: the simultaneous management of both ocular blood flow and the IOP. This relationship will be considered with special attention to the potential role that carbonic anhydrase inhibitors may play in simultaneous management of both risk factors in older persons with compromised vascular autoregulatory capacity.

Ischemic cellular damage mimics pathologic

changes seen in glaucoma

While the pathogenesis of primary open angle glaucoma (POAG) remains un- known, understanding of the disease process may be gained through models which demonstrate mechanisms of apoptotic neuronal cell death. In human glaucoma and in animal models of the disease, retinal ganglion cells primarily die via apoptosis (Quigley et al. 1995; Pease et al. 2000). Elevated intraocular pressure in the rat dilates these cells, leads to abnormal intracellular accumulation of tyrosine kinase receptor B, and blocks delivery of brain-derived neurotrophic factor, suggesting that neurotrophin deprivation causes retinal ganglion cell apoptosis in glaucoma (Pease et al. 2000). While the genetic factors that regulate these pro- cesses remain to be fully elucidated (Nickells 1999), a similar pathway appar- ently leads to ischemia-induced death of cells in the central nervous system (En- dres et al. 2000). In mice lacking both al- leles for neurotrophin-4 or deficient in a single allele for brain-derived neurotrophic factor, infarct size after occlusion of the middle cerebral artery is increased, suggesting that expression of neurotrophin-4 and brain-derived neurotrophic factor, and hence the tyrosine kinase B receptor, are essential for protection against ischemic injury (Endres et al.

2000). Further, brain cells resistant to hypoxic-ischemic insult are those highest in endogenous expression of brain-derived neurotrophic factor (Walton et al.

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Fig. 1. Three interrelated mechanisms for neuronal apoptosis in the Fig. 2. Conceptual model for the development of simultaneous clinical brain and eye, provoked by ischemia/reperfusion or by mechanical com- management of IOP and blood flow in the retina and optic nerve head.

pression. Because both mechanical and ischemic stimuli cause retinal Autoregulation in young, healthy individuals provides constant per- ganglion cell death via each of these pathways, retinal ganglion cell fusion over a wide range of ocular perfusion pressure. Regulatory dys- death in glaucoma could arise from either insult or their interaction. function which develops in susceptible older individuals, allows any fluctuation in ocular perfusion pressure (via changes in either systemic arterial pressure or the IOP) to change retinal and optic nerve head perfusion.

1999). Similarly, blocking brain-derived neurotrophic factor with the tyrosine kinase receptor B-Fc fusion protein causes greater neuronal loss in the forebrain during ischemia (Larsson et al. 1999), al- though the neuronal loss was selective, striking CA4 pyramidal neurons while sparing CA1 neurons (Larsson et al.

1999). A similar, linked pathway involves glutamate release and the activation of N-methyl-D-aspartate receptors (Gross et al. 2000; Osborne et al. 1999; Sucher et al. 1997). Using calcium influx as second messenger, this pathway is toxic to retinal ganglion cells in part via induction of oxygen radicals (Osborne et al. 1999).

Glutamate toxicity can be provoked by either IOP elevation or ischemia in susceptible cells (Osborne et al. 1999; Fig.

1). A third related mechanism may in- volve astroglial production of toxic levels of nitric oxide during ischemia: nitric oxide synthase inhibition increases retinal ganglion cell survival during anoxia or after administration of glutamate (Mor- gan et al. 1999). These results taken together suggest that neuronal apoptosis, provoked by either IOP elevation or by ischemia, may proceed along a common pathway, and that certain neurons, such as retinal ganglion cells, may be particu- larly susceptible to damage (Pease et al.

2000; Nickells 1999; Endres et al. 2000;

Walton et al. 1999; Larsson et al. 1999;

Fig. 1). Clearly, if IOP elevation poten- tates retinal and optic nerve head ischemia, this would accelerate retinal ganglion cell apoptosis with both factors acting in concert to cause cell death (Pease et al. 2000; Larsson et al. 1999).

Finally, in animal models, endothelin-1 induced ischemia generates glaucoma- like optic neuropathy despite normal IOP, a histopathologic result consistent with the possibility that ischemia may play a significant role in glaucoma development in some patients (Cioffi & Sulliv- an 1999; Haefliger et al. 1999; Oku et al.

1999).

Glaucoma patients with normal IOP show signs of ocular and cerebral

ischemia

Two magnetic resonance imaging studies find evidence for pan-cerebral ischemia in normal-tension glaucoma (NTG) patients. In one of these studies, patients suffering from NTG revealed confluent deep white matter lesions (Stroman et al.

1995). Such lesions are most often found in concert with a reduction in total cerebral perfusion and with impairments in cognitive function (Herholz et al. 1990;

Boone et al. 1992). A second study found atrophy of the corpus callosum and evidence for increased numbers of cerebral infarcts in normal-tension glaucoma (Ong et al. 1995). The close association of glaucoma with advancing age suggests that this illness could represent one as- pect of accelerated central nervous system aging (Ong et al. 1995). Evidence for diffuse, generalized cerebral ischemia in normal-tension glaucoma supports the hypothesis that the illness may represent a chronic, non-episodic form of anterior ischemic optic neuropathy (Hayreh 1975). These studies are at the level of pi- lot studies. A better view of the frequency of cerebral hemodynamic deficiencies, and the strength of their link to glaucoma and advancing age, will require epidemi- ology work which includes measurements in a large number of elderly normal subjects.

There are other, more circumstantial lines of evidence linking normal-tension glaucoma with vascular insufficiency. The first is the association of NTG with migraine (Wang et al. 1997; Curseifen et al.

2000), the latter illness presumably in-

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volving dysregulation of the cerebral vas- culature (Bednarczyk et al. 1998). Sec- ond, several experiments have found abnormal peripheral vascular responsiveness in NTG patients, suggesting that de- fects in systemic vascular control may be linked to development of glaucomatous optic neuropathy (Gass et al. 1997;

O’Brien & Butt 1999). These microvascular abnormalities manifest themselves as excessive responsiveness to endothelin- 1 mediated vasoconstriction, implying that endothelin-1 may be involved in glaucoma pathogenesis (Gass et al. 1997).

The increased levels of endothelin-1 found in aqueous humor and blood in some reports supports the possibility that elevated levels of this vasoconstrictor may contribute to glaucoma development in some patients (Cellini et al. 1997;

Hollo et al. 1998; Noske et al. 1997; Tezel et al. 1997). Third, administration of vasodilators can normalize retrobulbar flow velocities in NTG patients, indi- cating that for some patients vascular deficiencies in glaucoma may be revers- ible (Harris et al. 1994).

Increases in IOP worsen ischemia, linking the known and hypothetical risk factors, and

potentially contributing to the increased risk for glaucoma in persons with elevated IOP

In vitro models of retinal ischemic-reperfusion injury routinely use acute, severe IOP elevation to provoke apoptosis and to study cell resistance and susceptibility to injury (Ju et al. 2000; Katai & Yoshi- mura 1999). However, the relationship between IOP within ranges typically seen in NTG and primary open-angle glaucoma (POAG) and ocular blood flow remains incompletely defined.

In the healthy eye, retinal and optic nerve head blood flow are autoregulated during fluctuations in ocular perfusion pressure (Bill & Sperber 1990; Hayreh 1997). Because the metabolic needs of these tissues are unaffected during per- turbations of systemic arterial pressure and IOP seen during exercise, sleep, pos- tural change, diurnal changes, and other daily events, the arteries, arterioles, and possibly pericyte-regulated capillaries,

that supply these tissues constrict or di- late to maintain constant ocular blood flow over a wide range of perfusion pressure. Because the IOP represents the ocular outflow pressure within the physio- logical range (Bill & Sperber 1990), autoregulation in the retina and optic nerve head maintains constant blood flow and nutrient delivery over broad fluctuations in either the systemic arterial pressure or the IOP (Bill & Sperber 1990; Hayreh 1995, 1997; Riva et al. 1981, 1996; Dum- skyj et al. 1996; Robinson et al. 1986;

Sossi & Anderson 1983; Sperber & Bill 1985; Grunwald et al. 1982, 1988; Harris et al. 1996; Weinstein et al. 1983; Pillunat et al. 1997). The boundaries of the autoregulatory range, as determined in healthy, young humans and animals, are clearly outside the range of even the highest IOP and lowest mean arterial pressures encountered during everyday life (Hayreh 1995).

Data establishing the breadth and sta- bility of the autoregulatory ranges for optic nerve and retinal blood flow in young, healthy individuals cannot, however, be extrapolated to older persons who may also suffer from vascular illness, sleep or medication-related blood pressure reductions, or other changes rendering the eye more susceptible to ischemia. For ex- ample, aging per se is a major element in glaucoma risk, yet those factors respon- sible for the close association of age with disease incidence have not yet been defined (Fafowara & Osuntokun 1997;

Harris et al. 2000). While aging is associ- ated with modest elevation of the IOP, senescence is also linked to progressive declines in cerebral and ocular perfusion (Klein et al. 1992; Harris et al. 2000; No- mura et al. 1999). Reduced baseline blood flow suggests that autoregulation may not function in old age as it does in youth, a possibility supported by data from old, atherosclerotic monkeys. In these animals, retinal anaerobic metabolism during ocular hypertension is sharply increased (Hayreh et al. 1994). In similar studies in rats, young, healthy animals display robust choroidal hyperperfusion after ocular hypertension-induced ischemia, but in older rats variable responses occur that may include minimal hyperperfusion or even a no-reflow phenom- enon (Matsuura & Kawai 1998). These findings taken together suggest that aging per se can markedly alter the ocular blood flow response to IOP elevations (Matsuura & Kawai 1998), and raise the possibility that aging and/or atheroscler-

otic vascular changes may render some persons susceptible to ischemia-induced optic nerve head damage (Hayreh et al.

1994).

Emerging evidence supports this hypothesis linking aging, reduced ocular autoregulatory capacity, and ischemia. In POAG and NTG patients, optic nerve head and retinal perfusion are chronically reduced (Michelson et al. 1998; Chung et al. 1999; Grunwald et al. 1999). These reductions in optic nerve head blood flow are greater in persons with lower arterial blood pressure, such that within a group of POAG patients, optic nerve head blood flow directly correlates with mean arterial pressure (Grunwald et al. 1999).

Consequently, any reduction in ocular perfusion pressure (via changes in arterial pressure or IOP) will reduce optic nerve head blood flow (Grunwald et al. 1999).

In short, glaucoma patients, unlike healthy, young persons, may be char- acterized not by ocular blood flow autoregulation, but instead by dysfunction of both IOP and ocular blood flow (Flamm- er et al. 1999; Fig. 2). In the laboratory, some of these patients may be identified by cold pressor testing, hypercapnia stress testing, or other non-clinical tech- niques. In the future, vascular testing for a characteristic vasospastic response will become part of the examination regime of the glaucoma specialist, but not until the role of ischemia in the disease is better understood, and a proven medical treatment for vasospastic glaucoma subjects is identified.

Clinical management of both blood flow and IOP in glaucoma: implications for treatment

Evidence for the simultaneous clinical management of both IOP and blood flow in patients with glaucoma, in tandem with data showing that both high pressure and ischemia provoke apoptosis in CNS neurons, implies that therapy for glaucoma consider both pressor and vascular factors (Flammer et al. 1999). In this regard, any medical or surgical intervention that lowers IOP should directly benefit the retinal ganglion cells mechan- ically, and indirectly benefit these cells by relieving ischemia. Ideally, however, medical intervention would reduce IOP, provide additional local vasodilation, and also offer direct neuroprotection. While

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no single drug currently can boast all of these benefits, it is useful to consider the actions of a single class of medications in terms of this hypothetical framework for medical treatment.

One group of drugs currently used widely in glaucoma therapy are the carbonic anhydrase inhibitors. These drugs reduce IOP, thereby relieving mechanical forces on retinal ganglion cells and increasing ocular perfusion pressure. In ad- dition, systemic carbonic anhydrase inhibition remains a standard method for cerebral vasodilation (Ringelstein et al.

1992). Given the emerging evidence that cerebral ischemia may contribute to normal-tension glaucoma (Stroman et al.

1995; Ong et al. 1995), interventions that can additionally target vascular insufficiency may have special utility in treatment of this form of the disease.

Systemic carbonic anhydrase inhibitors have been used for nearly half a century to lower ocular tension (Becker 1954).

However, the protean side effects of systemic carbonic anhydrase inhibitors (chief among them fatigue, diarrhea, nausea, numbness, and loss of appetite) limit their usefulness and have stimulated the search for a viable topical agent (Mar- en 1987). In humans, carbonic anhydrase I and II are present in the corneal endo- thelium and in the lens, whereas carbonic anhydrase II is present in the ciliary process and in the retina (Maren 1987, Matsui 1996). More than 99% of the carbonic anhydrase in the ciliary body must be in- hibited for physiologically-relevant IOP reductions to occur (Maren 1967). Dorzo- lamide, a topical carbonic anhydrase II blocker, penetrates to the posterior seg- ment of the eye, significantly lowering IOP in glaucoma patients (Sugrue 2000) with many fewer side effects than systemic acetazolamide (Sugrue 2000; Ponticello et al.

1998). It appears that dorzolamide has a pharmacological effect in the fundus. In a comparison with betaxolol in NTG patients, both drugs lowered IOP equally, but only dorzolamide significantly hastened retinal hemodynamics (Harris 2000).

While it is clear that carbonic anhydrase inhibitors are vasodilators, the mechanisms that link enzyme inhibition to vascular smooth muscle relaxation are not understood. In healthy humans, systemic treatment with acetazolamide increases ocular fundus pulsations and mean flow velocity in the middle cerebral and ophthalmic arteries (Kiss et al.

1999). The mechanism for these changes is independent of nitric oxide, since ad-

ministration of a nitric oxide synthase inhibitor or L-arginine have no effect on the response (Kiss et al. 1999). Com- paring acetazolamide- with CO2-induced vasodilation suggests that similar bio- chemical cascades may be involved (Taki et al. 1999). Nitric oxide is not a factor in CO2-induced cerebral vasodilation (McPherson et al. 1995); instead, indo- methacin abolishes hypercapnic vasodilation, while prostacylin analogues relax cerebral vessels, increasing cGMP and cAMP, much as does elevated CO2 (Par- fenova et al. 1994). These results suggest that cyclic nucleotides are involved in hypercapnic vasodilation, via a prost- anoid-dependent mechanism (Parfenova et al. 1994). At the receptor level, CO2- induced cerebrovascular relaxation appears to be mediated via glibenclamide- sensitive potassium channels (Faraci et al. 1994). Taken together, these findings suggest that carbonic anhydrase inhibition may relax resistance vessels by in- ducing vasodilator prostanoids and activ- ating glibenclamide-sensitive potassium channels.

Two studies find that dorzolamide lowers IOP without changing retinal or optic nerve head perfusion in healthy persons (Grunwald et al. 1997; Pillunat et al.

1999). A third study using fluorescein an- giography to quantify retinal hemodynamics, as opposed to a laser Doppler device, found hastened arteriovenous passage times in normal subjects (Harris et al. 1996). Dorzolamide also increases retinal arteriovenous dye transit rate in conjunction with IOP reductions in glaucoma patients (Sugrue 2000; Harris et al.

In Press). In POAG and NTG, the topical medication also reduces resistance indices in the central retinal and posterior ciliary arteries, suggesting that choroidal and retinal vascular resistance and IOP may be reduced in tandem (Martinez et al.

1999; Tural et al. 2000).

An improvement in ocular blood flow, in order to be clinically significant, must be accompanied by measurable improve- ments in either oxygen delivery or visual function in the eyes of glaucoma patients.

In anesthetized animals, oxygen tension immediately anterior to the optic disc is increased during intravenous administration of either acetazolamide or dorzolamide (Stefansson et al. 1999). In normal tension glaucoma subjects, central visual function measured by contrast sensitivity is significantly increased after four weeks of dorzolamide treatment (Harris et al.

1999). Long term testing on dorzolamid-

e’s effect on the visual field is underway.

These promising results suggest that topical dorzolamide could chronically in- crease blood flow to and oxygen tension within the optic nerve head in glaucoma patients, potentially improving visual function.

Conclusion

The diminished ability of the aging, atherosclerotic eye to autoregulate blood flow magnifies the risk for ischemic damage under conditions that reduce ocular perfusion pressure. Without autoregulation, any rise in ocular tension reduces nutrient delivery, with both elevated IOP and reduced tissue perfusion potentially contributing to retinal ganglion cell apoptosis. Therapies developed from this concept of the simultaneous clinical management of IOP and blood flow should target both mechanical and vascular factors, recognizing that both may play im- portant and interacting roles in disease onset and progression.

Acknowledgement

Supported by Research to Prevent Blindness, and by NIH grant EY 10801 (Dr Harris).

References

Becker B (1954): Decrease in intraocular pressure in man by carbonic anhydrase inhibitor:

Diamox. A preliminary report. Am J Ophthalmol 37: 13–15.

Bednarczyk EM, Remler B, Weikart C, Nelson AD & Reed RC (1998): Global cerebral blood flow, blood volume, and oxygen metabolism in patients with migraine headache.

Neurology 50: 1736–1740.

Bill A & Sperber GO (1990): Control of retinal and choroidal blood flow. Eye 4: 319–325.

Boone KB, Miller BL & Lesser IM (1992):

Neuropsychological correlates of white-matter lesions in healthy elderly subjects: a threshold effect. Arch Neur 49: 549–554.

Chauhan BC (1995): The relationship between intraocular pressure and visual field progression in glaucoma. In: Drance SM (ed.) Update to Glaucoma, Blood Flow, and Drug Treatment. Amsterdam. Kugler: 1–6.

Cellini M, Possati GL, Profazio V, Sbrocca M, Caramazza N & Caramazza R (1997): Color Doppler imaging and plasma levels of endothelin-1 in low-tension glaucoma. Acta Ophthalmol Scand 224: 11–13.

Chung HS, Harris A, Kagemann L & Martin B (1999): Peripapillary retinal blood flow in

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normal-tension glaucoma. Br J Ophthalmol 83: 466–469.

Cioffi GA & Sullivan P (1999): The effect of chronic ischemia on the primate optic nerve.

Eur J Ophthalmol 9: S34–36.

Curseifen C, Wisse M, Curseifen S, Junemann A, Martus P & Korth M (2000): Migraine and tension headache in high-pressure and normal-pressure glaucoma. Am J Ophthal- mol 129: 102–104.

Dumskyj MJ, Eriksen JE, Dore KJ & Kohner EM (1996): Autoregulation in the human retinal circulation: assessment using iso- metric exercise, laser Doppler velocimetry, and computer-assisted image analysis.

Microvasc Res 51: 378–392.

Endres M, Fan G, Hirt L, Fujii M, Matsushita K, Liu X, Jaenisch R & Moskowitz MA (2000): Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression. J Cereb Blood Flow Metab 20:

139–144.

Fafowara OF & Osuntokun O (1997): Age-related eye disease in the elderly members of a rural African community. E African Med J 74: 435–437.

Faraci FM, Bruse KR & Heistad DO (1994):

Cerebral vasodilation during hypercapnia.

Role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke 25: 1679–

1684.

Flammer J, Haefliger IO, Orgul S & Resink T (1999): Vascular dysregulation: a principal risk factor for glaucomatous damage? J Glaucoma 8: 212–219.

Gass A, Flammer J, Linder L, Romerio SC, Gasser P & Haefeli WE (1997): Inverse cor- relation between endothelin-1-induced peripheral microvascular vasoconstriction and blood pressure in glaucoma patients. Graef- es Arch Clin Exp Ophthalmol 235: 634–638.

Gross RL, Hensley SH, Gao F, Yang XL, Dai SC & Wu SM (2000): Effects of betaxolol on light responses and membrane conductance in retinal ganglion cells. Invest Ophthalmol Vis Sci 41: 722–728.

Grunwald JE, Mathur S & DuPont J (1997):

Effects of dorzolamide hydrochloride 2% on the retinal circulation. Acta Ophthalmol Scand 75: 236–238.

Grunwald JE, Piltz J, Hariprasad SM, Dupont J & Maguire MG (1999): Optic nerve blood flow in glaucoma: effect of systemic hypertension. Am J Ophthalmol 127: 516–522.

Grunwald JE, Riva CE & Kozart DM (1988):

Retinal circulation during a spontaneous rise of intraocular pressure. Br J Ophthal- mol 72: 754–758.

Grunwald JE, Sinclair SH & Riva CE (1982):

Autoregulation of the retinal circulation in response to decrease of intraocular pressure below normal. Invest Ophthalmol Vis Sci 23: 124–127.

Haefliger IO, Dettmann E, Liu R, Meyer P, Prunte C, Messerli J & Flammer J (1999):

Potential role of nitric oxide and endothelin in the pathogenesis of glaucoma. Surv Ophthalmol 43: S51–S58.

Harris A, Arend O, Beck D, Martin BJ & Ar- end S (1996): Effects of Topical Dorzolami- de on Retinal and Retrobulbar Hemody- namics. Acta Ophthalmologica Scand 74:

4896–4899.

Harris A, Arend O, Bohnke K, Kroepfl E, Danis R & Martin B (1996): Retinal blood flow during dynamic exercise. Graefe’s Arch Clin Exp Ophthalmol 234: 440–444.

Harris A, Arend O, Chung HS, Kagemann L, Cantor L & Martin B (2000): A comparative study of betaxolol and dorzolamide on the ocular circulation in normal-tension glaucoma patients. Ophthalmology 107: 430–

434.

Harris A, Arend O, Kagemann L, Garrett M, Chung HS & Martin B (1999): Dorzolami- de, visual function and ocular hemodynamics in normal-tension glaucoma. J Ocu- lar Pharm and Therapeutics 15: 189–197.

Harris A, Harris M, Biller J, Kagemann L, Chung HS, Ciulla TA & Martin B (2000):

Aging affects the retrobulbar circulation dif- ferently in females and males. Arch Ophthalmol 118: 1076–1080.

Harris A, Sergott RC, Spaeth GL, Katz JL, Lieb WE, Shoemaker JA & Martin BJ (1994): Color Doppler analysis of ocular vessel blood velocity in normal tension glaucoma. Am J Ophthalmol 118: 642–649.

Hayreh S (1975): Anterior Ischemic Optic Neuropathy. New York, NY. Springer-Ver- lag NY, Inc.

Hayreh SS (1995): The optic nerve head circulation in health and disease. Exp Eye Res 61:

259–272.

Hayreh S (1997): Factors influencing blood flow in the optic nerve head. J Glaucoma 6:

412–425.

Hayreh S, Bill A & Sperber GO (1994): Effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeys. Graefe’s Arch Clin Exp Ophthalmol 232: 745–752.

Herholz K, Heindel W & Rackl A (1990): Re- gional cerebral blood flow in patients with leuko-araiosis and atherosclerotic carotid artery disease. Arch Neur 47: 392–396.

Hollo G, Lakatos P & Farkas K (1998): Cold pressor test and plasma endothelin-1 con- centration in primary open-angle and capsu- lar glaucoma. J Glaucoma 7: 105–10.

Ju W K, Kim KY, Hofmann HD, Kim IB, Lee MY, Oh SJ & Chun MH (2000): Selective neuronal survival and upregulation of PCNA in the rat inner retina following tran- sient ischemia. J Neuropath Exp Neurol 59:

241–250.

Katai N & Yoshimura N (1999): Apoptotic retinal neuronal death by ischemia-reperfusion is executed by two distinct caspase family proteases. Invest Ophthalmol Vis Sci 40: 2697–2705.

Kiss B, Dallinger S, Findl O, Rainer G, Eichler HG & Schmetterer L (1999): Acetazolami- de-induced cerebral and ocular vasodilation in humans is independent of nitric oxide.

Am J Physiol 276: R1661–1667.

Klein BE, Klein R & Linton KL (1992): Intra- ocular pressure in an American community.

The Beaver Dam Eye Study. Invest Ophthal- mol Vis Sci 33: 2224–2228.

Larsson E, Nanobashvili A, Kokaia Z & Lind- vall O (1999): Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab 19:

1220–1228.

Maren TH (1967): Carbonic anhydrase: chem- istry, physiology, and inhibition. Physiol Rev 47: 595–781.

Maren TH (1987): Carbonic anhydrase: gen- eral perspectives and advances in glaucoma research. Drug Dev Res 10: 266–276.

Martinez A, Gonzalez F, Capeans C, Perez R & Sanchez-Salorio M (1999): Dorzolami- de effect on ocular blood flow. Invest Ophthalmol Vis Sci 40: 1270–1275.

Matsui H, Murakami M, Wynns GC, Conroy CW, Mead A, Maren TH & Sears ML (1996): Membrane carbonic anhydrase (IV) and ciliary epithelium. Carbonic anhydrase activity is present in the basolateral mem- branes of the non-pigmented ciliary epithelium of rabbit eyes. Exp Eye Res 62: 409–417.

Matsuura K & Kawai Y (1998): Effects of hy- pothermia and aging on postischemic reperfusion in rat eyes. Jap J Physiol 48: 9–15.

McPherson RW, Kirsch JR, Ghaly RF &

Traystman RJ (1995): Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates. Stroke 26: 682–687.

Michelson G, Langhans M J, Harazny J &

Dichtl A (1998): Visual field defect and perfusion of the juxtapapillary retina and the neuroretinal rim area in primary open-angle glaucoma. Graefe’s Arch Clin Exp Ophthal- mol 236: 80–85.

Morgan J, Caprioli J & Koseki Y (1999): Ni- tric oxide mediates excitotoxic and anoxic damage in rat retinal ganglion cells cocul- tured with astroglia. Arch Ophthalmol 117:

1524–1529.

Nickells RW (1999): Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death.

Surv Ophthalmol 43: S151–S161.

Nomura H, Shimokata H, Ando F, Miyake Y & Kuzuya F (1999): Age-related changes in intraocular pressure in a large Japanese population: a cross-sectional and longitudi- nal study. Ophthalmology 106: 2016–2022.

Noske W, Hensen J & Wiederholt M (1997):

Endothelin-like immunoreactivity in aqueous humor of patients with primary open- angle glaucoma and cataract. Graefes Arch Clin Exp Ophthalmol 235: 551–552.

O’Brien C & Butt Z (1999): Blood flow velocity in the peripheral circulation of glaucoma patients. Ophthalmologica 213: 150–153.

Oku H, Sugiyama T, Kojima S, Watanabe T &

Azuma I (1999): Experimental optic cup en- largement caused by endothelin-1-induced chronic optic nerve head ischemia. Surv Ophthalmol 44: S74–84.

(7)

Ong K, Farinelli A, Billson F, Houang M &

Stern M (1995): Comparative study of brain magnetic resonance imaging findings in patients with low-tension glaucoma and control subjects. Ophthalmology 102: 1632–

1638.

Osborne N, Ugarte M, Chao M, Chidlow G, Bae JH, Wood JP & Nash MS (1999): Neur- oprotection in relation to retinal ischemia and relevance to glaucoma. Surv Ophthal- mol 43: S102–S128.

Parfenova H, Shibata M, Zuckerman S &

Leffler CW (1994): CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation. Am J Physiol 266: H1494–H1501.

Pease ME, McKinnon SJ, Quigley HA, Kerri- gan-Baumrind LA & Zack DJ (2000): Ob- structed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. In- vest Ophthalmol Vis Sci 41: 764–774.

Pillunat LE, Anderson DR, Knighton RW, Joos KM & Feuer WJ (1997): Autoregul- ation of human optic nerve head circulation in response to increased intraocular pressure. Exp Eye Res 64: 737–744.

Pillunat LE, Bohm AG, Koller AU, Schmidt KG, Klemm M & Richard G (1999): Effect of topical dorzolamide on optic nerve head blood flow. Graefe’s Arch Clin Exp Ophthal- mol 237: 495–500.

Ponticello GS, Sugrue MF, Plazonnet B & Du- rand-Cavagna G (1998): Dorzolamide, a 40- year wait. From an oral to a topical carbonic anhydrase inhibitor for the treatment of glaucoma. Pharma Biotech 11: 555–574.

Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ & Zack DJ (1995): Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:

774–786.

Ringelstein EB, Van Eyck S & Mertens I (1992): Evaluation of cerebral vasomotor re- activity by various vasodilating stimuli:

comparison of CO2 to acetazolamide. J Cer- eb Blood Flow Metab 12: 162–168.

Riva CE, Cranstoun SD & Petrig BL (1996):

Effect of decreased ocular perfusion pressure on blood flow and the flicker-induced flow response in the cat optic nerve head.

Microvasc Res 52: 258–269.

Riva C E, Sinclair SH & Grunwald JE (1981):

Autoregulation of retinal circulation in response to decrease in perfusion pressure. In- vest Ophthalmol Vis Sci 21: 34–38.

Robinson F, Riva CE, Grunwald JE, Petrig BL & Sinclair SH (1986): Retinal blood flow autoregulation in response to an acute in- crease in blood pressure. Invest Ophthalmol Vis Sci 27: 722–726.

Rossetti L, Marchetti I, Orzalesi N, Scorpig- lione N, Torri V & Liberati A (1993): Ran- domized clinical trials on medical treatment of glaucoma. Are they appropriate to guide clinical practice? Arch Ophthalmol 111: 96–

103.

Sossi N & Anderson DR (1983): Effect of elevated intraocular pressure on blood flow. Oc- currence in cat optic nerve head studied with iodoantipyrine I-125. Arch Ophthalmol 101:

98–101.

Sperber GO & Bill A (1985): Blood flow and glucose consumption in the optic nerve, retina and brain: effects of high intraocular pressure. Exp Eye Res 41: 639–653.

Stefansson E, Jensen PK, Eysteinsson T, Bang K, Kiilgaard JF, Dollerup J, Scherfig E & la Cour M (1999): Optic nerve oxygen tension in pigs and the effect of carbonic anhydrase inhibitors. Invest Ophthalmol Vis Sci 40:

2756–2761.

Stroman GA, Stewart WC, Golnik KC, Cure JK & Olinger RE (1995): Magnetic resonance imaging in patients with low-tension glaucoma. Arch Ophthalmol 113: 168–172.

Sucher NJ, Lipton SA & Dreyer EB (1997):

Molecular basis of glutamate toxicity in retinal ganglion cells. Vis Res 37: 3483–3493.

Sugrue MF (2000): Pharmacological and ocular hypotensive properties of topical carbonic anhydre inhibitors. Prog Ret Eye Res 19: 87–112.

Taki K, Kato H, Endo S, Inada K & Totsuka

K (1999): Cascade of acetazolamide-induced vasodilatation. Res Com Mol Path Pharm 103: 240–248.

Tezel G, Kass MA, Kolker AE, Becker B &

Wax MB (1997): Plasma and aqueous hum- or endothelin levels in primary open-angle glaucoma. J Glaucoma 6: 83–89.

Tielsch JM, Sommer A, Katz J, Royale RM, Quigley HA & Javitt J (1991): Racial variations in the prevalence of primary open- angle glaucoma. The Baltimore Eye Survey.

JAMA 266: 369–374.

Tural E, Dogan S, Ozcan H & Aytac S (2000):

The effect of dorzolamide on intraocular pressure and ocular blood flow with normal tension glaucoma. Eur Glaucoma Soc 6: 19 (Abstract).

Walton M, Connor B, Lawlor P, Young D, Siri- manne E, Gluckman P, Cole G & Dragunow M (1999): Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res – Brain Res Rev 29: 137–

168.

Wang JJ, Mitchell P & Smith W (1997): Is there an association between migraine headache and open-angle glaucoma? Findings of the Blue Mountains Study. Ophthalmology 104:

1714–1719.

Weinstein JM, Duckrow RB, Beard D & Bren- nan RW (1983): Regional optic nerve blood flow and its autoregulation. Invest Ophthal- mol Vis Sci 24: 1559–1565.

Correspondence:

Alon Harris, PhD Rotary 134

Department of Ophthalmology Indiana University School of Medicine Indianapolis, IN 46202-5175

Tel: 317 278 2566 Fax: 317 278 1007

e-mail: alharris/indiana.edu