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(Investigative Ophthalmology and Visual Science. 2003;44:2565-2572.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0913
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Effects of Cold-Induced Vasospasm in Glaucoma: The Role of Endothelin-1

Marcelo T. Nicolela, Suzanne N. Ferrier, Christine A. Morrison, Michele L. Archibald, Terry L. LeVatte, Karin Wallace, Balwantray C. Chauhan, and Raymond P. LeBlanc

From the Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. Vasospasm has been associated with glaucoma, but its mechanisms have not been elucidated. The present study was designed to evaluate the role of endothelin (ET)-1, a potent endogenous vasoconstrictor, in the genesis of vasospasm in glaucoma.

METHODS. Our sample contained patients with open-angle glaucoma (n = 43) and subjects with normal nonglaucomatous eyes and without acral vasospasm (n = 27). After the eligibility visit, all subjects underwent a provocative cooling test, consisting of wearing for 30 minutes a head-vest cooling garment containing coolant fluid. Blood was collected before and after cooling, and plasma ET-1 was determined by immunoassay. In addition, visual fields and retinal blood flow, measured with a confocal scanning laser and Doppler flowmeter, were measured before and after cooling. Peripheral finger flow, skin temperature, and blood pressure were monitored during the experiment. A recovery visit was performed within 1 month, when visual field and retinal blood flow measurements were repeated.

RESULTS. Baseline plasma ET-1 levels were similar between patients with glaucoma and control subjects (mean ± SD: 2.81 ± 1.29 and 2.56 ± 1.36 pg/mL, respectively, P = 0.465). Patients with glaucoma, however, had a significant increase in plasma ET-1 after cooling (mean ± SD increase of 34% ± 52%, P = 0.001), not observed in control subjects (mean ± SD increase of 7% ± 43%, P = 0.750). No significant change in visual fields or retinal blood flow was observed after cooling in either group. Patients with glaucoma who had evidence of acral vasospasm, however, were more likely to show deterioration in visual fields after cooling than patients without acral vasospasm (P = 0.007).

CONCLUSIONS. Patients with glaucoma have an abnormal increase in plasma ET-1 after the body cools. It is possible that at least in some patients, increased levels of ET-1 in response to vasospastic stimuli may be involved in the pathogenesis of glaucomatous damage.

The mechanisms that lead to the development of glaucomatous optic neuropathy are still not completely understood. In at least some patients, factors besides increased intraocular pressure (IOP) probably play a role in the pathogenesis of the disease. Among these other factors, vasospasm has been suggested to be causative by several investigators, leading to decreased blood flow or a diminished capacity to autoregulate blood flow to the optic nerve head.1 2 Indirect evidence has supported an association between vasospasm and glaucoma, including a high prevalence of vasospastic diseases, such as migraine,3 4 and an abnormal peripheral reactivity to cold in glaucomatous eyes.1 5 6 7 8 A recent study has also identified migraine as an important risk factor associated with progression of the disease in patients with untreated normal-tension glaucoma.9

Endothelin (ET)-1 is a peptide produced mainly by the vascular endothelium. It is a potent vasoconstrictor thought to be involved in a variety of diseases associated with deficient or disregulated blood flow, such as ischemic heart disease,10 11 cerebral vasospasm,12 13 diabetes,14 Raynaud’s disease,15 16 and others. Investigators in a few studies have examined the role of ET-1 in glaucoma, with controversial results.17 18 19 20

Raised basal levels of ET-1 or, more important, abnormal release of ET-1 after a vasospastic stimulus may be a hallmark of abnormal endothelial function and could be related to the genesis of vasoconstriction after vasospastic stimuli.

This study was designed to investigate the possibility of an abnormal ET-1–mediated vasospastic response in patients with glaucoma who are exposed to a strong cold stimulus. In addition, we wanted to investigate the possible effects of cold-induced vasospasm on visual function and retinal blood flow in these patients.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study Subjects
This study adhered to the tenets of the Declaration of Helsinki and was approved by the Research Ethics Committee of the Queen Elizabeth II Health Sciences Centre. Subjects with open-angle glaucoma and healthy control subjects were enrolled in the study, after providing informed consent, if they met the following inclusion and exclusion criteria. Inclusion criteria for the patients with glaucoma were presence of typical optic nerve head changes, including increased cupping and/or focal or diffuse loss of neuroretinal rim; compatible visual field loss, with an abnormal Glaucoma Hemifield Test (Statpac program; Zeiss-Humphrey Systems, Inc., Dublin, CA); open angle on gonioscopy; and age between 35 and 70 years. Inclusion criteria for the control subjects were no evidence of glaucomatous disc damage; visual field test results within normal limits (normal Mean Deviation and Glaucoma Hemifield Test; Zeiss-Humphrey Systems, Inc.); no evidence of vasospasm, including presence of Raynaud’s disease or migraine; and nonvasospastic acral blood flow test (defined later). Exclusion criteria for both patients and control subjects were presence of any retinal or optic nerve disease (except glaucoma in the patient group) that could lead to visual field loss and systemic use of any vasoactive drugs, including drugs for treatment of systemic hypertension or heart disease, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, ß-adrenergic blockers, and {alpha}-1 adrenergic blockers.

Prospective normal control subjects were initially submitted to an acral vasospasm test designed to evaluate reactivity to cold (finger-flow test), as described previously by Drance et al.6 Briefly, a probe of a laser Doppler flowmeter (ALF 21R; Transonic, Inc., Ithaca, NY) is attached to one finger, and the baseline blood flow is digitally recorded in real time and displayed on a computer monitor. The hand is then immersed in warm water (41°C) for 2 minutes, and the finger blood flow is continually monitored until stable measurements are obtained. The hand is immersed in ice-cold water (4°C) for 10 seconds and then removed from the water. The finger blood flow is continuously monitored until it returns to the baseline level, or for 5 minutes if it does not return to baseline level. An acral vasospastic response is defined as a ratio higher than 7 between maximum blood flow when warm and minimum blood flow after cold stimulus. Control subjects who were found to have an acral vasospastic response were excluded from further testing. This test was also performed on the patients with glaucoma, but patients with or without acral vasospasm were included in our study.

Study Procedures
All enrolled subjects had two study visits. If both eyes qualified for the study, one eye was randomly selected to be tested. On visit 1 (cooling visit), subjects initially underwent a baseline visual field test (program 24-2; Humphrey Field Analyzer; Zeiss-Humphrey Systems, Inc.), and baseline retinal blood flow was measured using the confocal scanning laser Doppler flowmeter (Heidelberg Retina Flowmeter; Heidelberg Engineering GmbH, Dossenhein, Germany). This device combines a laser Doppler flowmeter with a scanning laser system, generating a two-dimensional map of microvascular perfusion of the imaged tissue. The examined area is 2.7 x 0.7 mm in size, and the total acquisition time is approximately 2 seconds. Parameters such as blood volume, flow, and velocity can be quantified, in arbitrary units, at locations in the perfusion map in a reliable and reproducible way.21 22 23 Images focused on the peripapillary retina were taken from the superotemporal, temporal, and inferotemporal peripapillary retina, with the edge of the optic disc within each imaged area (Fig. 1) . At least three images were obtained with the retinal flowmeter for each of the three sections of the peripapillary retina, and the best image from each section was used for analysis, according to protocol described previously.23 24



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  		FIGURE 1. Example of three images of the optic disc and peripapillary retina obtained by retinal flowmetry. Retinal capillary blood flow was measured in the whole peripapillary retina, with exclusion of the optic disc.

 
Subjects then underwent body surface cooling (Mark VII Microclimate System; Life Support Systems, Inc., Mountain View, CA). The apparatus consists of a head-vest cooling garment containing a coolant fluid composed of 20% propylene glycol and 80% water. This method of body surface cooling has been used previously in clinical studies involving patients with multiple sclerosis and spinal cord injuries,25 26 as well as in patients with Raynaud’s disease.27 After 30 minutes of body surface cooling, perimetry and retinal flowmetry were repeated, with subjects still wearing the cooling apparatus. During cooling, subjects had skin temperature monitored (using disposable skin thermometers attached to the forearm) and finger flow continuously recorded, using the laser Doppler flowmeter probe previously described. Blood pressure and pulse rate were recorded immediately after retinal flowmetry, both before and after cooling. IOP was also recorded at the end of the experiment.

In addition, just before and after cooling, blood samples were collected from a peripheral vein in the arm to measure plasma ET-1. Plasma was immediately separated by centrifugation and frozen at -80°C. Plasma ET-1 was measured with a commercial immunoassay kit (R&D, Inc., Minneapolis, MN). In our study, plasma ET-1 was determined from the mean of two wells for each plasma sample. An internal calibration was performed with purified ET-1 at different concentrations during each assay. ET-1 concentrations in both samples from each subject (before and after cooling) were always measured in the same batch and on the same day.

Visit 2 (recovery visit) occurred within 1 month of visit 1. During this visit, subjects underwent visual field testing and retinal flowmetry by the same protocol as was used in the cooling visit. Blood pressure, pulse rate, and IOP were also recorded.

Ocular perfusion pressure was calculated before and after cooling and during the recovery visit, using arterial blood pressure and IOP, according to the formula: OPP = 2/3(2/3DBP + 1/3SBP) - IOP, where OPP is ocular perfusion pressure, DBP is diastolic blood pressure, SBP is systolic blood pressure, and IOP is IOP.

Data Analysis
The effects of the cooling provocation test on visual field function, retinal blood flow, and plasma level of ET-1 in the patients and control subjects were evaluated by comparing results before and after the cooling test. Visual fields were evaluated by comparing the global indices mean deviation (MD) and corrected pattern standard deviation (CPSD) before and after cooling. In addition, the visual field printouts (before and after cooling from visit 1 and the recovery visit from visit 2) were subjectively evaluated by two independent observers. The identity of the patient, diagnosis group, and order of visual fields tested in visit 1 were masked. The observers were asked to decide whether there was any clinical difference between the three fields—that is, whether a field was worse or similar to the other two fields. In cases of disagreement between the observers, a final decision was reached by consensus after reviewing the fields together.

The retinal flowmetry results were evaluated using the scanning laser Doppler flowmetry software (Heidelberg Engineering GmbH), as described by Michelson et al.28 After the image is imported from the flowmetry software, this program automatically excludes over- and underexposed areas and detects and excludes large retinal vessels. The operator can identify and exclude the effect of any saccades in the image. Before analysis, every image was qualitatively graded, ranging from 0 (poorest quality) to 5 (best quality), taking into consideration brightness and sharpness of the image, ability to identify small retinal vessels, and presence of saccadic eye movements. Images considered to have poor quality (grades ≤ 2) were excluded from further analysis. After selecting the best image from each of the peripapillary locations, we measured the mean blood flow from the peripapillary retina, using this automated full-field analysis.

Statistical analysis was performed using computer software (SPSS, ver. 10.0 for Windows; SPSS Inc., Chicago, IL). Two-tailed parametric or nonparametric tests (depending on the distribution of the samples) were used when appropriate. A paired t-test or the Wilcoxon test for related samples was used to evaluate the effects of cooling on the visual field indices, blood flow parameters, and plasma ET-1 levels. General linear model (GLM) repeated-measures analysis of variance was used to investigate the effects of cooling on parameters measured repeatedly during the experiment. Two-tailed statistical tests were used, and P < 0.05 was considered significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Forty-three patients with glaucoma (16 men, 27 women; mean ± SD age, 59.5 ± 12.6 years; range, 31–80) and 27 normal control subjects (7 men, 20 women; mean ± SD age, 46.9 ± 9.7 years; range, 34–64) were enrolled in the study. Eight normal control subjects (22.9% of all normal control subjects tested) exhibited acral vasospasm during the eligibility visit and were excluded from the study, according to the protocol. There was no significant difference in the gender distribution between the glaucoma and normal control groups (P = 0.328, {chi}2 test). The patients with glaucoma were significantly older than the control subjects (P < 0.001, t-test). Because of the age difference, the effect of age was analyzed in every parameter evaluated in the study, and parameters significantly affected by age were corrected, using age as a covariate in the appropriate test.

Of the 43 patients with glaucoma, 13 (30%) were classified as having acral vasospasm, based on the finger-flow test. There were no significant differences in gender or age between those patients with glaucoma with and without acral vasospasm (P > 0.565).

Effect of Cooling Test on Plasma ET-1 Levels
Basal plasma levels of ET-1 before the cooling test were not significantly different between patients with glaucoma and normal control subjects (P = 0.465, t-test). After cooling, however, plasma ET-1 was significantly higher in the glaucoma group (P = 0.020, t-test, Table 1 , Fig. 2 ). Paired t-tests showed a highly significant increase in ET-1 after cooling in the glaucoma group (P = 0.001), but no significant difference in the control group (P = 0.750).


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  		TABLE 1. Plasma (ET-1) and Average Individual Percentage Increase in ET-1 after Cooling

 


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  		FIGURE 2. Box plot distribution of plasma ET-1 before and after cooling in the control and glaucoma groups. Boxes: 75th and 25th percentiles and the median; error bars: largest and the smallest value.

 
To account for different baseline levels of plasma ET-1, we calculated the percentage change in ET-1 in each subject after cooling, according to the following formula

The glaucoma group showed a significantly higher percentage change after cooling than the normal control group (P = 0.037, Table 1 ).

Among the patients with glaucoma, the presence of acral vasospasm had little impact on the increase of plasma ET-1 observed after cooling. The percentage increase in ET-1 level after cooling in the glaucoma group with and without acral vasospasm was similar (Table 1 ; P = 0.616). The patients with glaucoma without acral vasospasm had a significantly higher percentage increase in ET-1 after cooling than did normal control subjects (P = 0.035, Table 1 ). The differences between the patients with glaucoma with acral vasospasm and normal control subjects did not reach statistical significance (P = 0.197, Table 1 ), despite the fact that the mean difference in percentage ET-1 increase after cooling between the two groups was 20.6%. Given the standard deviation observed in our study and assuming an {alpha} of 0.05, the power to detect a 10%, 20%, or 30% difference in the percentage of ET-1 increase after cooling between patients with glaucoma with or without acral vasospasm was only 8%, 20%, and 38%, respectively, and between patients with glaucoma with acral vasospasm and normal control subjects was only 9%, 22%, or 45%, respectively.

Age had no effect on the change in plasma ET-1 after the cooling test, both for all the subjects combined (Fig. 3 ; P = 0.595) and for each group separately (P = 0.417 and P = 0.803 for patients with glaucoma and normal control subjects, respectively).



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  		FIGURE 3. Scatterplot of percentage change in ET-1 after cooling by age, with the best-fit line superimposed. No significant linear correlation was observed between these two variables (P = 0.600).

 
Effect of Cooling Test on the Visual Field
The MD and CPSD observed during the experiment are displayed in Table 2 . After cooling, no significant effect was observed in the visual field indices, in either the glaucoma or control group (P > 0.190, Wilcoxon test). We calculated the power of our study to detect significant differences in these visual field indices in the glaucoma group after cooling, had they existed. Assuming an {alpha} of 0.05, the power to detect a 0.5- and a 1.0-dB change after cooling in either MD or CPSD was 57% and 99%, respectively.


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  		TABLE 2. Visual Field Indices before and after Cooling and during the Recovery Visit

 
No significant effect of cooling was observed in the qualitative assessment performed by the two observers of the visual fields in the whole glaucoma group (P = 0.242, {chi}2 test, Table 3 ). When patients with glaucoma were analyzed separately, based on the presence of acral vasospasm as defined in our study, there was a significant difference between the two subgroups (P = 0.007, {chi}2 test), with the acral vasospasm group showing a greater percentage of deteriorated visual fields after the cooling test (Table 3 , Fig. 4 ).


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  		TABLE 3. Qualitative Assessment of Visual Field Test Results of the Patients with Glaucoma Obtained before and after the Cooling Test

 


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  		FIGURE 4. Visual fields before and after cooling and during recovery visit of one patient with glaucoma. Two observers who were masked to the order of the visual fields judged that the postcooling visual field was worse than shown by results of the other two tests. In this patient, the plasma ET-1 before cooling was 2.02 pg/mL, increasing to 3.85 pg/mL after cooling (a 90.6% increase).

 
Effect of Cooling Test on Retinal Blood Flow
Table 4 and Figure 5 show the peripapillary retinal blood flow, measured with the retinal flowmeter before and after the cooling test. Retinal capillary blood flow in the temporal retina was reduced significantly after the cooling test in the normal control group (P = 0.038, paired t-test), but not in the other areas in the control group (P > 0.350) nor in any retinal area in the glaucoma group (P > 0.119). To evaluate whether our results were influenced by the baseline flow levels, we calculated the percentage change in retinal blood flow in each area, in a similar manner as described for ET-1. The percentage change in blood flow was very similar in the glaucoma and control groups for every retina area (Table 4) , with no statistically significant difference between the two groups (P > 0.106, t-test).


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  		TABLE 4. Retinal Peripapillary Capillary Blood Flow Measured with Retinal Flowmetry and Percentage Change in Blood Flow after Cooling

 


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  		FIGURE 5. Box plot distribution of retinal capillary blood flow measured with retinal flowmetry in the three sections of the peripapillary retina (temporal, superotemporal, and inferotemporal) in patients with glaucoma and control subjects.

 
We calculated the power of our study to detect retinal capillary blood flow changes after cooling. Given the observed standard deviations and assuming an {alpha} of 0.05, the power to detect a 5% and a 10% change after cooling in retinal capillary blood flow in the glaucoma group varied between 35% and 56% and between 91% and 98% respectively, depending on the region of the peripapillary retina evaluated (superior, temporal, or inferior).

Effect of Cooling Test on Skin Temperature and Finger Flow
There was a significant decrease in skin temperature during the cooling test (P < 0.001, GLM repeated-measurements analysis of variance), which was similar in patients with glaucoma and in control subjects (Fig. 6A) . Paradoxically, however, blood flow measured in the finger increased during the first 10 minutes of cooling, but returned to baseline levels in the glaucoma group and declined below baseline levels in the control group (Fig. 6B) . This finger-flow effect during cooling was significant (P = 0.001, GLM repeated-measurements analysis of variance) but no significant difference was observed between patients with glaucoma and control subjects (between-subjects effect with P > 0.050).



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  		FIGURE 6. Skin temperature (A) and finger flow (B), measured in arbitrary units with laser Doppler flowmetry, observed during the cooling test in patients with glaucoma and control subjects.

 
Effect of Cooling Test on Blood Pressure and Ocular Perfusion Pressure
Table 5 shows the systolic and diastolic blood pressures as well as the calculated ocular perfusion pressure during the study. No significant difference was observed in the glaucoma group in any of the parameters after cooling (P > 0.200), but there was a statistically significant increase in diastolic blood pressure and ocular perfusion pressure with cooling in the control group (P = 0.009 and P = 0.002 respectively, paired t-test). Age correlated positively with blood pressure (both systolic and diastolic) and ocular perfusion pressure (P < 0.020), but not with changes in these parameters after cooling (P > 0.555).


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  		TABLE 5. Blood Pressure and Ocular Perfusion Pressure and Percentage Change after Cooling

 
Correlation between Changes in Various Parameters after Cooling
To investigate any correlation between the effects of the cooling test on plasma ET-1, visual field indices (MD and CPSD), retinal capillary blood flow, finger flow, skin temperature, and calculated perfusion pressure, we calculated the Pearson’s coefficient of correlation for the percentage of change obtained after the cooling test (except for the visual field indices, where the actual difference between pre- and postcooling results was used). No correlation was observed between these parameters, both in all subjects combined as well as in patients with glaucoma and control subjects analyzed separately (P > 0.050). No correlation between these parameters was observed when analyzing the two subgroups of patients with glaucoma—namely, patients with and without acral vasospasm.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In the present study, our patients with glaucoma, in contrast to the control subjects, had an abnormal increase in plasma levels of ET-1 when they underwent body cooling, despite similar basal plasma ET-1 levels between the two groups. These results suggest that patients with glaucoma have a hyperactivity of the mechanisms that control the production and/or release of ET-1 in response to vasospastic stimuli such as cold, as used in our study. This hyperactivity observed in the patients with glaucoma seemed to be independent of the presence of acral vasospasm, as defined by the finger-flow test used in this study. Similar changes in plasma levels of ET-1 after cooling were observed in patients with glaucoma, with or without acral vasospasm, and, moreover, significant differences in increase of ET-1 after cooling were observed between patients with glaucoma without acral vasospasm and normal control subjects who, according to our study criteria, also did not have acral vasospasm.

Some previous cross-sectional studies have evaluated basal levels of plasma ET-1 in patients with glaucoma and control subjects. Two studies showed elevated plasma ET-1 in normal tension glaucoma compared with control subjects,18 29 whereas others showed no significant difference in plasma ET-1 between subjects with normal tension glaucoma19 or high-tension glaucoma17 20 and normal control subjects. ET-1 was also elevated in the aqueous of patients with glaucoma compared with the control subjects, which may suggest its involvement in the regulation of IOP.17 30 31 In the present study, the basal levels of ET-1 were similar between the glaucoma and control groups. We did not specifically segregate the patients with glaucoma into those with normal or high-tension glaucoma, because segregation of patients based on an arbitrary IOP cutoff may not be adequate to support an implication of potentially different pathogenic mechanisms.

ET-1 is a potent vasoconstrictor believed to be a major player in local autoregulation of blood flow.32 33 34 It is produced by the vascular endothelial cells and released primarily abluminally. There are two known ET-1 receptors: ET-A and ET-B. The former is mainly present on the vascular smooth cells and is responsible for the vasoconstriction caused by ET-1, and the latter is mainly present on the vascular endothelium and is believed to produce transient vasodilatation through release of nitric oxide and/or prostacyclin.31 32 35 36

High levels of circulating ET-1 have been demonstrated in several diseases characterized by abnormal vasoreactivity, such as cerebral vasospasm after subarachnoid hemorrhages,12 13 Raynaud’s phenomenon,15 16 diabetes,14 congestive heart failure,37 ischemic heart disease,10 11 and pulmonary arterial hypertension,38 39 among others. ET-1 is believed to play an important role in the pathogenesis of these diseases. A clinical trial has recently demonstrated a positive functional effect of bosentan, a dual ET-A and ET-B receptor blocker, in pulmonary arterial hypertension.40

An abnormal release of ET-1 has been shown after localized cold provocation (hand immersion in cold water) in individuals with known vasospastic disorders such as Raynaud’s disease15 and essential acrocyanosis.16 Individuals with drug-induced coronary spasm were also found to have an abnormal increase in plasma ET-1, contrary to individuals in whom coronary spasm could not be induced.10 It is believed that in these conditions there is an abnormal response of the vascular endothelium to certain stimuli, leading to abnormally high levels of ET-1 and consequent vasoconstriction. A similar mechanism may also be present in at least some patients with glaucoma, as demonstrated in our study. Kaiser et al.19 also demonstrated a faulty regulatory mechanism in the production of ET-1 in normal tension glaucoma. In that study, the baseline plasma ET-1 was slightly, but not significantly, higher in patients with normal-tension glaucoma than in normal control subjects, but the physiologic increase in plasma ET-1 levels observed when subjects moved from a supine to an upright position was absent in the patients with normal-tension glaucoma.

Vasospasm has been associated with glaucoma, particularly normal-tension glaucoma, but its mechanisms have not been well established.3 4 5 6 41 42 It has been postulated that an imbalance between vasoconstrictor substances such as ET-1 and vasodilators such as nitric oxide are the cause of vasospasm in glaucoma.34 43 Vasospasm may also be more prevalent in those individuals with more focal damage of the optic disc than in patients with other types of glaucoma-induced loss.42 44 45 There is some evidence that patients with glaucoma who have vasospasm have a higher susceptibility to glaucomatous damage, which could be a consequence of a decreased dilation of blood vessels to properly autoregulate blood flow.8 9

We could not find any ocular functional or hemodynamic effects of cold provocation in our whole glaucoma group, assessed respectively by standard automated perimetry and blood flow measurements of the peripapillary retina, despite the fact that our study had more than 90% power to detect a 1-dB change in global visual field indices (MD or CPSD) and to detect a 10% change in retinal capillary blood flow. Moreover, there was no correlation between the increase in plasma ET-1 and visual function or blood flow indices in these subjects. There are several possible explanations for the lack of correlation. First, an increase in plasma levels of ET-1 measured after cooling from a vein in the arm may not translate into higher ET-1 levels in the ocular circulation. However, it is reasonable to assume that there is some correlation between the measured plasma levels and the local concentration in the ocular circulation. Second, a higher ET-1 level may not produce a decrease in retinal blood flow or consequent compromise in visual function. ET-1 can have different actions, depending on the tissues and mode of administration. In cats, for instance, Nishimura et al.35 showed a decrease in blood flow of the optic nerve head after vitreous injection of ET-1, but a temporary increase in optic nerve head blood flow after a bolus intravenous injection of ET-1, probably by acting on ET-B receptors of the endothelium cells and increasing nitric oxide. In our study, we showed a temporary increase in blood flow in the finger after cooling, which could be caused by a similar mechanism of increased intravascular ET-1 concentration. It is possible that the same increase in blood flow occurs initially in the ocular circulation after cooling, with a subsequent decrease in blood flow closer to baseline levels after 30 minutes, which is when we measured blood flow in the retina. A third and, in our view, most plausible explanation is that our methods of assessing visual function and retinal blood flow are not sensitive or specific enough to detect the small, transient changes produced by cooling associated with increased levels of ET-1.

Patients with glaucoma and acral vasospasm had a significantly higher proportion of worsening visual fields after cooling than patients with glaucoma without acral vasospasm, as judged by observers who were masked to ocular status and order of examination of the fields. This finding is in agreement with Gasser et al.1 and Gasser,41 who have shown that some patients with normal-tension glaucoma can show deterioration in visual fields after one hand is cooled. In a previous study, using a similar cooling protocol, Chauhan et al.27 demonstrated that, whereas there were no group differences in visual fields after cooling between subjects without glaucoma who had Raynaud’s disease and normal control subjects, some of the subjects with Raynaud’s disease showed both diffuse and localized visual field defects after cooling that disappeared the following day.

In conclusion, we have shown that patients with glaucoma have an abnormal increase in plasma ET-1 after a cooling provocation test compared with normal control subjects. This response could be related to abnormal control mechanisms of production of ET-1 by the vascular endothelium. Increased ET-1 could lead to decreased ocular blood flow. In this study, we used scanning laser Doppler flowmetry to evaluate retinal blood flow and did not demonstrate any significant change after cooling. We did not, however, use scanning laser Doppler flowmetry to evaluate the optic nerve head blood flow, which could be affected by the increase in ET-1 levels, because this technique is not optimal for the optic nerve head. This abnormal ET-1 response to cold, and presumably to other stimuli, could make these individuals more susceptible to elevated IOP or decreased ocular perfusion pressure and eventually could influence the development of glaucomatous damage. Further studies are needed to investigate why plasma ET-1 increases after vasospastic stimuli in glaucoma and the relation between this increase and the development of glaucomatous damage.


   Footnotes
 
Presented in part at the Annual Meeting of the Association for Research and Visual Sciences, Fort Lauderdale, Florida, May 2002.

Supported by grants from the E. A. Baker Foundation and Grant 317E from the Nova Scotia Health Research Foundation.

Submitted for publication September 7, 2002; revised November 7 and November 22, 2002; accepted December 5, 2002.

Disclosure: M.T. Nicolela, None; S.N. Ferrier, None; C.A. Morrison, None; M.L. Archibald, None; T.L. LeVatte, None; K. Wallace, None; B.C. Chauhan, None; R.P. LeBlanc, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Marcelo T. Nicolela, Eye Care Centre, 1278 Tower Road, Halifax, NS, Canada B3H 2Y9; nicolela{at}is.dal.ca.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Gasser, P, Flammer, J, Guthauser, U, Mahler, F. (1990) Do vasospasms provoke ocular diseases? Angiology 41,213-220
  2. Gasser, P, Flammer, J. (1987) Influence of vasospasm on visual function Doc Ophthalmol 66,3-18[CrossRef][Medline][Order article via Infotrieve]
  3. Phelps, CD, Corbett, JJ. (1985) Migraine and low-tension glaucoma: a case-control study Invest Ophthalmol Vis Sci 26,1105-1108[Abstract/Free Full Text]
  4. Wang, JJ, Mitchell, P, Smith, W. (1997) Is there an association between migraine headache and open-angle glaucoma? Findings from the Blue Mountains Eye Study Ophthalmology 104,1714-1719[Medline][Order article via Infotrieve]
  5. Gasser, P, Flammer, J. (1991) Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma Am J Ophthalmol 111,585-588[Medline][Order article via Infotrieve]
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