Influence of Exercise on Intraocular Pressure, Schlemm's Canal, and the Trabecular Meshwork

Abstract

Purpose: We aimed to assess the changes in IOP, Schlemm's canal (SC), and the trabecular meshwork (TM) in healthy individuals after exercise.

Methods: The area and perimeter of SC, TM thickness, IOP, pupil diameter, blood pressure (BP), heart rate, and plasma catecholamine concentrations were measured in 29 young healthy individuals before and after exercise by jogging for 20 minutes. The TM and SC in the superior, inferior, nasal, and temporal regions were evaluated by 80-MHz ultrasound biomicroscopy.

Results: In comparison with the baseline values, the post-exercise values of IOP had significantly reduced, and those of the pupil diameter, systolic and diastolic BP, and plasma catecholamine concentrations had significantly increased (all, P < 0.05). There were no significant differences in the proportions of eyes with observable SC before (81.9%) and after (90.5%; X = 3.652; P = 0.057) exercise. In comparison with the baseline values, the mean values of area (132.83 ± 19.67 vs. 155.33 ± 21.46 pixels; P < 0.001) and perimeter (54.94 ± 4.95 vs. 60.23 ± 4.19 pixels; P < 0.001) of SC and TM thickness (10.30 ± 1.28 vs. 11.48 ± 1.07 pixels; P < 0.001) after exercise were increased. The increase in area (r = 0.019, P = 0.923) and perimeter (r = −0.109, P = 0.573) of SC and TM thickness (r = −0.088, P = 0.651) were not significantly correlated with the decrease in IOP.

Conclusions: Aerobic exercise could cause sympathetic nerve stimulation, consequently causing the expansion of the TM and SC, which, in turn, leads to IOP reduction. Furthermore, SC and the TM might have an autonomic regulation function, and their expansion and collapse might not be completely dependent on the IOP.

Exercise is known to result in changes in IOP. In fact, IOP is decreased following aerobic exercise. Moreover, the decrease in IOP is reportedly correlated with the intensity and duration of exercise—accordingly, an increase in exercise intensity and duration results in a greater reduction of IOP.^1-4 Nevertheless, the mechanism underlying the decrease in IOP remains unclear. 

A total of 75% to 80% of aqueous humor secreted by the ciliary body flows out through the conventional trabecular meshwork (TM)–Schlemm's canal (SC) pathway.⁵ The major resistance to aqueous outflow is located in the juxtacanalicular tissue (JCT) region and the inner wall of SC.^6,7 Previous studies have shown that an acute elevation of IOP might cause the collapse of SC as well as compression of the TM, both of which could further increase the resistance of the aqueous outflow pathway.⁸ Moreover, Bull et al.⁹ showed that canaloplasty successfully reduced the IOP from 23.0 ± 4.3 mm Hg before surgery to 15.1 ± 3.1 mm Hg at 3 years after surgery in eyes with POAG, indicating that changes in SC can affect IOP. Yang et al.¹⁰ found that the outflow facility increased after perfusion with Y27632, a Rho-kinase inhibitor; in fact, the increase in the outflow facility was positively correlated with the expansion of the TM and JCT. These findings suggest that the status of the TM-SC pathway is associated with IOP as well as the outflow capacity of aqueous humor. 

In 1969, Bron¹¹ reported that aqueous humor flow was reduced in patients with Horner's syndrome. The administration of topical catecholamine drugs led to an increase in aqueous flow in these patients. Bron¹¹ speculated that the flow of aqueous humor had decreased as a result of decrease in or absence of sympathetic activity. In 1987, Belmonte et al.¹² reported that continuous stimulation of the cervical sympathetic nerve on one side caused a decrease in the IOP of the ipsilateral eye. Moreover, Alvarado et al.¹³ found that adrenaline (A) and isoproterenol enhanced aqueous humor outflow by reducing the size of cells in the TM and SC, thus increasing the intercellular space through a β-adrenergic-mediated response. The application of isoproterenol led to decreases in SC cell stiffness and increase in SC cell compliance via its action on the β2 adrenergic receptor; consequently, the resistance to aqueous outflow was also resolved. In addition, the expression level of β2-adrenergic receptors has been found to be positively correlated with the degree of relaxation triggered by isoproterenol.¹⁴ These findings suggest that SC and the TM might have the foundation to receive innervation from the sympathetic nervous system. 

For now, it is unclear whether the decrease in IOP after physical exercise is associated with the status of SC and the TM and whether the status of SC and TM are under the control of the sympathetic nervous system. Exercise has been reported to influence IOP as well as the sympathetic nervous system.¹⁵ Christensen et al.¹⁶ observed that sympathetic nerve activity and noradrenaline (NA)/A concentrations increased during exercise. In the present study, we used exercise as an intervention to assess its effects on the morphology of SC and the TM and elucidate the mechanisms underlying IOP reduction during exercise. 

Materials and Methods

This observational, paired comparative study was approved by the ethics committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and adhered to the tenets of the Declaration of Helsinki. All subjects provided written informed consent prior to participation in the study. 

Subjects

A total of 30 healthy volunteers were recruited from the staff of the Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. All subjects underwent a comprehensive ophthalmologic examination, which included measurement of the best-corrected visual acuity (BCVA), refractive error, central corneal thickness (CCT), and axial length (AL), slit-lamp examination, gonioscopy, and fundus photography. The criteria for inclusion of healthy subjects were: (1) at least 18 years of age, (2) IOP between 10 and 21 mm Hg, (3) normal anterior chamber depth, with an open angle, and (4) no history of use of drugs affecting the circulatory system within a month prior to evaluation. Subjects with a family history of glaucoma, history of ophthalmic diseases or surgery, or systemic diseases were excluded. One eye of each subject was randomly selected for analysis of IOP, area and perimeter of SC, TM thickness, and pupil diameter. In addition to ocular examination, all participants underwent examinations for measurement of blood pressure (BP), oxygen saturation, heart rate (HR; for controlling exercise intensity), and plasma catecholamine concentrations (for estimation of activity of the sympathetic nervous system). Participants were requested to not consume any food or beverages for at least 30 minutes before the experiment. 

Measurement of IOP, BP, HR, and Oxygen Saturation and Control of Exercise Intensity

The participants exercised by jogging for 20 minutes. The IOP before and at 0 minutes after exercise were measured using a noncontact tonometer (NIDEK RT-2100; NIDEK, CO., LTD, Gamagori, Japan). Three measurements were obtained and the average IOP was recorded. The BP was recorded before and immediately after exercise by using an automatic sphygmomanometer (OmronHEM-7201; Omron, Dalian, Liaoning, China). Heart rate and oxygen saturation were monitored throughout the exercise. The intensity of exercise was maintained constant by evaluation of the percentage of heart-rate reserve (%HRmax).¹⁷ 

Imaging of SC and the TM

All subjects were examined using an 80-MHz ultrasound biomicroscopy (UBM) imaging system (iUltrasound; iScience Interventional, Inc., Menlo Park, CA, USA). Images were obtained using the following settings: transducer frequency, 80 MHz; axial resolution, 25 μm; lateral resolution, 50 μm; electronic resolution, 10 μm; tissue penetration depth, 2 mm; scan rate, 7 frames/s; and imaging window size, 4.5 × 4.5 mm. Before recording the iUltrasound measurements, the eyes were anesthetized with topical proparacaine hydrochloride eye drops, and a low-viscosity ultrasound gel was placed on the ocular surface. The iUltrasound probe was directly placed on the eye, and measurements were obtained in each eye at the 12-, 3-, 6-, and 9-o'clock positions. 

Image Processing

The SC and TM parameters were measured using the ImageJ software (http://imagej.nih.gov/ij/; provided in the public domain by the National Institutes of Health, Bethesda, MD, USA) with pixels as the unit of measurement. Schlemm's canal was defined as observable when a thin, black, lucent space was detected in two images. Optimum image contrast and magnification and previous histologic manifestations were subjectively defined in order to maximize the visualization of the SC. The percentage of sections with observable SC was calculated as: eyes with completely observable SC/total number of eyes × 100. The area and perimeter of SC were drawn freehand based on the outline of SC (Fig. 1). The thickness of TM was calculated as the average of measurements acquired at the anterior end point and the middle portion of SC, as reported in a previous study.¹⁸ The measurement of TM at the posterior end point of SC might not truly represent the thickness of the TM itself; instead it may represent the measurement of the ciliary muscle behind the scleral spur. Therefore, the measurement of TM at this point was not considered.^18–21 

Figure 1

 

Image showing SC and the TM. The yellow curve indicates the SC.

Measurement of Pupil Diameter

Pupil diameter was measured as the distance from one side of the pupillary tip of the iris to the opposite side on images acquired by anterior optical coherence tomography (OCT; Visante OCT, Carl Zeiss, Dublin, CA, USA; Fig. 2). 

Figure 2

 

Diagram of measurement of pupil diameter (solid red line).

Evaluation of Blood Samples

Blood samples (12 mL) were collected at resting state and immediately following exercise, in vacuum tubes containing EDTA. Plasma was separated by centrifugation of the blood samples at 1000g (Heraeus Multifuge X1R; Thermo Scientific, Osterode, Lower Saxony, Germany) for 10 minutes at 4°C and stored at −80°C for analysis of catecholamine concentrations. Plasma NA and A concentrations were evaluated by HPLC with electrochemical detectors (Waters HPLC pump, model 515: Waters electrochemical detector, model 2465; Waters autosampler, model 717; Atlantic C18 column (4.6 mm × 150 mm); Waters, Milford, MA, USA). 

Statistical Analyses

All statistical analyses were performed using the SPSS software package version 19.0 (SPSS, Inc., Chicago, IL, USA). The data are presented as the mean values ± SDs, where applicable. The χ² test was used to compare the proportions of sections with observable SC before and after exercise. The Wilcoxon test (paired samples) was used for the comparison of baseline and post-exercise values of the area and perimeter of SC, TM thickness, IOP, pupil diameter, plasma NA and A concentrations, and other parameters. The Mann-Whitney U test was used for the comparison of baseline and post-exercise values of parameters in each quadrant, whereas the Kruskal-Wallis H test was used for comparison of values of different parameters among the four quadrants in the same group. Nonparametric Spearman's correlation analyses were performed to statistically examine the relationships between IOP changes and changes in the SC and TM parameters. All tests were two-tailed, and statistical significance was defined as a P value less than 0.05. 

Results

A total of 30 healthy volunteers (30 eyes) were enrolled in this study, of whom one was excluded because of lack of imaging data. Thus, a total of 29 eyes (15 male; 14 female) were eventually included in the analyses. The mean patient age was 25.8 ± 2.3 years, the mean BCVA was 1.03 ± 0.16, the mean CCT was 543.9 ± 37.7 μm, the mean AL was 25.3 ± 1.1 μm, the mean refraction was −3.98 ± 2.0 diopters (D) and the mean HRmax% value was 70 ± 2%. 

We observed a significant decrease in IOP after exercise (15.4 ± 2.4 vs. 11.1 ± 2.7 mm Hg; P < 0.001), in comparison with the baseline value (Fig. 3). 

Figure 3

 

Scatter plot of IOP distribution before and after exercise.

The SC was observable in 81.9% of sections before exercise and 90.5% of sections after exercise; but the difference in these values was not significant (X = 3.652, P = 0.057; Table). 

Table

 

Proportion of Eyes With Observable Schlemm's Canal

 

In comparison with the baseline values, the mean values of area (132.83 ± 19.67 vs. 155.33 ± 21.46 pixels; P < 0.001) and perimeter (54.94 ± 4.95 vs. 60.23 ± 4.19 pixels; P < 0.001) of SC and TM thickness (10.30 ± 1.28 vs. 11.48 ± 1.07 pixels; P < 0.001) were found to have increased after exercise (Figs. 4, 5). In particular, the area of SC in the nasal region exhibited a significant increase after exercise compared with that at baseline (122.74 ± 37.11 vs. 162.58 ± 53.14 pixels; P = 0.004); however, the areas of SC in other regions did not exhibit any significant increase in comparison with the baseline values (inferior region, 133.67 ± 39.68 vs. 137.54 ± 35.40 pixels, P = 0.859; temporal region, 132.45 ± 40.74 vs. 161.62 ± 51.62 pixels, P = 0.087; and superior region, 139.86 ± 28.05 vs. 158.0 ± 44.16 pixels, P = 0.131). Moreover, in comparison with the baseline values, the perimeter of SC was found to have increased after exercise in the nasal (52.33 ± 7.51 vs. 60.92 ± 9.29 pixels; P = 0.003) and temporal (54.56 ± 9.76 vs. 61.24 ± 9.55 pixels, P = 0.012) quadrants, but not in the inferior (57.84 ± 7.76 vs. 56.42 ± 7.39 pixels; P = 0.465) or superior (55.89 ± 8.74 vs. 60.99 ± 10.47 pixels; P = 0.127) quadrants. Furthermore, in comparison with the baseline values, the TM thickness was found to have increased after exercise in the nasal (10.46 ± 2.15 vs. 12.12 ± 2.62 pixels; P = 0.041) and superior (9.82 ± 1.95 vs. 11.0 ± 1.95 pixels; P = 0.030) quadrants, but not in the inferior (10.25 ± 1.93 vs. 11.32 ± 2.16 pixels; P = 0.054) or temporal (10.77 ± 1.78 vs. 11.72 ± 2.15 pixels; P = 0.135) quadrants (Fig. 6). 

Figure 4

 

Morphology of SC (white arrow) before (A) and after (B) exercise.

Figure 5

 

Area and perimeter of SC and thickness of the TM before and after exercise. Asterisk indicates a statistically significant difference.

Figure 6

 

Area and perimeter of SC and thickness of the TM in the four quadrants before and after exercise. Asterisk indicates a statistically significant difference.

In addition, the increase in area (r = 0.019; P = 0.923) and perimeter (r = −0.109; P = 0.573) of SC and TM thickness (r = −0.088; P = 0.651) were not significantly correlated with the reduction of IOP (Fig. 7). 

Figure 7

 

Correlation of the increase in area and perimeter of SC and TM thickness with the decrease in IOP.

In comparison with the baseline values, there were significant increments in the mean values of ocular perfusion pressure (MOPP; 40.8 ± 5.2 vs. 54.9 ± 6.3 mm Hg; P < 0.001), systolic blood pressure (SBP; 113.7 ± 10.9 vs. 141.8 ± 11.8 mm Hg; P < 0.001), diastolic blood pressure (DBP; 69.4 ± 8.5 vs. 76.9 ± 10.9 mm Hg; P < 0.001), and mean arterial pressure (MAP; 84.3 ± 8.4 vs. 98.9 ± 10.0 mm Hg; P < 0.001; Fig. 8) after exercise. 

Figure 8

 

Changes in eye perfusion pressure (MOPP), SBP, DBP, and MAP after exercise. Asterisk indicates a statistically significant difference.

In addition, in comparison with the baseline value, there was a significant increase of 5.7% in pupil diameter after exercise (P = 0.001; Fig. 9). 

Figure 9

 

Pupil diameter at resting state (A) and during exercise (B).

The results of evaluation of plasma catecholamine responses to exercise have been presented in Figure 10. Plasma NA increased from a resting value of 2.47 ± 1.46 to 8.28 ± 7.84 nmol/L following exercise (P = 0.005). Plasma A increased from a resting value of 0.64 ± 0.38 to 1.50 ± 1.33 nmol/L following exercise (P = 0.011). 

Figure 10

 

Plasma noradrenaline and adrenaline concentrations at resting state and the end of exercise. Asterisk indicates a statistically significant difference.

Discussion

Numerous studies have reported the reduction in IOP following exercise.^1-4,22,23 Researchers have speculated that IOP reduction following exercise is caused by several reasons. First, the loss of sweat and water could increase the colloidal osmotic pressure of plasma during exercise, resulting in the decreased production of aqueous humor.² Second, exercise leads to an increase in blood supply primarily to the limbs, rendering the ocular ischemic, thus significantly decreasing the production of aqueous humor.^24,25 Third, activation of the sympathetic nervous system causes choroid vasoconstriction, reducing choroid blood flow, thus decreasing the IOP.²⁶ Fourth, exercise-induced increase in catecholamine concentrations might also play a role in IOP reduction by reducing aqueous humor formation and increasing trabecular outflow facility in a β-2-adrenergic receptor-dependent manner.²⁷ In the present study, we observed that 20 minutes of exercise in young healthy adults led to a reduction in IOP, consistent with the results of previous studies. 

The increase in area and perimeter of SC and the TM thickness following exercise were accompanied by IOP reduction. In addition, there was a slight increase in the proportion of eyes with observable SC after exercise. These findings suggest that exercise led to the expansion of SC and the TM. Therefore, we speculate that the expansion of SC and the TM might be another important factor leading to IOP reduction during exercise. 

What regulated the status of SC and the TM? Previous studies have found that sympathetic nerve fibers and their neurotransmitter receptors are widely distributed in the aqueous outflow pathway.^14,28–30 In addition, β2-adrenergic receptors have been detected in the TM and SC.^14,29,30 Alvarado et al.¹³ found that administration of adrenaline and isoproterenol led to the reduction in size of the TM and SC cells, enlargement of intercellular space, and increase in aqueous humor outflow because of β2-adrenergic receptor activation. Zhou et al.¹⁴ also found that isoproterenol led to decreases in SC cell stiffness and increase in SC cell compliance via its action on the β2 adrenergic receptor; consequently, the resistance to aqueous outflow was also resolved. In addition, the expression level of β2-adrenergic receptors has been found to be positively correlated with the degree of relaxation triggered by isoproterenol. These findings suggest the possibility of autonomic regulation of the TM and SC by the sympathetic nervous system. 

The concentrations of catecholamines have been found to be increased after dynamic exercise. Therefore, catecholamine concentrations might serve as indicators of changes in the activity of the sympathetic nervous system after exercise.^31,32 In particular, catecholamines NA and A serve as neurotransmitters of the sympathetic nerves. Our study found increase plasma NA and N concentrations after exercise. In addition, the HRmax% was 70%, and the pupils of subjects were found to be dilated after exercise, which indicates that the exercise intensity assessed in the present study was sufficient to achieve activation of the sympathetic nervous system.^25,33–36 Thus, we believe that, in the present study, exercise might have led to an increase in the activity of the sympathetic nervous system. We hypothesize that the stimulation of sympathetic nerves following exercise leads to an expansion of the TM and SC, which might be one of the major causes of IOP reduction after exercise. 

However, the reduction in IOP was not significantly correlated with the increase in the area or perimeter of the SC or TM thickness. The percentage reduction in IOP was greater than the percentage expansion of the TM and SC. Hence, the expansion of the TM and SC does not fully explain the IOP reduction following exercise. In fact, there might be several reasons for IOP reduction, including those suggested by previous researchers, as explained above. In addition, in the present study, although two subjects exhibited a decrease in IOP following exercise, their areas of SC were not increased. The TM and SC might have autonomic regulation functions, and hence, their expansion and collapse might not be completely dependent on the IOP. In fact, studies have reported that the TM and SC exhibit characteristics of contractility.^14,37,38 

A significant increase in outflow was observed after exercise in the nasal SC area but not in the other quadrants. In addition, the perimeter of SC was found to have increased after exercise in the nasal and temporal quadrants but not in the inferior and superior quadrants, whereas the TM thickness had increased in the nasal and superior quadrants but not in the inferior and temporal quadrants. Previous studies have indicated that aqueous outflow is segmental, and the preferred pathway for aqueous outflow involves the regions adjacent to the collector channels; in fact, only a fraction of the aqueous humor outflow pathways are active.^39-43 We hypothesize that the aqueous outflow pathways in these quadrants of SC are more likely to be activated by sympathetic nerve stimulation following exercise, even though our results indicated no significant differences in the area or perimeter of SC or TM thickness in any the four quadrants before and after exercise. 

The present study has certain limitations. First, our sample size was relatively small. Second, all participants in the present study were young adults. Hence, it is unclear whether similar effects of exercise would be observed in elderly subjects. Third, sex and physical fitness, which are significant factors influencing the changes in IOP due to exercise, should be taken into consideration in future studies.^22,23 

Conclusions

A decrease in IOP as well as an increase in area of the TM and SC were observed after aerobic exercise in healthy subjects. We speculate that the expansion of the TM and SC might be one of the reasons for the reduction in IOP. In particular, aerobic exercise might have led to the activation of the sympathetic nervous system, consequently leading to the expansion of the TM and SC, which, in turn, caused the reduction of IOP. Furthermore, SC and the TM might have autonomic regulation functions, and their expansion and collapse might not be completely dependent on the IOP. 

Acknowledgments

The authors thank Longfang Zhou, Jieling Gong, Yuanyu Xiang, and Zhiqi Chen of Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology for their help in conducting the experiment. 

Supported by National Natural Science Foundation of China (81471744; China). Supported by Science and Technology Project of Hubei Province (2014BEC091; Wuhan, Hubei, China). 

Disclosure: X. Yan, None; M. Li, None; Y. Song, None; J. Guo, None; Y. Zhao, None; W. Chen, None; H. Zhang, None