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Originally published In Press as doi:10.1167/iovs.08-1890 on May 16, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4590-4594.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-1890
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N-Methyl-D-Aspartic Acid Causes Relaxation of Porcine Retinal Arterioles through an Adenosine Receptor–Dependent Mechanism

Kim Holmgaard,1 Christian Aalkjaer,2,3 John D. C. Lambert,2 and Toke Bek1

1From the Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark; and 2The Water and Salt Research Center and the 3Institute of Physiology and Biophysics, University of Aarhus, Aarhus, Denmark.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be involved in the pathogenesis of several vision-threatening retinal diseases. Two recent studies have shown that the glutamate receptor agonist, N-methyl–D-aspartic acid (NMDA), and adenosine induce relaxation of isolated porcine retinal arterioles in vitro. However, it remains to be elucidated whether the relaxing action of the two substances are coupled.

METHODS. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph for isometric tone measurements. Changes in tone were induced by increasing concentrations of NMDA in the presence of blockers of adenosine receptors and ATP hydrolysis and by increasing concentrations of adenosine in the presence of the NMDA receptor blocker DL-APV (DL-amino-5-phosphonovaleric acid). The experiments were repeated after the perivascular tissue had been removed.

RESULTS. NMDA produced a relaxing effect on retinal vessels with preserved perivascular retinal tissue (P < 0.001) which disappeared after removal of the tissue. Blocking of the NMDA and adenosine receptors and hydrolysis of adenosine triphosphate (ATP) significantly reduced the vasorelaxing effect of NMDA in the presence of perivascular retinal tissue (P < 0.05 for all three comparisons). Adenosine produced a concentration-dependent relaxation that was not significantly affected by blocking the NMDA receptor with DL-APV (P = 0.088).

CONCLUSIONS. The findings suggest that the vasorelaxing effect of NMDA on porcine retinal arterioles in vitro is mediated by hydrolysis of ATP to adenosine in the perivascular retinal tissue.

Disturbances in retinal perfusion due to impaired regulation of vascular tone are believed to be involved in the pathogenesis of several vision-threatening retinal diseases, including hypertensive retinopathy, radiation retinopathy, and diabetic retinopathy.1 2 In the pursuit of new treatments for these diseases, a deeper insight into the basic mechanisms involved in regulating vascular tone in the retina is crucial. The results of previous studies suggest that the regulation of vascular tone in the brain and the retina involves an interplay between the vascular wall and the perivascular tissue.3 4 5 6 7 In two recent studies, it was shown that the glutamate receptor agonist N-methyl-D-aspartic acid (NMDA) and adenosine, induce relaxation of porcine retinal arterioles in vitro.8 9 Furthermore, the vasorelaxing effect of NMDA, but not adenosine, was shown to be blocked by the prostaglandin synthesis inhibitor, ibuprofen. However, the pathway(s) through which vasorelaxation is induced by these substances and whether these pathways are separate or coupled remain to be elucidated.

In the present study, we investigated the relationship between the relaxing effect of NMDA and adenosine on porcine retinal arterioles in vitro in the presence and absence of perivascular tissue. The working hypothesis that the two mechanisms of action are coupled was tested by studying how blocking of the adenosine receptors and ATP hydrolysis affect NMDA-induced vasorelaxation and how blocking of the NMDA receptor affects adenosine-induced vasorelaxation.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Solutions
Physiological saline solution (PSS) contained (in mM): NaCl 119, KCl 4.7, MgSO4 1.17, NaHCO3 25, KH2PO4 1.18, CaCl2 1.6, EDTA 0.026, glucose 5.5, and HEPES 5.0 (pH 7.4) and was used for transportation, storage of the eyes, and pharmacologic experiments. During dissection and normalization of the vessel diameter, a solution was used in which CaCl2 had been omitted (Ca2+-free PSS).

Tissue
The details of the procedure are described in Holmgaard et al.8 In brief, porcine eyes were collected from a local abattoir and were transported to the laboratory in 4°C PSS within 1 hour. The eyes were bisected by a frontal section, the vitreous was removed, and the retina was detached from the underlying pigment epithelium by injection of PSS between these two structures. Subsequently, an arteriolar segment located 1 to 2 mm from the optic disc with a length of approximately 1.8 mm with approximately 2 mm retinal tissue attached on each side of the vessel was dissected from the retina.

Mounting Procedure
The vascular segment was placed in the chamber of a small-vessel myograph (610M Multi-Myograph; Danish Myo Technology, Aarhus, Denmark) and mounted on 25-µm-diameter tungsten wires.8 After it was mounted, the preparation was suspended freely in PSS between the myograph jaws, and bubbling of the bath was commenced with a mixture of 95% atmospheric air and 5% CO2 to give a pH of 7.4.

Normalization
Normalization of the preparation was performed according to procedures previously described in detail.10 In short, the arteriole diameter was increased in four steps in Ca2+-free PSS solution, and the passive tensions (corresponding to transmural pressures between 0 and approximately 70 mm Hg) were measured. This diameter-tension relationship was exponential, and the intercept between this curve and a straight line based on the Laplace equation (wall tension, transmural pressure x radius) with the transmural pressure set to 70 mm Hg was calculated. Using the built-in micrometer screw, the jaws of the myograph were adjusted to 93.5% of the intercept length, at which the arteriole can develop the maximum tone (i.e., the optimal length for contraction of the vascular smooth muscle cells). After they were mounted in the myograph, the diameter of the arterioles ranged between 126 and 179 µm.

Compounds
Preconstriction.
U46619 (9,11-dideoxy-11{alpha},9{alpha}-epoxymethano-prostaglandin F2{alpha}), a thromboxane analogue, was used in a concentration of 10–6 M.

Vasorelaxing Compounds.
These were added in increasing concentrations at increments of 0.5 log unit. Thus, adenosine was added in eight concentration steps in the interval between 10–7 and 3 x 10–4 M, and NMDA was added in seven concentration steps between 10–6 and 10–3 M.

Antagonists.
The nonselective (A1/A2) adenosine receptor antagonist 8-parasulphophenyl-theophylline (8-PSPT) was used at 5 x 10–4 M; the selective NMDA receptor antagonist DL-amino-5-phosphonovaleric acid (DL-APV) at 5 x 10–5 M; and the ecto-nucleotidase inhibitor, adenosine-5'-O-({alpha},β-methylene)-diphosphonate (AOPCP) at 2.5 x 10–4 M.

All compounds were purchased from Sigma-Aldrich (Vallensbaek, Denmark). 8-PSPT was prepared on the day of the experiment. DL-APV was prepared by dissolving in 20 mM NaOH to give a final concentration of 50 mM (i.e., 103 times that used in the experiments). All other compounds were dissolved in distilled water as stock solutions 103 times the highest concentration used in the experiments and were stored frozen for later use. The stock solutions were thawed and diluted to the final concentration in PSS immediately before use.

Experiments
The arteriole was precontracted with 10–6 M U46619, and if the vascular tone increased more than 0.2 N/m compared with the condition in Ca2+-free PSS, the vessel was considered to be viable, and the experiment was continued. Each experiment included the following three steps, with and without the retina (Fig. 1) .


Figure 1
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  		FIGURE 1. The experimental sequence.

 
Step 1.
Addition of Antagonists.
One of the following compounds was added to the preparation to be present throughout the experiment: 8-PSPT, DL-APV, AOPCP, or nothing (control).

Preconstriction.
After a 10-minute resting period, U46619 was added to a concentration of 1 µM to preconstrict the vessel, and the vascular tone was allowed to stabilize.

Concentration-Response Experiment.
Subsequently, NMDA was added cumulatively to the myograph chamber to study the effect on arterioles preincubated with 8-PSPT, DL-APV, AOPCP, or nothing (controls). Adenosine was added cumulatively only after preincubation with DL-APV or nothing (controls), since the effect of this compound after preincubation with 8-PSPT and AOPCP has been reported previously.9 Each change in concentration was followed by a period of at least 3 minutes during which the vascular tone stabilized. When the tone had been registered after addition of the highest concentration of the relaxing compound, the myograph chamber was washed four times with PSS.

Step 2.
The myograph was moved to the stereo microscope and the perivascular retina was gently removed within 2 minutes using two pairs of fine forceps without touching the arteriole.

Step 3.
The myograph was returned to the beginning and the procedures described in step 1 were repeated on the isolated arteriole.

Data Analysis
The tension produced by the mounted arterioles was sampled at 1 Hz and displayed on a computer monitor as a function of time during the experiments. The data were stored in a spreadsheet file (Excel; Microsoft, Redmond, WA) for subsequent analysis. The tone obtained after addition of each concentration of NMDA or adenosine was normalized to the tone produced after addition of 10–6 M U46619. This normalized tone was plotted as a function of the agonist concentration. Using commercial software (Prism, ver. 4.02; GraphPad, San Diego, CA), the data from experiments showing an overt response to increasing concentrations of agonist was fitted to the Michaëlis-Menten equation to obtain the EC50.

Statistical Analysis
Repeated-measures ANOVA was used to test whether the concentration response after addition of NMDA or adenosine showed a significant concentration-dependent decline.

At each concentration of NMDA or adenosine, the tone was compared between isolated arterioles and arterioles with preserved perivascular retinal tissue using Student’s paired t-test. In cases in which EC50 could be calculated, the values were logarithmized to become normally distributed for the statistical analysis. The mean ± 1.96 SD was antilogarithmized to describe the interval including 95% of the values (CI95). Differences between responses obtained with different agonists with and without preserved perivascular retinal tissue were tested with two-way ANOVA.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
NMDA produced a concentration-dependent relaxing effect on retinal arterioles with preserved perivascular retinal tissue (P < 0.001, repeated-measures ANOVA) with EC50 = 56.8 µM, 2.9 x 10–6 to 1.1 x 10–3 M (mean, CI95; n = 8), and this effect totally disappeared after removal of the perivascular tissue (P = 0.39, repeated-measures ANOVA; Fig. 2a ). Blocking of the NMDA receptor with DL-APV (Fig. 2b) , but also blocking of adenosine receptors with 8-PSPT (Fig. 2c) and degradation of ATP to adenosine with AOPCP (Fig. 2d) , significantly reduced the vasorelaxing effect of NMDA in the presence of perivascular retinal tissue (Student’s nonpaired t-test at the highest concentration, P < 0.05 for all three comparisons). Although the EC50 could not be determined in the presence of the antagonists, a small vasorelaxing effect at the highest concentration of NMDA was still present after addition of DL-APV (P = 0.023; Fig. 2b ) and 8-PSPT (P = 0.015; Fig. 2c ).


Figure 2
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  		FIGURE 2. Concentration–response experiments showing the effect of NMDA on vascular tone (a) alone or in the presence of (b) the NMDA receptor antagonist DL-APV (50 µM), (c) the adenosine receptor antagonist 8-PSPT (500 µM), or (d) the nucleotidase inhibitor AOPCP (250 µM). *Significant differences in vascular tone in the presence and absence of perivascular retinal tissue.

 
Adenosine showed a significant concentration-dependent vasorelaxation (P = 0.015, repeated-measures ANOVA; Fig. 3a ). EC50 did not change significantly from before (EC50 = 0.91 µM, 4.7 x 10–10 to 1.8 x 10–3 M [mean, CI95], n = 8) to after (EC50 = 13.0 µM, 2.7 x 10–6 to 6.4 x 10–5 M [mean, CI95], n = 8), removal of the retina (P = 0.094, Student’s paired t-test); and, after the NMDA receptor was blocked with DL-APV (Fig. 3b) , the vasorelaxing effect of adenosine with and without preserved perivascular retinal tissue was unchanged (P = 0.088, two-way ANOVA).


Figure 3
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  		FIGURE 3. Concentration–response experiments showing the effect of adenosine on vascular tone (a) alone (control) or (b) in the presence of the NMDA receptor antagonist DL-APV (50 µM).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study has confirmed that the vasorelaxing effect of NMDA depends on the perivascular retinal tissue, whereas this tissue does not influence the vasorelaxing effect of adenosine.8 9 In addition, the study has shown that these mechanisms are coupled so that NMDA-induced vasorelaxation of porcine retinal arterioles in vitro is mediated through adenosine.

Glutamate is a widely distributed excitatory neurotransmitter in the vertebrate retina and has specific activity on two major classes of receptors (i.e., metabotropic receptors and ionotropic counterparts), such as receptors selectively activated by NMDA. The NMDA receptor has been suggested to be an important contributor to the neurotoxic effects of glutamate observed during ischemia and cell death in retinal disease.11 12 13 14 15 In the perivascular retinal tissue, NMDA receptors have been identified on retinal ganglion cells, amacrine cells, and cone photoreceptors,11 as well as in Müller cells,16 but not on astrocytes.17 On the other hand, NMDA receptors have neither been identified on vascular smooth muscle cells nor on endothelial cells of the retinal vascular walls.11 15 This anatomic evidence is in accordance with the finding that NMDA-induced vasorelaxation depends on the presence of perivascular retinal tissue. However, it remains to be shown how the different NMDA receptor-containing retinal cell type(s) participate in this response.

Adenosine is synthesized by 5'-nucleotidase dephosphorylation of AMP, which results from increased turnover of ATP in retinal neurons and glial cells. Both adenosine and adenosine A1 and A2 receptors have been demonstrated in all layers of the human retina.18 In the present study, inhibition of the NMDA receptor did not affect adenosine-induced vasorelaxation. However, inhibition of both adenosine receptors and hydrolysis of ATP significantly reduced the vasorelaxing effect of NMDA. Combined with evidence from a previous study showing that the vasorelaxing effect of ATP is abolished by blocking its hydrolysis to adenosine,9 it can be hypothesized that the vasorelaxing effect of adenosine is due to an action on the vascular wall, either directly on the vascular smooth muscle cells or via the endothelial cells. Furthermore, the formation of adenosine is by hydrolysis of ATP which is released after stimulation of NMDA receptors in the perivascular retinal tissue. These data are consistent with data from pial arterioles, where administration of adenosine receptor antagonists have been shown to prevent NMDA-induced vasorelaxation.19

The interaction between NMDA and adenosine in the dilation of retinal arterioles includes components that have still not been elucidated in detail. Thus, previous studies have shown that vasodilation induced by NMDA but not by adenosine can be blocked by the prostaglandin synthesis inhibitor ibuprofen.8 9 Prostaglandins are synthesized from arachidonic acid by the cyclooxygenase (COX) enzyme, of which two subtypes, COX-1 and -2, have been identified.20 21 22 COX-1 is ubiquitously expressed in the retinal cells and is required for cell homeostasis, whereas COX-2 is abundantly present in synaptic regions of the retina.23 COX-2 has been shown to be upregulated in response to oxidative stress in ischemia–reperfusion studies,24 25 which implies that prostaglandins are involved in changing retinal perfusion during pathologic conditions. However, prostaglandins may have both vasorelaxing and vasoconstricting effects,3 4 26 27 and most prostaglandin receptors have been found in the retinal vascular walls.28 Therefore, it is an important challenge to identify which of the prostaglandins and corresponding receptors are involved when ibuprofen abolishes NMDA-induced vasorelaxation and to explain why adenosine-induced vasorelaxation is unaffected by prostaglandin synthesis inhibition.

In summary, the present findings suggest that the vasorelaxing effect of adenosine is due to an action on the vascular wall and that adenosine is synthesized by hydrolysis of ATP, which is released after stimulation of NMDA receptors in the perivascular retinal tissue. A more detailed elucidation of the mechanisms involved in this reaction pattern is needed, but the reactions may be part of a pathway that is especially active during ischemia or high metabolic activity where a relative lack of nutrients and accumulation of metabolites would induce a compensatory vasorelaxation and a consequent regulation of the blood flow. The present findings may therefore contribute to a deeper understanding of the mechanisms underlying the regulation of vascular tone in the response to metabolic changes in the retina.


   Footnotes
 
Supported by The Faculty of Health Sciences, University of Aarhus; The Danish Association for the Prevention of Eye Diseases and Blindness; Maskinfabrikant Jochum Jensen og hustru Mette Marie Jensens Mindelegat; The Danish Eye Research Foundation; and The Velux Foundation.

Submitted for publication February 15, 2008; revised April 22 and May 8, 2008; accepted July 22, 2008.

Disclosure: K. Holmgaard, None; C. Aalkjaer, None; J.D.C. Lambert, None; T. Bek, 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: Kim Holmgaard, Department of Ophthalmology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; khj{at}akhphd.au.dk.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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