Involvement of adenosine in retinal ischemia. Studies on the rat.
OBJECTIVE
The aim of this study was to determine whether adenosinergic agents can be used to slow down the changes seen in the rat retina after ischemia-reperfusion.


METHODS
Ischemia-reperfusion injury to the rat retina was induced by raising the intraocular pressure above the systolic blood pressure for 45 minutes, followed by reperfusion for 3 days. This insult caused a reduction of the b-wave of the electroretinogram (54% +/- 5%, n = 23) relative to the contralateral control retina, an expression of glial fibrillary acidic protein (GFAP) in the Müller cells, and an alteration in the "staining" pattern of the calretinin immunoreactivity. The normal two to three bands of calretinin immunoreactivity in the inner plexiform layer appeared as a single band. Elevation of the intraocular pressure for 60 minutes, followed by reperfusion of 2 weeks, caused a 40% reduction in the thickness of the inner nuclear and plexiform layers. No statistically significant changes in the other retinal layers were recorded.


RESULTS
When the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl)adenine (EHNA) was injected into the eye just before ischemia, the ischemia-reperfusion changes in the b-wave and calretinin immunoreactivity were largely prevented. Similar results were observed when the adenosine A1 receptor agonist, R-N6-(2-phenylisopropyl)adenosine (R-PLA), was administered intraperitoneally just before ischemia. Injection of adenosine deaminase into the eye before ischemia seemed to potentiate the ischemia-reperfusion effect because the reduction of the b-wave was almost complete (8% +/- 4%, n = 6). The ischemia-reperfusion-induced expression of GFAP in the Müller cells was not reduced by any of the adenosinergic agents tested. This suggests that GFAP expression in the Müller cells is not related to a reduction in the b-wave. An injection of EHNA into the eye before ischemia reduced the thinning of the inner plexiform and nuclear retinal layers so that no significant difference between them and the control retinas existed. However, an injection of R-PIA just before ischemia did not reduce the thinning of the retinal layers in a statistically significant way, possibly because the R-PIA protective effect is less than that of EHNA and is difficult to detect when thickness of the retinal layers is measured. It may be necessary to use higher concentrations of R-PIA to observe a protective effect.


CONCLUSIONS
The combined data show that substances resulting in the activation of adenosine A1 receptors protect the retina against changes induced by ischemia-reperfusion.
Larsen
A K
AK
Nuffield Laboratory of Ophthalmology, University of Oxford, United Kingdom.
Osborne
N N
NN
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000502:physiology*; D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D064032:Calbindin 2; D004398:Dyneins / Q000037:antagonists & inhibitors; D004596:Electroretinography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
C576512:Calb2 protein, rat; D064032:Calbindin 2; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D018047:Receptors, Purinergic P1; D064030:S100 Calcium Binding Protein G; D010660:Phenylisopropyladenosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D000243:Adenosine Deaminase; D004398:Dyneins; D000225:Adenine; D000241:Adenosine