Diabetes-induced vascular dysfunction in the retina: role of endothelins.
OBJECTIVE
Vasoactive factors like endothelins, by virtue of the microvascular regulation as well as by other effects, possibly play important parts in the pathogenesis of diabetic retinal microangiopathy. We investigated retinal vascular dysfunction in streptozotocin-induced diabetes and its relation with endothelins in short- and long-term diabetes.


METHODS
Diabetic rats with or without an endothelin receptor antagonist (bosentan) treatment were investigated after 1 month and 6 months of follow-up. Retinal blood flow was measured and compared with age- and sex-matched non-diabetic control animals. Retinal tissues were analysed for endothelin-1, endothelin-3, endothelin A and endothelin B mRNA. Distribution of endothelin-1 and endothelin-3 was investigated by immunocytochemistry and that for endothelin receptors by ligand binding and autoradiography.


RESULTS
Diabetic animals showed hyperglycaemia, glycosuria, elevated glycated haemoglobin values and reduced body weight gain. Retinal blood flow showed an increased resistivity index, an indicator of vasoconstriction, after 1 month of diabetes which was prevented by treatment with bosentan. This functional change in diabetes was eliminated after 6 months of follow-up. The retina from the diabetic animals showed increased mRNA expression for endothelin-1, endothelin-3 and endothelin A after one month. In addition, endothelin B mRNA expression was increased after 6 months. Furthermore, endothelin-1 and endothelin-3 immunoreactivity and endothelin receptor concentrations were increased in the retina of diabetic rats.


CONCLUSIONS
The results from this study indicate that the endothelin system is of importance in mediating retinal changes in diabetes although mechanisms of the endothelin system alteration as well as their effects might vary depending on the duration of diabetes. [Diabetologia (1999) 42: 1228-1234]
Deng
D
D
Department of Pathology, University of Western Ontario, London, Ontario, Canada.
Evans
T
T
Mukherjee
K
K
Downey
D
D
Chakrabarti
S
S
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001345:Autoradiography; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019334:Endothelin-3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012160:Retina / Q000378:metabolism / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D018615:Ultrasonography, Doppler, Color
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D000077300:Bosentan