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C.–J. Dong, Y. Guo, W.A. Hare; 2 Adrenergic Receptor Mediated Suppression of High K+–Elicited Intracellular Ca++ Signals in the Inner Plexiform Layer (IPL) of the Rat Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3756.
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© ARVO (1962-2015); The Authors (2016-present)
There is compelling evidence from animal models of glaucoma and acute retinal ischemia that α2 agonists, such as brimonidine, protect retinal ganglion cells (RGCs) from injury. However, the mechanism of action as well as the physiological role of the α2 adrenergic system in the retina is not well understood. A major goal of this work was to explore the role of the α2 adrenergic system in modulation of intracellular Ca++ signaling at the IPL where communication between RGCs and their presynaptic cells takes place.
Using a high speed (Nipkow spinning disk) confocal system, we conducted functional Ca++ imaging at the IPL of rat retinal slices. The relative changes of intracellular free Ca++ were monitored with the fluorescent Ca++ dye fluo–4. The Ca++ signal was elicited by a high K+ (40 mM) Ringer solution. The high K+ Ringer and α2 adrenergic agents were delivered rapidly to the IPL region by a custom–made multi–channel local perfusion system.
A brief application (5–10 sec) of high K+ Ringer elicited a robust Ca++ signal at the IPL. This Ca++ signal was eliminated by nimodipine, an L–type Ca++ channel blocker, or when the extracellular Ca++ in the Ringer was replaced with equal molar EGTA. The Ca++ signal was recovered partially after wash out of nimodipine and fully when normal Ca++ Ringer was reintroduced. The Ca++ signal was also suppressed in a dose–dependent manner by brimonidine and other α2 receptor pan agonists, such as medetomidine. The suppressive action of brimonidine and medetomidine can be completely blocked by classic α2 receptor pan antagonists, such as atipamezole, yohimbine, and rauwolscine. The suppressive action of brimonidine was also partially blocked by BRL 44408 and ARC 239, respective α2A and 2B receptor subtype–selective antagonists.
Our results indicate that high K+ Ringer elicited a Ca++ influx through Ca++ channels on the cell membrane at the IPL and that this Ca++ influx can be modulated by the retinal α2 adrenergic system. These results suggest that brimonidine may protect RGCs under disease conditions by preventing abnormal elevation of intracellular free Ca++ in RGCs as well as their presynaptic cells.
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