Nimodipine enhancement of alpha2 adrenergic modulation of NMDA receptor via a mechanism independent of Ca2+ channel blocking.

Cun-Jian Dong, Yuanxing Guo, Peter Agey, Larry Wheeler, William A Hare

Department of Biological Sciences, Allergan Pharmaceuticals, Irvine, California 92612, USA. dong_james@allergan.com

Investigative ophthalmology & visual science 2010 Aug

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To further understand alpha2 receptor signaling in the retina and the mechanisms that mediate ocular beneficial effects of brimonidine (an alpha2 agonist) and nimodipine (an L-type Ca(2+) channel blocker). The authors used in situ retinal ganglion cells (RGCs) in the isolated rat retina to characterize alpha2 modulation of NMDA receptor function and a rabbit retinal NMDA excitotoxicity model to verify in vitro findings under in vivo conditions. Electrophysiological (whole-cell patch clamp) recordings and Ca(2+) imaging were used to characterize NMDA receptor function and to verify the effect of various Ca(2+) channel blockers. In vivo drug application in rabbits was achieved by intravitreal injections. Application of NMDA elicited a robust whole-cell inward current in individual in situ RGCs voltage clamped at -70 mV. Pretreatment with brimonidine significantly reduced NMDA-elicited currents in RGCs. This suppressive effect of brimonidine was substantially enhanced by background addition of nimodipine or isradipine, but not by diltiazem, verapamil, or cadmium. This effect of nimodipine was blocked by either a selective alpha2 antagonist, a cyclic adenosine monophosphate (cAMP) analogue, or an adenylate cyclase activator, indicating that nimodipine acts through the alpha2 receptor-G(alphai)-coupled pathway. Brimonidine protects RGCs in the rabbit excitotoxicity model. This brimonidine protection is also enhanced significantly by application of nimodipine but not of diltiazem. These in vitro and in vivo findings demonstrate a novel neural mechanism involving nimodipine enhancement of alpha2 signaling in RGCs. This nimodipine effect appears to be independent of its classic L-type Ca(2+) channel-blocking action.

Citation

Cun-Jian Dong, Yuanxing Guo, Peter Agey, Larry Wheeler, William A Hare. Nimodipine enhancement of alpha2 adrenergic modulation of NMDA receptor via a mechanism independent of Ca2+ channel blocking. Investigative ophthalmology & visual science. 2010 Aug;51(8):4174-80