dihydropyridines and Retinal-Degeneration

Although a blockade or lack of N-type Ca(2+) channels has been reported to suppress neuronal injury induced by ischemia-reperfusion in several animal models, information is still limited regarding the neuroprotective effects of a dual L/N-type Ca(2+) channel blocker, cilnidipine. We histologically examined the effects of cilnidipine on neuronal injury induced by ischemia-reperfusion, intravitreous N-methyl-D-aspartate (NMDA) (200nmol/eye) and intravitreous NOC12 (400nmol/eye), an nitric oxide donor, in the rat retina, and compared its effects with those of omega-conotoxin MV IIA, an N-type Ca(2+) channel blocker and amlodipine, an L-type Ca(2+) channel blocker. Morphometric evaluation at 7 days after ischemia-reperfusion showed that treatment with cilnidipine (100microg/kg, i.v. or 0.5pmol/eye, intravitreous injection) prior to ischemia dramatically reduced the retinal damage. Treatment with omega-conotoxin MV IIA before ischemia (0.1pmol/eye, intravitreous injection) significantly reduced the retinal damage. However, amlodipine (30-100microg/kg, i.v. or 0.1-1pmol/eye, intravitreous injection) did not show any protective effects. Treatment with cilnidipine (100microg/kg, i.v.) reduced the retinal damage induced by intravitreous NMDA, but not NOC12. These results suggest that cilnidipine reduces Ca(2+) influx via N-type Ca(2+) channels after NMDA receptors activation and then protects neurons against ischemia-reperfusion injury in the rat retina in vivo. Cilnidipine may be useful as a therapeutic drug against retinal diseases which cause neuronal cell death, such as glaucoma and central retinal vessel occlusion.

Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Drug Evaluation, Preclinical; In Situ Nick-End Labeling; Injections; Injections, Intravenous; Male; N-Methylaspartate; Neuroprotective Agents; Nitroso Compounds; omega-Conotoxins; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Retinal Degeneration; Retinal Diseases; Vitreous Body

There is little known about the membrane properties of retinal pigment epithelial (RPE) cells with respect to calcium. The authors attempted to characterize membrane calcium channels from solitary fresh and cultured RPE cells from normal and dystrophic rat retinas.. RPE cells were enzymatically dissociated from eyes of neonatal rats of several strains, including dystrophic RCS strains. Membrane currents were recorded using the whole-cell version of the patch-clamp technique from either fresh or cultured cells.. The authors observed sustained high-voltage-activated calcium channels that were dihydropyridine sensitive and closely resembled neuronal L-type calcium channels. The RCS-rdy+p+ strain was mainly investigated, but high-voltage-activated calcium channels were also recorded from fresh RPE cells of other rats regardless of age or strain, including RCS p+, RCS rdy+, Long Evans, Sprague Dawley, and also cultured RPE cells taken from a neonatal Long Evans strain. Low-voltage-activated calcium channels were not observed in any of these cells.. Voltage-operated calcium channels of the L-type are the main calcium channels present in rat RPE cells. Cultured cells retained the identical channels. The dystrophic RCS strains (studied until 17 days postnatal) also exhibited these channels.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Dihydropyridines; Membrane Potentials; omega-Conotoxin GVIA; Peptides; Pigment Epithelium of Eye; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Retinal Degeneration