1. D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo
- Author
-
Berkowitz, Bruce A, Podolsky, Robert H, Farrell, Benjamin, Lee, Hojun, Trepanier, Christopher, Berri, Ali M, Dernay, Kristin, Graffice, Emma, Shafie-Khorassani, Fatema, Kern, Timothy S, and Roberts, Robin
- Subjects
Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Biomedical Imaging ,Eye Disease and Disorders of Vision ,Neurosciences ,Neurodegenerative ,3-Pyridinecarboxylic acid ,1 ,4-dihydro-2 ,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)- ,Methyl ester ,Animals ,Calcium Channel Agonists ,Calcium Channel Blockers ,Calcium Channels ,L-Type ,Dark Adaptation ,Diltiazem ,Magnetic Resonance Imaging ,Male ,Mice ,Mice ,Inbred C57BL ,Oxidative Stress ,Retinal Degeneration ,Retinal Rod Photoreceptor Cells ,Superoxides ,Tomography ,Optical Coherence ,Biological Sciences ,Medical and Health Sciences ,Ophthalmology & Optometry ,Ophthalmology and optometry - Abstract
PurposeNew perspectives are needed to understand decades of contradictory reports on the neuroprotective effects of the Cav1.2 L-type calcium channel blocker d-cis-diltiazem in retinitis pigmentosa (RP) models. Here, we address, in vivo, the following two knowledge gaps regarding d-cis-diltiazem's actions in the murine outer retina: (1) do normal mouse rods contain d-cis-diltiazem-insensitive Cav1.2 L-type calcium channels? (2) Can d-cis-diltiazem modify the normal rod redox environment?MethodsFirst, transretinal Cav1.2 L-type calcium channels were noninvasively mapped with manganese-enhanced magnetic resonance imaging (MRI) following agonist Bay K 8644 in C57BL/6 (B6) and in Cav1.2 L-type calcium channel BAY K 8644-insensitive mutant B6 mice. Second, d-cis-diltiazem-treated oxidative stress-vulnerable (B6) or -resistant [129S6 (S6)] mice were examined in vivo (QUEnch-assiSTed [QUEST] MRI) and in whole retina ex vivo (lucigenin). Retinal thickness was measured using MRI.ResultsThe following results were observed: (1) manganese uptake patterns in BAY K 8644-treated controls and mutant mice identified in vivo Cav1.2 L-type calcium channels in inner and outer retina; and (2) d-cis-diltiazem induced rod oxidative stress in dark-adapted B6 mice but not in light-adapted B6 mice or dark-adapted S6 mice (QUEST MRI). Oxidative stress in vivo was limited to inferior outer retina in dark-adapted B6 mice approximately 1-hour post d-cis-diltiazem. By approximately 4 hours post, only superior outer retina oxidative stress was observed and whole retinal superoxide production was supernormal. All groups had unremarkable retinal thicknesses.ConclusionsD-cis-diltiazem's unexpectedly complex spatiotemporal outer retinal oxidative stress pattern in vivo was dependent on genetic background and rod membrane depolarization, but not apparently dependent on Cav1.2 L-type calcium channels, providing a potential rationale for contradictory results in different RP models.
- Published
- 2018