Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa.
OBJECTIVE
D-cis-diltiazem, a calcium channel blocker, has been reported to enhance photoreceptor survival in the rd mouse, a model of retinitis pigmentosa (RP) resulting from mutation of the PDE6B gene. We tested the hypothesis that diltiazem treatment would similarly rescue the canine rcd1 model of RP, which is also caused by a null mutation in the PDE6B gene.


METHODS
D-cis-diltiazem was delivered orally twice daily to rcd1 affected dogs beginning at 4 weeks of age; untreated age-matched rcd1 dogs served as controls. At 14 weeks, electroretinograms (ERG) were performed on all animals; 14 dogs were euthanized at this age, and 2 dogs at 25 weeks of age. Eyes were enucleated, fixed, and processed for routine histological examination.


RESULTS
No significant differences were found in ERG or histopathologic parameters between diltiazem-treated and untreated rcd1 dogs. Neither rcd1 group showed a rod b-wave; ERGs evoked by single white flashes (dark- or light-adapted) and flicker were also identical between groups. Similarly, treated and untreated animals did not differ in the degree of preservation of the photoreceptor layer, confirmed in cell counts within the outer nuclear layer.


CONCLUSIONS
Treatment of rcd1 affected dogs with D-cis-diltiazem did not modify the photoreceptor disease when results were assessed using either ERG or histopathologic criteria. The positive photoreceptor-rescue effect of calcium channel blockers reported in the rd mouse was thus not generalizable to another species with retinal degeneration due to mutation in the PDE6B gene. Caution needs to be exerted in extrapolation to the comparable human forms of RP.
Pearce-Kelling
S E
SE
Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Aleman
T S
TS
Nickle
A
A
Laties
A M
AM
Aguirre
G D
GD
Jacobson
S G
SG
Acland
G M
GM
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics*; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D003623:Dark Adaptation; D004110:Diltiazem / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008297:Male; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology
D002121:Calcium Channel Blockers; D005136:Eye Proteins; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; C517438:Pde6b protein, mouse; D004110:Diltiazem