PUBLICATION

Phosphodiesterase Inhibitors Sildenafil and Vardenafil Reduce Zebrafish Rod Photoreceptor Outer Segment Shedding

Authors
Campbell, L.J., Jensen, A.M.
ID
ZDB-PUB-171103-6
Date
2017
Source
Investigative ophthalmology & visual science   58: 5604-5615 (Journal)
Registered Authors
Jensen, Abigail
Keywords
none
MeSH Terms
  • Zebrafish
  • Animals
  • Cell Line
  • Dark Adaptation/drug effects
  • Dark Adaptation/physiology*
  • Animals, Genetically Modified
  • Sildenafil Citrate/pharmacology*
  • Vardenafil Dihydrochloride/pharmacology*
  • Models, Animal
  • Phosphodiesterase 5 Inhibitors/pharmacology
  • Rod Cell Outer Segment/drug effects*
  • Rod Cell Outer Segment/metabolism
  • Cyclic GMP/metabolism*
(all 13)
PubMed
29094165 Full text @ Invest. Ophthalmol. Vis. Sci.
Abstract
Purpose The vertebrate rod photoreceptor undergoes daily growth and shedding to renew the rod outer segment (ROS), a modified cilium that contains the phototransduction machinery. It has been demonstrated that ROS shedding is regulated by the light-dark cycle; however, we do not yet have a satisfactory understanding of the molecular mechanisms that underlie this regulation. Given that phototransduction relies on the hydrolysis of cGMP via phosphodiesterase 6 (PDE6), we examined ROS growth and shedding in zebrafish treated with cGMP-specific PDE inhibitors.
Methods We used transgenic zebrafish that express an inducible, transmembrane-bound mCherry protein, which forms a stripe in the ROS following a heat shock pulse and serves as a marker of ROS renewal. Zebrafish were reared in constant darkness or treated with PDE inhibitors following heat shock. Measurements of growth and shedding were analyzed in confocal z-stacks collected from treated retinas.
Results As in dark-reared zebrafish, shedding was reduced in larvae and adults treated with the PDE5/6 inhibitors sildenafil and vardenafil but not with the PDE5 inhibitor tadalafil. In addition, vardenafil noticeably affected rod inner segment morphology. The inhibitory effect of sildenafil on shedding was reversible with drug removal. Finally, cones were more sensitive than rods to the toxic effects of sildenafil and vardenafil.
Conclusions We show that pharmacologic inhibition of PDE6 mimics the inhibition of shedding by prolonged constant darkness. The data show that the influence of the light-dark cycle on ROS renewal is regulated, in part, by initiating the shedding process through activation of the phototransduction machinery.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b4
    		Insertion
    fl1TgTransgenic Insertion
      zf2007TgTransgenic Insertion
        zf2008TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          No data available
          Fish
          No data available
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab4-rhomonoclonalMouse
          1 - 1 of 1
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          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          mCherryEFGmCherry
          1 - 2 of 2
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          Mapping
          No data available
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          Citation
          Campbell, L.J., Jensen, A.M. (2017) Phosphodiesterase Inhibitors Sildenafil and Vardenafil Reduce Zebrafish Rod Photoreceptor Outer Segment Shedding. Investigative ophthalmology & visual science. 58:5604-5615.