Effect of HCN channel inhibition on retinal morphology and function in normal and dystrophic rodents.
OBJECTIVE
To elucidate short- and long-term effects of ivabradine, an inhibitor of the hyperpolarization-activated current (I(f)) recently approved for treatment of stable angina, on retinal function and integrity. As careful ivabradine administration is recommended for patients with retinitis pigmentosa, an additional objective was to test the consequences of repeated ivabradine delivery on retinal integrity in the rd10 mouse, an animal model of the human degenerative disease.


METHODS
The electroretinogram (ERG) was recorded in intact anesthetized animals in response to flashes or time-varied sinusoidal light stimuli of different frequency. Retinal integrity and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel distribution were assessed by immunocytochemistry, confocal microscopy, and Western blot analysis.


RESULTS
Neither a- nor b-waves of the flash-ERG were significantly affected by ivabradine administration. Conversely, reversible changes in the response to sinusoidal stimuli were observed during both acute and continued treatment. HCN inhibition enhanced the gain of frequency-response curves (FRCs) at the lowest stimulus frequencies and reduced it in the 1- to 7-Hz range. These effects were dose dependent and reverted to normal 1 week after discontinuation of ivabradine. Retinal morphology and distribution of HCN were preserved and no signs of retinal damage were observed in healthy animals. HCN inhibition in dystrophic mice had no effect on either extent or progression of retinal degeneration.


CONCLUSIONS
The results are consistent with the hypothesis that the visual symptoms reported by patients during prolonged treatment with ivabradine are due only to a reversible pharmacologic effect.
Della Santina
Luca
L
Dipartimenti di Scienze Fisiologiche, Università di Pisa, Pisa, Italy.
Bouly
Muriel
M
Asta
Antonella
A
Demontis
Gian Carlo
GC
Cervetto
Luigi
L
Gargini
Claudia
C
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001552:Benzazepines / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D020287:In Situ Nick-End Labeling; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D000077550:Ivabradine; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D055355:Opsins / Q000378:metabolism; D010775:Photic Stimulation; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000378:metabolism / Q000503:physiopathology*; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000503:physiopathology*
D000199:Actins; D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D005904:Glial Fibrillary Acidic Protein; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D055355:Opsins; D015221:Potassium Channels; D000077550:Ivabradine