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Antihypertensive drug could be useful for eye disorder

Deborah Josefson, San Francisco

A commonly used antihypertensive drug, the calcium blocker diltiazem, may some day be prescribed to stave off the effects of retinitis pigmentosa, a leading cause of hereditary blindness (Nature Medicine 1999; 5:1183-7).

Retinitis pigmentosa is due to the death of retinal photoreceptors, and its onset is gradual, with night blindness and loss of peripheral vision dominating early in its course. Typically, the effects are first noted in young adulthood.

The disorder is genetically heterogeneous and defects in over 100 genes have been implicated in causing the disease.

Using a mouse model, researchers at the Université Louis Pasteur, in Strasbourg, France, demonstrated that diltiazem is capable of rescuing photoreceptors from an untimely death. Drs Maria Frasson and Serge Picaud and colleagues, studied the effects of diltiazem on the retinal degeneration mouse, a mouse in which the gene for the rod cyclic GMP phosphodiesterase is mutated, a defect shared by some human families afflicted with retinitis pigmentosa.

Cyclic GMP is responsible for gating cationic channels which control the current in light sensitive photoreceptors. Sustained high concentrations of cyclic GMP occur in the retinal degeneration mouse and have been shown to be toxic to photoreceptors.

The mechanism of this toxicity may be due to the unmitigated influx of cations (positively charged ions, such as sodium, potassium, and calcium).

To test this hypothesis, scientists injected mice daily with diltiazem, beginning on postnatal day 9. Control mice received saline injections. Both controls and diltiazem treated mice were sacrificed at days 25 and 36, and the number of their rods were quantified by immunostaining—counting those which picked up antibodies to rhodopsin, a protein produced by rods.

The treated mice had 186% more rods at day 25 than the untreated mice (38 613 v 20 718), and the effects were even more pronounced by day 36 when the treated mice exhibited 248% more rod cells than their untreated counterparts. (18 656 v 7519).

The immunostaining results were confirmed on histological examination of retinal sections. Moreover, the rod rescue seemed to have functional significance and led to cone preservation as well.

To see whether diltiazem induced photoreceptor rescue correlated with improved visual function, the scientists recorded electroretinograms in retinal degeneration and control mice. In retinal degeneration mice, signals in electroretinograms normally decrease regularly from postnatal day 12 to extinction by postnatal day 25. Treated retinal degeneration mice still had measurable signals, compared with untreated control mice.

Furthermore, mice at day 36 had higher amplitude signals than untreated mice at day 19. These signals were shown to be due to cones, which normally follow the degenerative path of rods in retinitis pigmentosa.

Although the drug preserved visual function it was not entirely successful, as rod cells continued to degenerate compared with normal mice.

Moroever, the study is small, and it is unclear if the doses used would be tolerated in humans, as they far exceeded the equivalent doses prescribed for hypertension and angina. Another concern is that the results may not be applicable in all types of retinitis pigmentosa.

Currently there is no treatment or cure for the condition.

Strategies that have been investigated for treating it range from vitamin supplementation to retinal cell transplants. In this climate, the current study offers considerable hope. The authors point out that because photoreceptor degeneration in the condition is gradual, diltiazem has the potential to "postpone considerably the occurrence of blindness in this population." Moreover, the drug's "long record in human therapy would facilitate its approval for clinical trials in some identified forms of the disease."