Viagra causes blindness by effecting the retina at the molecular level?
One of my previous posts that was quickly dismissed:
Found the following article. Anyone want to give an opinion on any possible correlation between the visual disturbances of Viagra, and changes in the retina at the molecular level?? Not my area of expertise, but looked interesting enough to post for discussion and review.
Sildenafil <Viagra> is described as a potent and selective inhibitor of cGMP specific PDE (type 5).
This stuff was never very interesting to me, or i'd be in a lab somewhere, but let me give brief overview.
1.) Cyclic nucleotides are important intracellular messengers. <cGMP, for example>
2.) Phosphodiesterases <PDE's> are intracellular enzymes that hydrolyze cyclic nucleotides, <hydrolyzes cGMP, for example>
3.) Viagra is a potent inhibitor of cGMP specific PDE-type 5 <hence causing the erections> ; in other words, sildenafil inhibits PDE-5 from hydrolyzing cGMP.
4.) cGMP and PDE are both found in the retina.
5.) the following article states that aberrations in the structure of PDE can lead to retinal degeneration and blindness. PFE inhibitors, by the very nature, cause changes in the structure of the PDE molecule, hence inhibiting them. The big question is, does Viagra cause these molecular changes, and the symptomatic visual abnormalities reported, and possibly lead to blindness and retinal degeneration from prolonged use??
THE MOLECULAR BASIS OF RETINAL DEGENERATION
SCIENCE NEWS DIGEST FOR PHYSICIANS AND SCIENTISTS
THE MOLECULAR BASIS OF RETINAL DEGENERATION
Retinits pigmentosa encompasses a group of genetic disorders that involves 1 in 3000 individuals worldwide and gradually leads to blindness. Premature death of photoreceptors leads to progressive night blindness, contaction of the field of vision and finally to the complete loss of vision. Some forms of this disease have a mitochondrial pattern of inheritance whereas other types of disorder are inherited in a sex-linked or autosomal recessive or
autosomal dominant pattern.
Retinits pigmentosa results from degeneration of the photoreceptors. It has been shown that this denereation is associated with mutations of certain proteins that are implicated in the phototransduction. Visualization is a complex process which begins with absorption of light by the visual pigment, rhodopsin. This is followed by the following series of interactions:
The heterogimderic guanine nucleotide binding protein, tansducin has alpha, beta and gamma subunits. Photoactivated rhodopsin leads to stimulation of the alpha subunit of transducin to exchange its GDP to GTP.
The transducin alpha dissociates from transducin beta-gamma complex.
The transducin alpha binds to gamma subunit of cGMP-phosphodiesterase (PDE). This interaction relieves the inhibitory effect of the gamma subunit on the catalytic alpha and beta subunits of PDE and allows the hydrolytic activity of these subunits to be increased almost 300 fold.
The activated PDE leads to a decrease in the amount of c-GMP.
The decrease in the cGMP-gated cation channels on the plasma membrane of rods leads to a neural response.
The termination of the response to light requires reversal of these molecular interactions such as quenching of the photoactivated rhodopsin, transducin alpha and PDE and restoration of the concentration of the cGMP.
The dominant form of retinits pigmentosa is associated with certain types of mutations in the rhodopsin whereas other types involve mutations in peripherin/RDS. The function of peripherin which is found in the periphery of the outer segment discs is currently unknown. The autosomal recessive type of retinitis pigmentosa in mice (rd1/rd1) and Irish Setter dogs is associated with mutations in the beta subunit of PDE. Mutation in the alpha subunit of
PDE is also known to be associated with retinits pigmentosa. In the May 17, 96 issue of Science, Tsang et al report that lack of the gamma subunit of the PDE also results in retinal degeneration. Thus, presence of rhodopsin, and the subunits of the PDE is vital to the integrity of the photoreceptors and aberrations in these proteins leads to the degeneration of these cells and blindness.
References:
Tsang SH, 1996
Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase. Science, 272, 1026-1029, 1996
Dryja, 1995
Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.
Proc Natl Acad Sci U S A 92, 10177-10181 (1995) [96036047]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Peng, 1992
Retinal rods and cones have distinct G protein beta and gamma subunits.
Proc Natl Acad Sci U S A 89, 10882-6 (1992) [93066347]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Dhallan, 1992
Human rod photoreceptor cGMP-gated channel: amino acid sequence, gene structure, and functional expression.
J Neurosci 12, 3248-56 (1992) [92356211]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., 30 MEDLINE neighbors, 2 protein links, or 1 nucleotide link )
Yau, 1991
Sodium-calcium exchange and phototransduction in retinal photoreceptors.
Ann N Y Acad Sci 639, 275-84 (1991) [92152749]
(no abstract available) (View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Yau, 1989
Cyclic GMP-activated conductance of retinal photoreceptor cells.
Annu. Rev. Neurosci. 12, 289-327 (1989) [89192135]
(no abstract available) (View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Nakatani, 1988
Calcium and light adaptation in retinal rods and cones.
Nature 334, 69-71 (1988) [88261547]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Yau, 1985
Light-suppressible, cyclic GMP-sensitive conductance in the plasma membrane of a truncated rod outer segment.
Nature 317, 252-5 (1985) [86014348]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Farber, 1991
Studies leading to the isolation of a cDNA for the gene causing retinal degeneration in the rd mouse.
Prog Clin Biol Res 362, 67-86 (1991) [91164400]
(no abstract available) (View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Bowes, 1990
Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase [see comments]
Nature 347, 677-80 (1990) [91015387]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., 30 MEDLINE neighbors, 2 protein links, or 1 nucleotide link )
Bowes, 1989
Isolation of a candidate cDNA for the gene causing retinal degeneration in the rd mouse [published erratum appears in Proc Natl Acad Sci U S A 1990 Feb;87(4):1625]
Proc Natl Acad Sci U S A 86, 9722-6 (1989) [90099336]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors )
Suber, 1993
Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene.
Proc Natl Acad Sci U S A 90, 3968-72 (1993) [93248211]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., 30 MEDLINE neighbors, 4 protein links, or 2 nucleotide links )
McLaughlin, 1995
Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa.
Proc Natl Acad Sci U S A 92, 3249-3253 (1995) [95241481]
(View Citation format,Abstract format,MEDLARS format,ASN.1 format,Save As..., or 30 MEDLINE neighbors) >> |
