Indian J Med Res 117, May 2003, pp 211-215
Histopathologic effect of chronic use of sildenafil citrate on thechoroid & retina in male rats
H.S. Vatansever, O. Kayikcioglu* & B. Gumus†
Departments of Histology & Embryology, *Ophthalmology & †Urology, Faculty of MedicineCelal Bayar University, Manisa-TurkeyBackground & objectives: Sildenafil citrate is an oral medication used to treat male impotence by the inhibition of phosphodiesterase-5 in the corpus cavernosum and subsequent facilitation of penile erection. Though the ocular side effects of sildenafil have been reported, no information is available on the histopathologic effects of chronic use of sildenafil citrate on the ocular vasculature. The present study was undertaken to study the histopathologic effects of chronic use of sildenafil on the retina and choroid of male rats. Methods: Twelve adult male Wistar rats were used in the study. Six of them were given 8 mg/kg/day sildenafil citrate orally on alternate days, the other six rats were used as control. The animals were sacrificed after 4 wk of treatment, and the eyes were fixed in 10 per cent formalin solution and sectioned after embedding in paraffin. Sections were cut, stained with haematoxylin-eosin (HE) or periodic acid Schiff (PAS) and examined under light microscope. The choroidal capillary diameter was also measured. Results: The choroidal capillaries were more dilated in the sildenafil citrate treated group (mean capillary diameter 3.44 ± 1.68 µm versus the control of 1.78±1.36 µm, P<0.001). The retinal layers and their configuration were unchanged in both the groups. Interpretation & conclusion: Chronic use of sildenafil citrate can cause dilatation and congestion in the choroidal vasculature of male rats. Key words Choroid vasculature - sildenafil citrate - wistar rat
Sildenafil citrate is an effective drug for erectile
potentially retinotoxic due to an associated increase
dysfunction due to organic causes1-3, however, side-
in retinal c-GMP, and it has been shown to cause a
effects have been reported such as flushing,
depression of electroretinogram (ERG) functions
headache, and congestion4,5. Sildenafil is a selective
suggesting clinical toxicity of the retina 7-9. In
inhibitor of the cyclic guanosine monophosphate
addition to the inhibitory effect on PDE in the
(cGMP)-specific phosphodiesterase (PDE)-5. It has a
retina, sildenafil may also alter choroidal blood flow
mild inhibitory effect on PDE-6 (about 10-fold lower
due to its systemic effects on vascular smooth
affinity than for PDE-5), which is located in the
muscle. Ocular side-effects of sildenafil have been
retinal photoreceptors and regulates the levels of
frequently reported, generally in terms of changes
cGMP in the retina 5,6. Sildenafil is therefore
in colour vision and light flashes10. It is thus
and evaluated the measurements. The data were
circulation11,12. However, sildenafil citrate is still
analysed statistically using Mann-Whitney U test,
considered to be a safe drug despite reports of its
P value < 0.05 was considered significant.
ocular side-effects. To the best of our knowledge,there are no reports on the histopathological changes
in the eye vasculature following chronic sildenafiluse. Therefore, the present study was undertaken to
Dilatation and congestion of the choroidal
investigate the histopathological effects of chronic
capillaries was observed in the sildenafil treated
use of sildenafil citrate on the choroid and retina of
group compared to controls (Fig. 1A-D). The mean
capillary diameter being 3.44±1.68 µm in thesildenafil treated group and 1.78 ± 1.36 µm in the
Material & Methods
control group (P<0.001). Despite this dilatation ofthe choroidal capillaries in the treated group, the
The study was performed in the Department of
basement membranes of the capillaries in the choroid
Histology and Embryology at the University of Celal
were seen as continuous sheets, same as in controls
Bayar, Manisa, Turkey. The Ethics Committee at
Celal Bayar University, School of Medicine,approved the study protocol.
When the other anatomical areas of the eyes were
compared under the light microscope, no histological
Twelve fertile adult male Wistar rats were used
differences were detected between controls and the
in the study. The animals were fed a standard
treated group (data not shown). No histopathological
laboratory rat diet, and six were given 8 mg/kg/day
changes were seen in the retina of the control
sildenafil citrate orally on alternate days (three days
(Fig. 2-A) or the treated (Fig. 2-B) groups.
in a week) for 4 wk13, the remaining six rats wereleft untreated and served as controls. The animals
were sacrificed after 4 wk of treatment, and the eyeswere dissected out and fixed in 10 per cent of
Sildenafil citrate is shown to be effective in
formalin solution following treatment in 95 per cent
treating erectile dysfunction by selectively inhibiting
ethanol for 24 h and then in chloroform for 5 h. The
the cGMP-specific PDE-5 in the corpus cavernosum
eyes were embedded in paraffin wax and 5 µm serial
smooth muscle cells 16. It also weakly inhibits
sections were taken. Random sections were selected
PDE-6, which is present in high concentrations in
and stained with either haematoxylin and eosin
the cone and rod cells and plays a key role in the
(Sigma, USA) (H-E) or with periodic acid Schiff
light signal phototransduction of the retina. The most
(PAS) (Sigma, USA) according to the recommended
common adverse effects associated with sildenafil
routine protocols14,15. The slides were mounted
are headache, flushing and dyspepsia 17, the ocular
using entellan (Surgipath, MX-004) and covered
side-effects include altered vision, mainly involving
with glass coverslips prior to viewing under the
changes in colour, hue or brightness perception12,18.
Olympus BX-40 light microscope (Tokyo, Japan).
Cardiovascular deaths and retinal vascular events inindividuals taking sildenafil have also been
To estimate the diameter of the choroidal
reported19,20. However, some investigators supported
capillaries, the H-E stained serial sections were
that PDE-6 inhibition causes the dose-dependent
recorded using a video camera (JVC) which was
clinical effects of visual disturbance in men taking
attached to the light microscope, and then
sildenafil and the implications of the long-term daily
downloaded to a computer for the measurements.
use of sildenafil in men are not clear11,21.
The diameter of the capillaries was measured acrosscapillary lumen. For each capillary, at least four
The results of the present study demonstrated that
sildenafil citrate can cause dilatation of the choriodal
observers, blinded to the sample origin, recorded
capillaries in the rat, although the retina was not
VATANSEVER et al : EFFECTS OF SILDENAFIL CITRATE ON RAT EYE 213
Fig. 1. Histochemical staining of the choroidea in the control (A,C) and sildenafil-treated (B,D) groups. While increased choroidal capillaries (arrows) were observed by H-E staining in the sildenafil-treated group (B), a normal basement membrane was seen with PAS staining in both groups (C,D). H-E (A-B), PAS (C,D). magnification X400. seen to be affected histopathologically. Thus the eyes of rat. However, choroidal dilatation was sildenafil has its major effect on the choroidal found and it may cause choroidal disfunction. In circulation in male rats, suggesting the potential addition to effects on PDE in the retina, there is involvement of sildenafil in circulatory defects of a possibility that sildenafil may alter the vascular
flow or choroidal volume because of its systemic effects on vascular smooth muscle. Birch et al23
Toxicity studies on dogs22 with a high dose reported no significant changes in intraocular
(60 mg/kg) of sildenafil over extended periods pressure after acute treatment with sildenafil
have not shown changes in the retinal citrate, but choroidal diameter or volume were
architecture on histological examination. not measured. Our results show that there is a
Therefore, it may not be possible to show dilatation of the choroidal vessels after sildenafil
histologically the retinotoxicity of chronic use treatment and this may lead to congestive effects
of sildenafil. Our study also did not reveal any within the eye. An increase in choroidal vessels
changes in the retinal morphology in the
Fig. 2. Histochemical staining of the retina in the control (A) and sildenafil-treated (B) groups. All layers of the retina were examined and there were no structural differences in the retinas of both the control (A) and treated (B) groups. H-E. magnification X400.
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