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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-Turkey Background & 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 Discussion
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.
affect retinal and retinal pigment epithelial functions Luu JK, Chappelow AV, Mcculley TJ, Marmor MF. Acuteeffects of sildenafil on the electroretinogram and multifocal and, if severe, could predispose to retinal electroretinogram. Am J Ophthalmol 2001; 132 : 388-94.
detachment, or oedema, or even to glaucoma.
Vobig MA, Klotz T, Staak M, Bartz-Schmidt KU, The results of the present study demonstrate that Engelmann U, Walter P. Retinal side-effects of sildenafil.
chronic use of sildenafil citrate causes complications in the choroid of the rat. These visual effects need Kretschmann U, Gockeln R, Meschi M, Stief CG, Winter R. Short time influences of sildenafil on visualfunction. Invest Ophthalmol Vis Sci 1999; 40 : S766.
10. Yajima T, Yajima Y, Koppiker N, Grunwald JE, Laties AM. No clinically important effects on intraocular Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, pressure after short-term administration of sildenafil citrate Steers WD, Wicker PA. Sildenafil Study Group. Oral (Viagra). Am J Ophthalmol 2000; 129 : 675-6.
sildenafil in the treatment of erectile dysfunction.
N Engl J Med 1998; 338 : 1397-404.
11. Sponsel WE, Paris G, Sandoval SS, Sanford DK, Hackett G. Managing erectile dysfunction. Practitioner Harrison JM, Elliott WR, et al. Sildenafil and ocular perfusion. N Engl J Med 2000; 342 : 1680.
Medina P, Segarra G, Vila JM, Domenech C, Martinez- 12. Gabrieli CB, Regine F, Vingolo EM, Rispoli E, Fabbri A, Leon JB, Lluch S. Effects of sildenafil on human penile Isidori A. Subjective visual halos after sildenafil (Viagra) blood vessels. Urology 2000; 56 : 539-43.
administration: Electroretinographic evaluation.
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, Ophthalmology 2001; 108 : 877-81.
a novel effective oral therapy for male erectile dysfunction.
Br J Urol 1996; 78 : 257-61.
13. Ishikura F, Beppu S, Hamada T, Khandheria BK, Marmor MF, Kessler R. Sildenafil (Viagra) and Seward JB, Nehra A. Effects of sildenafil citrate (Viagra) ophthalmology. Surv Ophthalmol 1999; 44 : 153-62.
combined with nitrate on the heart. Circulation 2000;102 : 2516-21.
Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME,Naylor AM. Effects of sildenafil on the relaxation of 14. Stevens A, Wilson I. The haematoxylins and eosin. In: human corpus cavernosum tissue in vitro and on the Bancroft JD, Stevens A, Turner DR, editors. Theory and activities of cyclic nucleotide phosphodiesterase isozymes.
practice of histological techniques, 4th ed. Hong Kong: J Urol 1998; 159 : 2164-71.
Churchill Livingstone; 1996 p. 99-112.
VATANSEVER et al : EFFECTS OF SILDENAFIL CITRATE ON RAT EYE 15. Cook HC. Carbohydrates. In: Bancroft JD, Stevens A, 20. Cunningham AV, Smith KH. Anterior ischemic optic Turner DR, editors. Theory and practice of histological neuropathy associated with Viagra. J Neuroophthalmol techniques, 4th ed. Hong Kong: Churchill Livingstone; 16. Moreland RB, Goldstein I, Traish A. Sildenafil a novel 21. Gonzalez CM, Bervig T, Podlasek C, Huang CF, inhibitor of phosphodiesterase type 5 in human corpus McKenna KE, McVary KT. Sildenafil causes a dose- andtime-dependent downregulation of phosphodiesterase type cavernosum smooth muscle cells. Life Sci 1998; 62 :309-18.
6 expression in the rat retina. In J Impot Res 1999;11 (Suppl 1) : S9-14.
17. Moreira SG Jr, Brannigan RE, Spitz A, Orejuela FJ, Lipshultz LI, Kim ED. Side-effect profile of sildenafil 22. Wallis RM, Leishman D, Pullman L, Graepel P, citrate (Viagra) in clinical practice. Urology 2000; 56 : Heywood R. Effects of Sildenafil on retinal histopathology and electroretinogram (ERG) in dogs. Ophthalmic Res 18. McCulley TJ, Lam BL, Marmor MF, Hoffman KB, Luu JK, Feuer WJ. Acute effects of sildenafil (Viagra) onblue on yellow and white-on-white Humprey perimetry.
23. Birch DG, Toler SM, Swanson WH, Fish GE, Laties AM.
J Neuroophthalmol 2000; 20 : 227-8.
A double-blind placebo-controlled evaluation of the acute 19. Corbin JD, Francis SH, Osterloh IH. Effects of sildenafil effects of sildenafil citrate (Viagra) on visual function in on cAMP and cGMP levels in isolated human cavernous subjects with early-stage age-related macular degeneration.
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Reprint requests : Dr H. Seda Vatansever, 198 sok No : 7/4 35040, Bornova-Izmir, Turkey

Source: http://icmr.nic.in/ijmr/2003/0505.pdf?origin=publication_detail

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