Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects

Abstract

Objective We tested the effect of two phosphodiesterase type-5 (PDE5) inhibitors, sildenafil and tadalafil, on ophthalmic artery (OA) blood flow velocity and investigated the presence of the PDE5 enzyme on human retinal tissue in comparison with the PDE6 enzyme localization. Methods Using Colour Doppler ultrasonography (CDU) we investigated, in 30 healthy young subjects (27.8 years of age; range, 24.3-33.7 years), the effects of a single oral dose of sildenafil (100 mg), tadalafil (20 mg), and placebo on OA blood flow velocity. Western blot for PDE6 and PDE5 protein expression was performed on frozen samples of human retina, testis, sperm, skin, and corpus cavernosum. Immunohistochemistry was performed on two ocular globes from dead donors. Results CDU showed a relationship between the administration of PDE5 inhibitors and OA blood flow velocity modifications in a timedependent manner. Western blot and immunohistochemical analysis showed PDE6 and PDE5 presence in human retinal tissue and gave a map of its distribution. Conclusion We demonstrated that (a) tadalafil and sildenafil are able to modify the OA flux in a time-dependent manner; (b) the PDE5 enzyme is expressed on retinal and choroid vasculature (smooth muscle and endothelial cells), on ganglion and bipolar cells; (c) human retinal tissues express the PDE6 enzyme in the rod and cone photoreceptors; (d) visual side effects after PDE5 inhibitors administration may be linked to a specific effect on the PDE5 enzyme; and (e) the PDE5 enzyme may have a physiologic role on ganglion and bipolar cells that need to be further investigated.

Sildenafil citrate on retrobulbar and retinal circulation of rabbits

“…The ophthalmic artery was easily located at the ultrasonography, enabling the visibilization of anatomical ultrasonography standard feasible of repeatability. The consulted literature reports that the ophthalmic artery tends to be more sensitive to the vasodilator action of PDE5 inhibitors (GRUNWALD et al, 2001;PARIS et al, 2001;FORESTA et al, 2008).…”

“…Nevertheless, PDE-5 inhibitors may also act by inhibiting the type-6 phosphodiesterase (PDE-6) present in the retina, with complications to the vision (ASHBY, 2006). There is evidence that the sildenafi l citrate increases retinal blood circulation and it is speculated that the event is a consequence of increased blood fl ow, per vasodilation, similar to what happens within the corpus cavernosum sphere (GRUNWALD et al, 2001;POLAK et al, 2003;FORESTA et al, 2008).…”

“…Potential effects on the retina, heart and blood pressure were the targets of investigations (PACHE et al, 2002 Ciência Rural, v.44, n.8, ago, 2014. POLAK et al, 2003;AMERI et al, 2008;FORESTA et al, 2008;CORDELL et al, 2009).…”

High Dosage Sildenafil Induces Hearing Impairment in Mice

“…However, a few studies to date have reported side effects of sildenafil that include flushing, headache, nasal congestion, heartburn, and non-arteritic anterior ischemic optic neuropathy. [3][4][5][6][7] Recently, sildenafil was reported to induce profound bilateral sensorineural hearing loss (SNHL) in a 44-year-old male patient following ingestion at 50 mg/d doses for 15 d. 8) SNHL is a type of hearing loss that involves the auditory nerve, inner ear, or central processing centers of the brain. SNHL can be evaluated as mild, moderate, or severe, and can cause complete deafness.…”

Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

“…[16][17][18][19][20][21][22][23][24][25] Recent studies have suggested that sildenafil may have direct effects on inner retinal cells, 17,26,27 because PDE5 is expressed in the inner nuclear layer and the ganglion cell layer in the human retina. 28 PDE5 also is expressed in the choroidal and retinal blood vessels. 28 Furthermore, sildenafil also inhibits, but with a reduced efficiency, the PDE6 that is expressed in the outer segment of photoreceptors and is involved in phototransduction 16,19,21,29 and the survival of photoreceptors.…”