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Representative results from the paracentesis of either 50 L (A), or 100 L (B) and sildenafil ingestion on rabbit IOP. Values from OD are plotted with solid symbols; those from OS with open symbols.
Source publication
Sildenafil increases ocular blood flow. Thus, the authors investigated if it also increases anterior chamber (AC) refilling after paracentesis.
Corriedale sheep and albino rabbits were used as animal models. Intraocular pressure (IOP) was measured, paracentesis performed on one eye, and AC refilling followed by observation using oblique illuminatio...
Contexts in source publication
Context 1
... the above indications that sildenafil should increase the AH turnover of the normal eye (presumably due to in- creased flow in the CB stroma-to-iris pathway), as well as the rate of AH refilling after paracentesis (due primarily to an increased ultrafiltration), we suggest that the drug be consid- ered as a potential prophylactic agent to augment the rate of AH refilling after eye surgeries of the anterior segment. In some cases, the angle collapses, leading to a potential complication of damage to the corneal endothelial cells due to mechanical interaction with the iris. Presently, many surgeons inject saline into the AC and/or with viscoelastic material to maintain nor- mal ocular dimensions until CE secretory function and AH volume are fully restored. However, it can take 4 to 8 hours for freshly secreted AH to completely replace the saline in the AC. 34 One surgeon recommended withdrawing the aqueous at the beginning of surgery and returning it at the end of the procedure. 35 Sildenafil could be tested as an important adjunct in these types of procedures. It may also have utility in treating cases of ocular hypotony that result from insufficient AH for- mation. 36,37 Rabbits were subjected to paracentesis of the left eye, followed by oral administration of sildenafil and the paracentesis of the right eye as described in text and shown in Figure ...
Context 2
... experiments with rabbits are illustrated in Figure 3. On the withdrawal of 50 L AH, approximately 13.5 minutes, on average, were needed for IOP recovery, signifying a mean AH refilling rate of 3.9 L/min (Table 4). After the rabbits were fed sildenafil, the time necessary for IOP restora- tion shortened to approximately 6 minutes with the average AH refilling rate increased to approximately 8 L/min. Virtually identical recovery times were obtained when the volume of the paracentesis was increased to 100 L, both before and after sildenafil ingestion (i.e., 13 and 6 minutes, respectively; Table 4). However, these recovery times reflect higher estimated rates (2-fold) for AH refilling (Table 4). Overall, these data indicate that although AH refilling occurs relatively promptly in rabbits, the inflow mechanisms involved can still be acceler- ated by the ingestion of ...
Context 3
... it was observed with rabbits that paracentesis, in itself, evoked a large IOP overshoot above the control level as the pressure was restored (Fig. 3), a phenomenon in rabbits attributed to the base of the iris bowing forward, thereby closing the angle and blocking the outflow. 25 We merely re- corded this excess in pressure and calculated the time point at which the IOP was approximately equal to that of the control level for determining the recovery time. Since the protocol was designed so that AH was withdrawn from each eye only once, the IOP overshoot evoked by paracentesis was a unilateral effect that did not influence the IOP of the fellow eye. In our data, elevated IOPs evoked by paracentesis gradually declined to control levels within 90 minutes (n 24 ...
Context 4
... additional comparative difference between the two animal models was that sildenafil ingestion did not directly increase the IOP of rabbits. Neither the elevated IOP produced secondarily by para- centesis, nor the baseline IOP of the contralateral eye not yet sub- jected to paracentesis, was affected by sildenafil (Fig. 3). With three other rabbits that were not subjected to paracentesis and solely fed sildenafil, no significant effects on IOP were observed (data not shown). As such, sildenafil accelerated the AH refilling rate indepen- dently of whether it also increased baseline IOP, as saliently occurs with sheep ( Figs. 1 and 2). 12 Thus, an explanation is necessary for the absence in rabbits of an IOP-elevating effect by the drug, which nevertheless stimulated the AH refilling rates after paracentesis. We pre- sume that if the drug indeed increased AH turnover in the normal rabbit eye, it concomitantly increased the pressure- dependent outflow via the trabecular meshwork in this spe- cies, thereby not producing a detectable change in IOP. Our present emphasis is the finding that sildenafil increased the AH refilling rate in a species in which such refilling after paracen- tesis occurs rapidly. After the removal of 50 and 100 L AH, IOP recovered, on average, within 14 minutes (Table 4), re- sulting in estimated AH-refilling rates of 3.9 and 8.3 L/min, respectively (Table 4). These rates are markedly higher than the 2 to 3 L/min rate of AH formation attributed to secretion by the CE in rabbit. 26 -28 After sildenafil treatment, the time necessary for IOP restoration was approximately halved, and the estimated AH refilling rates therefore ...
Citations
... This is challenged by a few ani- mal studies and subsequent human studies that demonstrate how sildenafil may lead to elevation of IOP due to increased choroidal perfusion. [62][63][64] Previously the visual disturbances produced by sildenafil were believed to be the result of PDE6 inhibition in the photoreceptors. Recent studies have demonstrated the influence of sildenafil on bipolar cells. ...
Sildenafil citrate is a selective oral phosphodiesterase 5 (PDE5) inhibitor, a widely used drug for erectile dysfunction that acts by elevating cGMP levels and causing smooth muscle relaxation. It also has 10% activity against PDE6, a key enzyme in phototransduction cascade in the retina. Recent ocular imaging developments have further revealed the influence of sildenafil on ocular hemodynamics, particularly choroidal perfusion. Choroidal thickness is increased, and choroidal perfusion is also enhanced by autoregulatory mechanisms that are further dependent on age and microvascular abnormalities. Studies demonstrating high intraocular pressure via a "parallel pathway" from increased choroidal volume and blood flow to the ciliary body have challenged previous concepts. Another new observation is the effect of sildenafil on bipolar cells and cyclic-nucleotide gated (CNG) channels. We discuss potential deleterious effects (central serous chorioretinopathy, glaucoma, ischemic optic neuropathy, and risks to recessive carriers of retinitis pigmentosa), potential beneficial effects (ameliorate choroidal ischemia, prevent thickening of Bruch membrane, and promote recovery of the ellipsoid zone) in macular degeneration, as well as potential drug interactions of sildenafil.
... Accordingly, an animal model with persistent hypotony is required to investigate pathophysiological changes in the CB during the process of hypotony and to identify the mechanisms associated with these changes. A range of animal models have been described of hypotony thus far (Gerometta et al., 2012;Jasien et al., 2017;Kim et al., 1998;Pederson et al., 1979;Suguro et al., 1985). However, to the best of our knowledge, none of these models are ideal, mostly because experimental surgery can result in transient hypotony or cause severe damage to the CB. ...
... However, the pathophysiological processes associated with the CB during the process of hypotony remain unclear. Existing animal models of hypotony have been established by several methods, including direct CB injury (cyclocryopexy (Schubert and Federman, 1989) or cyclophotocoagulation (Choi et al., 1996;Gurelik et al., 2019;Rosenberg et al., 1995;Schubert and Federman, 1989), cyclodialysis (Suguro et al., 1985), or ciliochoroidal detachment (Pederson et al., 1979), the creation of a fistula (Barak et al., 1995;Chi et al., 1995;Gerometta et al., 2012;Jaffe et al., 1988;Jasien et al., 2017;Minckler and Bunt, 1977), or by establishing PVR (Kim et al., 1998). However, none of these existing models are ideal because of the severe mechanical injury incurred by the CB or non-sustainable R. Zhao, et al. ...
... The main limitation of this type of model is the failure to achieve longterm filtration. Indeed, a previous study showed that IOP returned to normal within 1 h following AC cannulation (Jasien et al., 2017) or paracentesis (Gerometta et al., 2012). Various lasers have been used to form full-thickness sclerostomy; however, IOP returned to normal levels in 83% (Jaffe et al., 1988) or 100% (Barak et al., 1995) of animals by the fourth or third post-operative day, respectively. ...
In order to study the pathophysiological alterations of the ciliary body (CB) during persistent hypotony, it is necessary to develop an animal model without CB injury. In this study, we successfully established a modified model of persistent hypotony without CB injury in New Zealand rabbits. A 23 gauge pars plana vitrectomy (PPV) was performed and a trocar-formed fistula was remained in situ, to produce a continuous outflow of intraocular fluid. Both eyes underwent PPV with normal intraocular pressure (IOP) and eyes with no surgical intervention were used as controls. The IOP was monitored and used to evaluate the reliability of the model. Secondary changes of hypotony were evaluated by slit-lamp biomicroscopy and B scans while morphological changes of the CB were observed by haematoxylin and eosin staining. The mean IOP in the hypotony groups were consistently lower than 6 mmHg. Furthermore, there were no significant differences in IOP between the PPV control group and normal eyes. Collectively, our data indicate that this model successfully simulates the secondary changes of hypotony, including a reduction in corneal size, corneal oedema, anterior chamber inflammation, morphological alterations of the CB, cataract, retinal detachment, and choroidal detachment. The morphological structure of the CB tissue changed dramatically after persistent hypotony, indicating that normal IOP may be required in order to maintain normal function in the CB. This model of persistent hypotony potentially represents a valuable tool for future studies aiming to investigate the pathophysiological mechanisms underlying CB dysfunction and other secondary changes that occur during hypotony.
... 14,16,19 Several studies have investigated short-term hypotony following AC cannulation or paracentesis without the ability to measure IOP immediately after needle removal. [20][21][22][23][24] Lu et al. 6 performed AC paracentesis with a 27-G needle as treatment for elevated IOP in angle closure glaucoma patients; they reported IOP measurements obtained with Goldmann Applanation Tonometry (GAT) prior to AC paracentesis, then 15 minutes and 24 hours after AC needle removal. Intraocular pressure was approximately 30 mm Hg lower than baseline measurement at both 15 minutes and 24 hours after AC needle removal, but no hypotony was reported during the study, as the average baseline IOP was 58 mm Hg, and hence postparacentesis IOP was approximately 28 mm Hg. 6 Several other studies report similar results, also showing the safety and efficacy of AC paracentesis for the treatment of elevated IOP associated with acute angle closure. ...
... Gerometta et al. 23 performed AC cannulation and paracentesis with a 28-G needle and recorded recovery times following varying aqueous humor volume withdrawals from the AC. Intraocular pressure was measured with a Perkins tonometer in sheep and Tono-Pen in rabbits. ...
... In studies of AC cannulation and paracentesis in sheep and rabbits, IOP recovery was not assessed using accurate continuous measurement; although IOP recovered within an hour. 23 These recovery times are somewhat similar in duration to our measurements. ...
Purpose
To determine the magnitude of ocular hypotony and the length of recovery time to 6 and 10 mm Hg IOP following anterior chamber (AC) cannulation.
Methods
Bilateral IOP was recorded 500 times per second via telemetry immediately before, during, and immediately after AC cannulation with a 27-G needle in 10 different sessions at least 2 weeks apart in four male rhesus macaques (nonhuman primates; NHPs) aged 3- to 6-years old. Bilateral IOP was recorded continuously using a proven telemetry system while the NHPs were under general anesthesia during IOP transducer calibration experiments involving manometric control of IOP via AC cannulation, then continuously after the AC needles were removed until IOP recovered to precannulation levels. The change in IOP from baseline to AC cannulation was tested using the signed-rank test. The times necessary for IOP to recover to 6 and 10 mm Hg, respectively, were calculated.
Results
Average precannulation IOP was 11.5 mm Hg and significantly decreased to an average of 2.3 mm Hg immediately following AC needle removal (P = 0.0156). On average, IOP recovered from 2.3 to 6 and 10 mm Hg in 32.4 and 63.7 minutes, respectively. Recovery times of IOP were not affected by repeated AC cannulations every 2 weeks.
Conclusions
Generally, IOP recovers relatively quickly after repeated AC cannulation, and did not result in extended duration hypotony. It is important to consider hypotony in animal experiments and clinical procedures involving AC cannulation and paracentesis when consideration of IOP or its effects is important.
... 11 This theory is confirmed by the observations that sildenafil restores aqueous humor refilling after anterior chamber paracentesis, resulting in IOP recovery. [11][12][13] However, a previous study by Grunwald et al had revealed that the maximum therapeutic dose of sildenafil of 100 mg caused no statistically significant change in IOP or systemic blood pressure in men having treated chronic open-angle glaucoma. 14 ...
Aim
The aim of this review was to summarize the ocular action of the most common phosphodiesterase (PDE) inhibitors used for the treatment of erectile dysfunction and the subsequent visual disorders.
Method
This is a literature review of several important articles focusing on the pathophysiology of visual disorders induced by PDE inhibitors.
Results
PDE inhibitors have been associated with ocular side effects, including changes in color vision and light perception, blurred vision, transient alterations in electroretinogram (ERG), conjunctival hyperemia, ocular pain, and photophobia. Sildenafil and tadalafil may induce reversible increase in intraocular pressure and be involved in the development of non-arteritic ischemic optic neuropathy. Reversible idiopathic serous macular detachment, central serous chorioretinopathy, and ERG disturbances have been related to the significant impact of sildenafil and tadalafil on retinal perfusion.
Discussion
So far, PDE inhibitors do not seem to cause permanent toxic effects on chorioretinal tissue and photoreceptors. However, physicians should write down any visual symptom observed during PDE treatment and refer the patients to ophthalmologists.
... As for intraocular pressure, no statistical differences were found between the groups. Like this study, other studies on rabbits have shown no significant increases in IOP with the use of sildenafil citrate [14][15][16]. However, sheep treated with the minimum (50 mg) and maximum (100 mg) doses recommended for humans showed an elevation of IOP [17] . ...
Background
It has been proposed that sildenafil citrate can increase ocular blood flow, and that this property can be used to treat ocular disorders that involve reflex vasoconstriction. This study therefore proposes to ascertain the vasodilator effect of the drug on retrobulbar circulation in healthy rabbits. For this matter rabbits treated with sildenafil citrate or saline solution had their intraocular pressure (IOP), mean arterial pressure (MAP), ocular perfusion pressure (OPP) and color Doppler imaging of the external ophthalmic artery measured prior to treatment and on days one (moment M1), seven (when M2), fourteen (moment M3), twenty-one (moment M4), and thirty (moment M5) of treatment.
Results
The MAP and OPP values of treated group were lower than those of control group at all times, and the mean values differed statistically at moments M1 (S = 71.52 mmHg, C = 84.76 mmHg, p = 0.0356) and M5 (S = 71.38 mmHg, C = 85.52 mmHg, p = 0.0252). The IOP and color Doppler values of the external ophthalmic artery did not differ between tested groups.
Conclusions
The dose of 10 mg of sildenafil citrate administered to healthy rabbits causes systemic vasodilation and consequently lower values of MAP and OPP. However, it does not induce changes in IOP and retrobulbar hemodynamics identifiable by color Doppler assessment of the external ophthalmic artery.
... Consistent with the latter possibility, we reported that sildenafil elevated intraocular pressure (IOP) and AC protein concentration in a sheep animal model (Gerometta et al., 2010), effects consistent with a stimulation of plasma-like fluid entry into the eye, and increased the rate of IOP recovery after paracentesis in sheep and rabbit animal models (Gerometta et al., 2012). ...
... The fact that such IOP recovery, with concomitant aqueous humor (AH) refilling, was saliently enhanced by sildenafil in two different animal models, implied that the vasodilator not only provided more fluid for secondary aqueous formation after paracentesis, but might also stimulate AH turnover in the normal eye. However, we did not measure AH turnover directly in our previous studies (Gerometta et al., 2010(Gerometta et al., , 2012, and there are no reports in the literature on the effects of the PDE5 inhibitors on AH turnover and/or the rate of AH formation. Both the accelerated rates of IOP restoration after paracentesis in animals administered sildenafil (Gerometta et al., 2012), as well as, the findings that sildenafil increases vascular flow in the eye due to dilations of intraocular arteries (Koksal et al., 2005;Harris et al., 2008), suggest that the vasodilator may stimulate the turnover of AH of the normal eye. ...
... However, we did not measure AH turnover directly in our previous studies (Gerometta et al., 2010(Gerometta et al., , 2012, and there are no reports in the literature on the effects of the PDE5 inhibitors on AH turnover and/or the rate of AH formation. Both the accelerated rates of IOP restoration after paracentesis in animals administered sildenafil (Gerometta et al., 2012), as well as, the findings that sildenafil increases vascular flow in the eye due to dilations of intraocular arteries (Koksal et al., 2005;Harris et al., 2008), suggest that the vasodilator may stimulate the turnover of AH of the normal eye. The aim of this study was to directly test this hypothesis. ...
Sildenafil citrate increases ocular blood flow and accelerates the rate of anterior chamber refilling after paracentesis. The latter effect could have resulted from a reduction in outflow facility or from an increase in aqueous humor (AH) production. In this study, we used scanning ocular fluorophotometry to examine the effects of sildenafil on AH turnover, and thus, AH production in eyes of live normal rabbits. For this, the rate of aqueous humor flow (AHF) was quantified with a commercially available fluorophotometer that measured the rate of fluorescein clearance from the anterior segment, which predominantly occurs via the trabecular meshwork. After ≈ 2 hrs of control scans to determine the baseline rate of AHF, the rabbits were fed 33 mg of sildenafil and allowed ≈ 45 min for the drug to enter the systemic circulation. Thereafter, fluorescence scans were retaken for an additional 90-120 min. Sildenafil ingestion increased AHF by about 36%, from 2.31 μL/min to 3.14 μL/min (P< 0.001, as two-tailed paired data, n= 20 eyes). This observation indicates that sildenafil citrate, which is a phosphodiesterase type-5 inhibitor currently marketed as a vasodilator (e.g., Viagra, Revatio), stimulates AHF in rabbits. Our results seem consistent with reports indicating that the drug dilates intraocular arteries and augments intraocular vascular flow. These physiological responses to the agent apparently led to increased fluid entry into the anterior chamber. As such, the drug might have utility in patients with ocular hypotony resulting from insufficient AH formation.
The aim of this study was to determine intraocular pressure (IOP) and central corneal thickness (CCT) measurements in healthy rabbits to establish clinical reference values and to investigate the possible relationship between these measurements. The study included 40 eyes of 20 New Zealand albino rabbits, aged 1.5-2 years. All the eyes were healthy with no abnormalities, corneal disease, or evidence of glaucoma. An ultrasonographic pachymeter was used to measure CCT and TonoVet® was used to measure IOP. Correlations between IOP and CCT measurements were examined. The mean CCT was 388.2 ± 38.22 µm in the right eye and 391.8± 59.18 µm in the left eye. IOP was measured as 16 ± 3.76 mmHg in the right eye and 16 ± 2.73 mmHg in the left eye. No correlation was determined between the IOP and CCT, and this indicated that the TonoVet® readings of CCT and IOP did not cause a deviation that could be determined. There is a need for further studies of different animals to investigate the effect of corneal thickness on the IOP measurements made with TonoVet®.
Introduction
Phosphodiesterase type 5 (PDE5) hydrolyses cyclic guanylate monophosphate specifically to 5′ guanylate monophosphate, promoting corporeal vascular relaxation and penile erection in response to sexual stimulation. Oral PDE5 inhibitors (PDE5-Is) have afforded effective and well-tolerated treatment for erectile dysfunction. In addition, PDE5-Is have stimulated academic and clinical interest for their potential benefits in diverse non-sexual applications.
Aim
To highlight possible potential non-sexual implications of PDE5-Is.
Methods
A systematic review was conducted until January 2016 based on a search of all relevant articles in Medline Medical Subject Heading, Scopus, Cochrane Library, EMBASE, and CINAHL databases without language restriction. Key words used to assess outcome and estimates for the relevant associations were PDE5 inhibitors, sildenafil, tadalafil, vardenafil, and avanafil.
Main Outcome Measures
Different non-sexual implications for PDE5-Is.
Results
PDE5-Is demonstrated beneficial effects in different medical applications with possible widespread implications for cardiovascular, pulmonary, cutaneous, gastrointestinal, urogenital, cellular, musculoskeletal, neurologic, and reproductive disorders. However, most applications were carried out experimentally in preclinical studies of off-label indications.
Conclusion
PDE5-Is are a conceptually attractive therapeutic class of agents with pleiotropic effects. Exploring PDE5-Is for their possible implications seems to be valuable in different medical disorders. However, well-designed clinical trials are needed before these agents can be recommended for selected applications.
Mostafa T. Non-Sexual Implications of Phosphodiesterase Type 5 Inhibitors. Sex Med Rev 2017;5:170–199.
Based on the therapeutic potential of sildenafil citrate for treatment of patients with ocular conditions that generate vasoconstriction, it was proposed to verify the vasodilator action of the drug on retrobulbar circulation of healthy rabbits and using for it the mean arterial pressure, intraocular pressure and calculation of the ocular perfusion pressure. Sildenafil citrate caused a reduction of mean arterial pressure and ocular perfusion pressure of rabbits treated at all time points, verifying statistically significant difference only in the first day of treatment.
Glaucoma is a leading cause of blindness, which is treatable but currently incurable. Numerous animal models therefore have both been and continue to be utilized in the study of numerous aspects of this condition. One important facet associated with the use of such models is the ability to accurately and reproducibly measure (by cannulation) or estimate (by tonometry) intraocular pressure (IOP). At this juncture there are several different approaches to IOP measurement in different experimental animal species, and the list continues to grow. We feel therefore that a review of this subject matter is timely and should prove useful to others who wish to perform similar measurements. The general principles underlying various types of tonometric and non-tonometric techniques for non-continuous determination of IOP are considered. There follows discussion of specific details as to how these techniques are applied to experimental animal species involved in the research of this disease. Specific comments regarding anesthesia, circadian rhythm, and animal handling are also included, especially in the case of rodents. Brief consideration is also given to possible future developments.
Copyright © 2015. Published by Elsevier Ltd.
