Current Biology Vol 16 No 2 R44 Viagra slows the visual response to flicker Andrew Stockman1, Lindsay T. Sharpe1, Adnan Tufail2, Philip D. Kell3 and Glen Jeffery1 As an undesirable side effect, sildenafil citrate (Viagra) partially
Target radiance (log quanta s–1 deg–2)
Target radiance (log quanta s–1 deg–2)
inhibits the phosphodiesterase PDE6 , which plays an essential role in phototransduction (reviewed in [2,3]). PDE6 not only activates the visual transduction cascade, but also controls the time over which the visual response is integrated, thereby helping to maintain the size of the visual response within an optimal range as the light level is increased . Consistent with an increase in temporal integration following Viagra ingestion, performance improvements have Figure 1. Critical flicker fusion (A,B) and modulation sensitivity (C,D) data for L.T.S. been reported for an identification (A,C) and G.J. (B,D). task that relies on the integration A centrally fixated flickering target of 4° of visual angle in diameter and 650 nm in wave- of two temporally separated length was presented in the centre of a 9° background field of 481 nm. The background stimuli . Using more of 8.26 log quanta s–1 deg–2 at the cornea was there primarily to saturate the rods. The conventional psychophysical mean radiance of the 650 nm target was varied for the c.f.f. measurements and fixed at measures of temporal sensitivity 9.52 log quanta s–1 deg–2 for the modulation sensitivity measurements. In each panel, the pre-Viagra baseline data (dotted open circles) are the averages of three or more and resolution [6,7], we find that separate measurements made before drug ingestion. The shapes of the coloured therapeutic 100 mg doses of symbols denote the dose numbers: dose 1 (triangles); dose 2 (circles); dose 3 (inverted Viagra can cause mild to triangles); and dose 4 (hexagons). The time after dose ingestion is coded by the colour moderate transient losses in of the symbols (see key). The times noted are the midpoints of the time periods after human temporal visual sensitivity. dose ingestion during which a given curve was measured (from the first setting made These losses imply that in the at the end of a 3 min pre-adaptation period to the last setting). A c.f.f. curve required on average 12 min to complete, whereas a modulation sensitivity curve required 8 min. more affected observers, Viagra Crossed symbols distinguish between two runs made during the same colour-coded may provide a unique tool for time window. pharmacologically manipulating the activity of PDE6 in humans in known as the temporal resolution Below the plateau, the losses vivo, and thus for investigating the limit or critical fusion frequency increase slightly with target role of PDE6 in light adaptation. At (c.f.f.) — as a function of the radiance, reaching ~10 Hz for the light levels tested, the radiance of the 650 nm target. L.T.S. and 5 Hz for G.J. (coloured frequency-dependent sensitivity Under these conditions of symbols). losses caused by the inhibition of adaptation, flicker detection is To characterize the losses at PDE6 by Viagra are consistent mediated by long-wavelength frequencies below the c.f.f., we with an almost doubling of the sensitive (L–) cones, and to a measured modulation thresholds time over which visual events are lesser extent by middle- as a function of temporal normally integrated (from ~6.9 to wavelength sensitive cones (M–) frequency. Subjects were asked 12.6 ms, assuming a single cones. The results are shown in to adjust the target modulation integration stage). Figure 1 for observers L.T.S. (A) until the apparent flicker was just Observers were presented with and G.J. (B). With increasing visible. Modulation is adjusted by a flickering red (650 nm) target target radiance, their baseline varying the fraction of the light superimposed in the centre of a (pre-Viagra) c.f.f. functions (open that flickers, while keeping the moderate-intensity blue (481 nm) dotted circles) rise steadily until time-average intensity of the light background field. They were reaching a plateau between 38 constant. Figure 1 shows asked to set the highest temporal and 52 Hz. Ingestion of Viagra temporal modulation sensitivities frequency at which the flicker induces moderate losses in c.f.f. for L.T.S. (C) and G.J. (D) appeared to be just visible — also for both subjects at all levels. measured at a 650 nm radiance Magazine R45 change occurs at a single By inhibiting PDE6, Viagra integrating stage with an lengthens the time over which the exponential decay (which we visual response is integrated, assume reflects the activity of thus impairing the overall ability some biochemical process or of the eye to light adapt and to processes, such as the regulate its sensitivity. hydrolysis of cGMP catalyzed by PDE6). We model this change by Acknowledgements applying a standard equation for This work was supported by a a leaky integrator  and Wellcome Trust awarded to A.S. We determining the change in thank Sabine Apitz, Bruce Henning and integration time that will best Rhea Eskew for helpful advice. account for our data (see Supplemental Data available on- Supplemental data line). Given that the mean data Supplemental data including for L.T.S. (dotted circles) and G.J. Experimental Procedures are available (grey dotted squares) are similar, at http://www.current-biology.com/ we have fitted this model cgi/content/full/16/2/R44/DC1/ simultaneously to both mean data sets. The model has three References parameters: a baseline Wallis, R.M., Casey, J., Howe, L., integration time, a Viagra- Leishman, D., and Napier, C.M. (1998). induced integration time and a Characterisation of retinal frequency-independent phosphodiesterase (PDE) isozymes and sensitivity scaling factor. the effects of sildenafil in vitro. Ophthalmic Res. 30 (suppl. 1), 111. The best-fitting model is shown Stryer, L. (1988). Molecular basis of by the continuous red line in the visual excitation. Cold Spring Harb. lower panel. The best-fitting Symp. Quant. Biol. 53, 283–294. parameters (± the asymptotic Pugh, E.N., Jr., Nikonov, S., and Lamb, Figure 2. Modulation sensitivity losses standard error for each T.D. (1999). Molecular mechanisms of vertebrate photoreceptor light for L.T.S. (A) and G.J. (B). parameter) are 6.91(±2.64) ms for adaptation. Curr. Opin. Neurobiol. 9, The data, from Figure 1, are plotted rela- the baseline integration time, 410–418. tive to the mean baseline measurements 12.57(±3.79) ms for the Viagra- Nikonov, S., Lamb, T.D., and Pugh, E.N., (horizontal lines). Symbol and symbol induced integration time, and Jr. (2000). The role of steady colours are as in Figure 1. The continu- 0.34(±0.05) log unit for the phosphodiesterase activity in the ous lines are the mean losses, plotted in kinetics and sensitivity of the light- (C) for L.T.S. (dotted circles) and G.J. scaling factor. The scaling factor adapted Salamander rod (grey dotted squares), which also shows is needed to compensate for photoresponse. J. Gen. Physiol. 116, the model fit (red line). changes in sensitivity caused by 795–824. the background becoming more Mollon, J.D., Regan, B.C., Foo, R., and Morris, B.J. (2003). Sildenafil increases of 9.52 log quanta s–1 deg–2 effective when the integration persistence of vision. Invest. (Figure 1, vertical dashed lines). time is lengthened (by 0.26 log10 Ophthalmol. Vis. Sci. 44 (suppl), 4097. Consistent with the changes in unit for a 6.91–12.57 ms change Hecht, S., and Verrijp, C.D. (1933). The their c.f.f. data, both L.T.S. and in time constant). This increase in influence of intensity, color and retinal G.J. show some losses of effectiveness is partially offset by location on the fusion frequency of intermittent illumination. Proc. Natl. modulation sensitivity after the comparable increase in Acad. Sci. USA 19, 522–535. ingesting Viagra at most sensitivity to low frequency De Lange, H. (1958). Research into the frequencies. The relative losses flicker, but not entirely so (a dynamic nature of the human fovea- compared with baseline are complete offset would be cortex systems with intermittent and highlighted in Figure 2 for LTS (A) consistent with Weber’s Law). modulated light. I. Attenuation characteristics with white and colored and GJ (B) for data collected The fact that the overall light. J. Opt. Soc. Am. 48, 777–784. between 60 and 166 min after modulation sensitivity drops by Watson, A.B. (1986). Temporal Viagra ingestion, in which it 0.08 log10 represents a partial sensitivity. In Handbook of Perception becomes clear that the losses for failure of light adaptation as and Human Performance, Volume 1, K. both subjects increase with Viagra presumably drives the Boff, L. Kaufman and J. Thomas, eds. (New York: Wiley), pp. 6–1-6–43. temporal frequency. This system into a less optimal steepening suggests that Viagra (nonlinear) part of its operating is associated with a lengthening range. The data are clearly of the visual integration time. consistent with a lengthening of 1Institute of Ophthalmology, University We can model the mean losses the integration time, but the College London, 11-43 Bath Street, London EC1V 9EL, UK. 2Moorfields Eye (continuous lines in Figure 2A,B precise values of the time Hospital, 162 City Road, London EC1V and symbols in 2C) and thus constants are only moderately 2PD, UK. 3Archway Sexual Health obtain a rough estimate of the well constrained by the model, Clinic, Whittington Hospital Highgate change in the time constant of and should be considered as Hill and Institute of Urology, Middlesex integration by assuming that the preliminary estimates. Hospital, London N19 5NF, UK.
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