Introduction
Since its approval in 1998, over 1 billion doses of sildenafil citrate (Viagra®) have been prescribed as a treatment for erectile dysfunction (Pfizer, 2007). It works by inhibiting cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), which is an enzyme expressed in the smooth muscle of the corpus cavernosa (Beavo, 1995; Moreland, Goldstein, & Traish, 1998). As an undesirable secondary effect, it inhibits a closely related phosphodiesterase enzyme PDE6 (e.g., Wallis, Casey, Howe, Leishman, & Napier, 1998). Estimates suggest that Viagra has about 10% of the effect on PDE6 that it has on PDE5 (Food and Drug Administration Joint Clinical Review, 1998a; see Table 1 of Laties & Zrenner, 2002). PDE6 plays an essential role in phototransduction, the process by which photons of light are absorbed and converted into electrical signals for transmission to the visual centers of the brain. Activated PDE6 (PDE6*) catalyzes the hydrolysis of cGMP to GMP. The reduction in cGMP results in the closure of ion channels in the plasma membrane, which blocks the inward flow of Na+ and Ca2+ ions leading to cell hyperpolarization (for reviews, see Arshavsky, Lamb, & Pugh, 2002; Pugh & Lamb, 2000; Pugh, Nikonov, & Lamb, 1999). PDE6, however, not only activates the transduction cascade but also regulates visual sensitivity. As the concentration of PDE6* increases as the light level rises, the time over which the visual signals are integrated shortens and the visual response speeds up (e.g., Govardovskii, Calvert, & Arshavsky, 2000; Nikonov, Lamb, & Pugh, 2000).
Tests to determine whether Viagra causes visual side effects have so far been largely restricted to standard measures of human visual performance, such as visual acuity and color discrimination. Although such tests can be important for clinical diagnosis, most are not particularly well suited for monitoring the visual effects that are likely to be caused by the inhibition of PDE6. As a result, perhaps, the outcomes of these tests have been inconclusive, providing, at best, evidence that is largely subjective or anecdotal (reviewed in Laties & Fraunfelder, 1999; Laties & Zrenner, 2002; Marmor & Kessler, 1999). Any visual side effects are typically described in subjective reports as a bluish tinge or haze to vision or increased sensitivity to light. These effects are rarely reported (3%) at the lowest clinical doses of 25 and 50 mg, more often reported (11%) at the highest clinical doses of 100 mg, and frequently reported (50%) at doses of 200 mg or higher (Food and Drug Administration Joint Clinical Review, 1998b; Marmor & Kessler, 1999; Morales, Gingell, Collins, Wicker, & Osterloh, 1998). Otherwise, Viagra is claimed to have little or no effect on visual performance. For example, in controlled clinical trials, doses of up to 200 mg of Viagra do not affect visual acuity, visual fields, the Amsler grid, spatial contrast sensitivity, or pupillary responses (Food and Drug Administration Joint Clinical Review, 1998c, 1998d; Laties, Ellis, Koppiker, Patat, & Stuckey, 1998; Laties, Ellis, & Mollon, 1999). Transient, mild impairment of color discrimination has been found with the Farnsworth–Munsell 100 test at the peak plasma levels with doses of 100 mg or more (Food and Drug Administration Joint Clinical Review, 1998c, 1998d; Laties et al., 1998, 1999). However, any effects of Viagra on chromatic discrimination are inconsistent between subjects (see Laties & Fraunfelder, 1999; Laties & Zrenner, 2002; Marmor & Kessler, 1999) and have not been confirmed in recent double-blind studies (Birch, Toler, Swanson, Fish, & Laties, 2002; Jägle et al., 2004).
Such standard visual tests, however, do not address the most likely effect of Viagra, which is to disrupt light adaptation by preventing the visual integration time from shortening enough to offset increases in light level. More appropriate tests for lengthened integration time include those that probe the temporal response, such as measures of temporal acuity or resolution (also known as critical fusion frequency [cff]) and temporal modulation sensitivity (e.g., De Lange, 1958a; Hecht & Verrijp, 1933; Kelly, 1961). In cff measurements, the highest frequency that can be detected is determined as a function of adaptation level. These measurements are complemented by temporal modulation sensitivity measurements, which can be used to determine sensitivity at temporal frequencies below cff and, thus, define the overall temporal frequency response.
If buy Viagra bitcoin effectively lengthens the visual integration time, then the way in which it alters temporal sensitivity will depend on the integration times involved. If the integration times are long enough to selectively attenuate visible flicker frequencies (by integrating over more than one cycle at some frequencies), then Viagra should impair the detection of higher rates of flicker relative to low rates, so that the cff is reduced and the falloff in modulation sensitivity with increasing temporal frequency steepens (before the final limiting slope). If, on the other hand, the integration times are very short, Viagra should cause a frequency-independent divisive scaling of sensitivity and, thus, a loss of cff and a vertical shift in the logarithmic modulation sensitivity functions, without a change in shape. Frequency-independent losses might also arise because the lengthening of the integration time makes steady components in the visual stimuli (produced either by the background or by the flickering target, which must be modulated around a mean level) more effective. This greater effectiveness arises simply because the steady (0 Hz) signals are integrated over a longer time. Such effects are particularly likely under S-cone isolation conditions because the intense long-wavelength background typically needed to desensitize the L- and M-cones also chromatically attenuates the S-cone signal (e.g., Pugh & Mollon, 1979). We find both frequency-dependent and frequency-independent changes in our data. Other explanations of these changes are considered in the Discussion section.
Methods
Apparatus
The optical apparatus was a conventional Maxwellian-view optical system with a 2-mm entrance pupil illuminated by a 900-W Xenon arc. Wavelengths were selected by the use of interference filters with full-width at half-maximum bandwidths of between 7 and 11 nm (Ealing or Oriel). The radiance of each beam could be controlled by the insertion of fixed neutral density filters (Oriel) or by the rotation of circular, variable neutral density filters (Rolyn Optics). Sinusoidal modulation was produced by the pulse-width modulation of fast, liquid crystal light shutters (Displaytech) at a carrier frequency of 400 Hz. The position of the observer’s head was maintained by a dental wax impression. The experiments were under computer control. The apparatus is described in more detail elsewhere (Stockman, Plummer, & Montag, 2005).
Stimuli
The experimental conditions were chosen to measure the temporal properties of either the S-cones or the L- (and M-) cones.
S-cone measurements
A flickering target of 4° of visual angle in diameter and 440 nm in wavelength was presented in the center of a 9° diameter background field of 620 nm. Fixation was central. The 620-nm background field, which delivered 11.51 log 10 quanta • s −1 • deg −2 at the cornea (4.95 log 10 photopic trolands), selectively desensitized the M- and L-cones but had comparatively little direct effect on the S-cones.
For the cff measurements, the 440-nm target was modulated at 92% contrast and varied in intensity in steps from approximately 6.5 to 11 log 10 quanta • s −1 • deg −2 (c. −1.13 to 3.37 log 10 photopic trolands). These conditions isolate the S-cone response up to a 440-nm target radiance of about 10.5 log 10 quanta • s −1 • deg −2 (e.g., Stockman, MacLeod, & DePriest, 1991; Stockman, MacLeod, & Lebrun, 1993; Stockman & Plummer, 1998). The intrusion of the M-cones at the highest levels is clearly marked by a change in the appearance (hue and sharpness) of the target and by an abrupt increase in cff. For the modulation sensitivity measurements, the 440-nm target was fixed at time-averaged radiances of 7.54, 8.82, or 9.75 log quanta • s−1 • deg−2 (−0.09, 1.19, or 2.12 log10 photopic trolands).
L-cone measurements
A flickering target of 4° of visual angle in diameter and 650 nm in wavelength was presented in the center of a 9° diameter background field of 480 nm. Fixation was again central. The 480-nm background, which delivered 8.26 log quanta • s −1 • deg −2 at the cornea (1.37 log 10 photopic trolands), served primarily to not only saturate the rods but also selectively desensitize the M-cones at lower target radiances.
For the cff measurements, the 650-nm target was varied in intensity from approximately 6.5 to 11.0 log 10 quanta • s −1 • deg −2 (−0.63 to 3.87 log 10 photopic trolands) and was modulated at 92%. These conditions isolate the L-cone response over most of the 650-nm intensity range, but at high intensities, the M-cones are also likely to contribute to flicker detection (Stiles, 1978; see Figure 1b of Stockman & Mollon, 1986). We were not concerned about the possibility of a mixed M- and L-cone response at higher levels because there is no reason to suppose that Viagra has a selective effect on either the M- or the L-cones. However, we note that Viagra might have differential effects on the two cone types because the M-cones are at a much lower level of adaptation at high, 650-nm target radiances than are the L-cones. For the modulation sensitivity measurements, the 650-nm target was fixed at time-averaged radiances of 7.56 and 9.52 log quanta • s−1 • deg−2 (0.43 or 2.39 log10 photopic trolands).