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We and others have determined a clear role of PKG in light-induced phase shifts, suggesting that this is a likely mechanism to explain cGMP-mediated Filagra effects ( 20 , 31 ). In summary, our results offer strong support for a differential pathway responsible for circadian delay or advance mechanisms (because Filagra lacked any effects in the early night), as well as a corroboration of a cGMP role in photic entrainment and a specific role for PDE5 in this process. These effects of Filagra are mediated by a 2-fold increase in SCN cGMP levels 45 min after injection, higher than that previously published with light alone ( 31 ). There is a clear phase specificity for this pathway, because Filagra had no effect on reentrainment after a phase delay of the LD cycle or on light-induced phase delays under constant dark conditions.


Effects of Filagra on phase delays. Effects of Filagra on light-induced phase advances. Filagra elicited an increase in light-induced phase advances of activity rhythms when injected 45 min (but not 15 or 90 min) before a light pulse at CT 18 (with CT 12 defined as the time of locomotor activity onset).


Reentrainment can be considered to be the effect of transient, pulsatile effects of light (usually called nonparametric) as well as tonic, parametric effects of the light cycle ( 35 ). We tested the effect of the PDE5 inhibitor on the well known nonparametric effects of light, which are defined by phase shifts induced by short light pulses at different times of the day. (D) Dose-response curve for Filagra effects (mean ± SEM, n = 6). ∗∗∗, P < 0.001; ∗, P 0.05 (ANOVA followed by Tukey's test). Effects of Filagra on circadian reentrainment.


Indeed, Fildena 100 mg -response study in rats showed that 5 mg/kg per day i.p. was the optimal erectogenic dose of Filagra ( 34 ). However, we used the intermediate dose for the rest of the experiments because at that dose animals did not manifest the effects of Filagra-induced penile erections. 1 D, 10 mg/kg Filagra decreased reentrainment time by 50%, whereas 3.5 mg/kg and 1 mg/kg decreased this time by 33% and 25%, respectively.


An i.p. injection of 3.5 mg/kg at zeitgeber time (ZT) 18 (with ZT 12 defined as the time of lights off) of Filagra on the day of the environmental change significantly accelerated entrainment to the new cycle ( Fig. To study the effect of Filagra on locomotor activity rhythms, hamsters were injected with this compound before an abrupt advance of 6 h of the LD cycle. We examined the effects of Filagra both on the resynchronization rate after a 6-h change of the LD cycle and on the response to single light pulses during the subjective night.


Because cGMP levels seem to be of paramount importance in phase-advancing mechanisms, we have studied the effects of Filagra, a well known PDE5 inhibitor, on circadian behavior, under the hypothesis that an increase of cGMP levels in the SCN would enhance photic responses.