Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

Patricia V. Agostino; Santiago A. Plano; Diego A. Golombek

doi:10.1073/pnas.0703388104

New Research In

Communicated by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, April 12, 2007 (received for review November 2, 2006)

Abstract

Mammalian circadian rhythms are generated by a master clock located in the suprachiasmatic nuclei and entrained by light-activated signaling pathways. In hamsters, the mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase, cGMP and its related kinase (PKG). It is not completely known whether interference with this pathway affects entrainment of the clock, including adaptation to changing light schedules. Here we report that cGMP-specific phosphodiesterase 5 is present in the hamster suprachiasmatic nuclei, and administration of the inhibitor sildenafil (3.5 mg/kg, i.p.) enhances circadian responses to light and decreases the amount of time necessary for reentrainment after phase advances of the light–dark cycle. These results suggest that sildenafil may be useful for treatment of circadian adaptation to environmental changes, including transmeridian eastbound flight schedules.

Footnotes

*To whom correspondence should be addressed. E-mail: dgolombek{at}unq.edu.ar
Author contributions: P.V.A. and D.A.G. designed research; P.V.A. and S.A.P. performed research; P.V.A., S.A.P., and D.A.G. analyzed data; and P.V.A. and D.A.G. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0703388104/DC1.
Abbreviations:
CT,
circadian time;
LD,
light–dark;
PDE,
phosphodiesterase;
SCN,
suprachiasmatic nuclei;
ZT,
zeitgeber time;
PKG,
cGMP-dependent protein kinase;
GFAP,
glial fibrillary acidic protein.
© 2007 by The National Academy of Sciences of the USA