Background：Scleral extracellular matrix may play a central role in development of myopia. Given the important role of cAMP in the synthesis of collagens in cardiac and lung fibroblasts, we hypothesized that the cAMP level is a critical regulator of visual development and myopia occurrence.

Methods：We examined the effects of cAMP level on normal visual development and on form deprivation-induced myopia in guinea pigs by subconjunctival injection of adenylyl cyclase agonist forskolin, cAMP analogue db-cAMP, and adenylyl cyclase inhibitor SQ22536. The refraction and ocular biometric parameters were measured in drug- or vehicle-treated eyes during normal postnatal development and following form-deprivation-induced myopia before and after treatment for 2 or 4 weeks.  Collagen I, III and IV mRNA expression of cultured human scleral fibroblast (HSF) were measured after treatment with forskolin alone or with SQ22536, or db-cAMP. Total soluble collagen in the cell supernatants was also measured.

Results: Treatment of forskolin or db-cAMP for four weeks induced myopia (-2.42±1.07D and -2.13±1.06D), accompanied by significantly increased vitreous chamber depth (VCD) and axial length (AL) of eye in normal guinea pigs.  However, increasing cAMP levels had no effect on form-deprived eyes. After daily subconjunctival injection on form-deprived eyes for 4 weeks, SQ22536 reduced form deprivation-induced myopic refraction (-6.21±1.55D) in comparison with the vehicle-treated animals (-8.67±1.81D). The elongation of VCD and AL by form deprivation was also reduced compared to the vehicle-treated animals. However reducing cAMP levels had no effect on normal eyes. In HSF, forskolin and db-cAMP inhibited the expression of collagen I, III, and V mRNA that were partially reversed by co-treatment withSQ22536. Both forskolin and db-cAMP treatments also reduced the total soluble collagen secreted from cultured human scleral fibroblasts in concentration-dependent manner.

Conclusion: Selective induction of myopia in normal animals and selective attenuation of form-deprivation-induced myopia by pharmacological increase and decreasing cAMP levels, respectively, strongly argue for the critical role of abnormal high level of cAMP level in development of myopia. Furthermore, altered cAMP level may modulate visual development and myopia occurrence by regulating scleral collagen synthesis. Thus, targeting cAMP level in the eye may selectively counteract myopic pathogenesis without affecting normal visual development.