Effect of a cGMP-specific phosphodiesterase inhibitor on retinal function

Abstract

Multiple forms of phosphodiesterase have been reported in many tissues. Phosphodiesterase 6, a cGMP-specific phosphodiesterase, is described as a photoreceptor cell-specific phosphodiesterase. Phosphodiesterase 6 is known to play a crucial role in visual function. A novel phosphodiesterase inhibitor, GF248 (5[″(propoxy),7′(4-morpholino)-phenacyl],[1-methyl-3 propyl]pyrazolo[4,3 d]pyrimidin-7-one), has been described to be a very potent cGMP-specific phosphodiesterase inhibitor. In the present study, we compared the potency of GF248 and other known cGMP-specific phosphodiesterase inhibitors on phosphodiesterase 5 and phosphodiesterase 6. GF248 displayed an IC 50 of 2 and 5 nM for phosphodiesterase 5 and phosphodiesterase 6, respectively. Thereafter, we assessed the effect of GF248 on retinal function, using an ex vivo model of isolated retina electroretinogram recording. Exposure of retina to GF248 resulted in a dose-dependent decrease in electroretinogram amplitude (PIII and b-waves), with no marked modification of PIII and b-wave implicit time. Among other phosphodiesterase inhibitors, DMPPO (1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolol[3,4 d]-pyrimidin-4-(5 H)-one) and dipyridamole, cGMP-specific phosphodiesterase inhibitors, and IBMQ (1-isobutyl-3-methylimidazol[1,5- a]quinoxalin-4-(5 H)one), a nonselective phosphodiesterase inhibitor, altered retinal function but less potently than GF248, consistent with their in vitro phosphodiesterase 6 inhibition. Phosphodiesterase 3- and phosphodiesterase 4-selective inhibitors, cilostamide and rolipram, respectively, did not affect retinal function at 10 μmol l −1. Our conclusion from these data is that GF248, a potent phosphodiesterase 6 inhibitor, could interfere with visual transduction by cGMP accumulation.