The role of cGMP hydrolysing phosphodiesterases 1 and 5 in cerebral arterydilatation

The aim was to investigate the presence and activity of cGMP hydrolysing ph osphodiesterases in guinea pig basilar arteries and the effect of selective and non-selective phosphodiesterase inhibitors on cerebral artery dilatati on involving the nitric oxide (NO)-guanosine cyclic 3 '5-monophosphate (cGM P) pathway. Immunoreactivity to phosphodiesterases 1A, 1B and 5, but not ph osphodiesterase 1C was found in fractions of homogenised cerebral arteries eluted by high-pressure liquid chromatography (HPLC). Both the phosphodiest erase 1 inhibitor 8-methoxymethyl-1methyl-3-(2methylpropyl)-xanthine (8-MM- IBMX) and the phosphodiesterase 5 inhibitors zaprinast and dipyridamole ind uced dilatation of cerebral arteries. The dilatory response to 8-MM-IBMX wa s reduced by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 muM) and endothelial removal and restored by sodium nitroprusside (0.1 muM) pretrea tment, indicating a close relation to the nitric oxide-cGMP pathway. The re sponses to zaprinast and dipyridamole, however, were not only moderately af fected, but also restored by sodium nitroprusside(0.1 muM) pretreatment. At high concentrations, the dilatory effects of zaprinast and dipyridamole we re partly caused by cGMP-independent mechanisms. Targeting the phosphodiest erases present in cerebral arteries, with selective inhibitors or activator s of phosphodiesterase, may be a possible new way of treating cerebrovascul ar disease. (C) 2001 Published by Elsevier Science B.V.