Phosphodiestrase 5 and effects of sildenafil on cerebral arteries from man and guinea pig
KeywordsMigraine Sodium Nitroprusside Effective Plasma Concentration Endothelial Removal cGMP Hydrolysis
The specific inhibitor of the cGMP degrading enzyme phosphodiesterase 5 (PDE5), sildenafil (Viagra®), induces migraine without significant cerebral artery dilatation in vivo. This is in contrast to other migraine inducing substances such as glyceryl trinitrate and histamine which are effective vasodilators. Sildenafil is also recently found to enhance functional recovery, neurogenesis and angiogenesis in stroke models. We evaluated the presence of PDE5 and functional effects of three selective PDE inhibitors in human and guinea pig cerebral arteries.
Materials and methods
RT-PCR and Western blot were used to establish the presence of PDE5 mRNA and protein respectively. The effects of sildenafil, UK-114,542 (both PDE5 specific) and UK-90,234 (PDE1 specific) on cyclic nucleotide hydrolysis were investigated using homogenates of human and guinea pig cerebral arteries. In isolated guinea pig basilar arteries the cerebral vasodilator responses of the PDE inhibitors were investigated. Concomitantly the tissue levels of cAMP and cGMP were analysed.
Sildenafil in vitro mainly dilates cerebral arteries above relevant plasma concentrations of sildenafil, unless a nitric oxide donor is co-administered. These results supports the lack of vascular response previously found in human in vivo studies and may suggest a possible neuronal rather than vascular effect of sildenafil in migraine induction.