Another level of complexity between the interaction of cAMP and EFAs is our recent observation that phosphodiesterase inhibitors (PDEIs) as a class can modulate the levels of EFAs as dramatically as sEHIs. Various PDEIs increase the plasma levels of EFAs along with elevating cAMP levels [60]. There seems to be a great deal of selectivity in this regard since PDE4 and PDE5 inhibitors have the most remarkable effects. These effects interestingly are regioisomer selective and specific for EFAs of LA, AA and DHA but not of EPA origin. Though PDEIs elevate the plasma levels of EFAs, unlike the sEHIs they do not seem to influence the levels of dihydroxy-fatty acid degradation products. Inhibitors of sEH not only elevate EFAs but they quite efficiently decrease the levels of their degradation products. Lipolysis that is activated by high concentrations of cAMP seems to be responsible for the elevation of EFAs by PDEIs although this hypothesis needs to be further evaluated.
