Dihydroergotoxine mesylate (DHET; active substance of Hydergine®) was shown to be a stronger inhibitor of the low-Km than of the high-Km phosphodiesterase (PE) in cat and rat brain homogenates. The inhibition due to DHET was greater when a purified low-Km PE preparation originating from a sonicated pellet (100,000 ¿r) of rat brain tissue was used. The drug alters the kinetic properties of the enzyme, producing a lowering of the negative cooperativity effect. This kind of PE inhibition is of particular importance at normal cellular cAMP levels, but does not interfere with cAMP production by hormonal stimulatio