Fig. 1.

Phosphodiesterase 5 (PDE5) inhibitors are believed to enhance memory and learning via facilitation of long-term potentiation (LTP) mediated by the “glutamate–nitric oxide–cyclic GMP intracellular pathway.” Glutamate binding to the N-methyl-d-aspartate (NMDA) receptor results in calcium (Ca²⁺) influx, which binds to calmodulin and activates nitric oxide synthase (NOS). NOS catalyzes the production of nitric oxide (NO) from arginine; NO activates guanylyl cyclase, which increases production of cyclic guanosine monophosphate (GMP) from guanosine triphosphate (GTP). Cyclic GMP mediates LTP and activates protein kinases (PK), which are believed to mediate memory consolidation via phosphorylation and protein formation. PDE5 inhibitors block the conversion of cGMP to 5′GMP; by elevating cGMP levels, LTP is facilitated