Molecular mechanisms of the effects of sildenafil (VIAGRA).

Exp Gerontol. 1999 Jun;34(3):305-18.
Glossmann H, Petrischor G, Bartsch G.

Institute of Biochemical Pharmacology, Innsbruck, Austria. Hartmut.Glossmann@uibk.ac.at

The molecular mechanisms of the effects of sildenafil, a specific inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterases are briefly reviewed. The second messenger cGMP as well as its molecular targets (with the exception of the photoreceptor signal transduction machinery) have long played an underdog role compared with cyclic adenosine monophosphate and other signalling molecules such as inositoltrisphosphate. The same holds for guanylyl cyclase, which, albeit being the main effector molecule of the gaseous neurotransmitters carbon monoxide and nitric oxide (NO), has received much less attention relative to its activators and their synthases. Stimulation of the arginine –> NO –> cGMP pathway by bypassing NO-synthase is a well-established pharmacological principle in the treatment of cardiovascular disorders. In contrast, local application of NO-donors or oral feeding of excessive amounts of precursor amino acid L-arginine to treat erectile dysfunction were met with variable success or failure. The advent of a new principle, amplification of the NO-signaling cascade by means of target organ selective phosphodiesterase inhibition, has renewed interest in phosphodiesterases and cGMP.

• Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.
• [Phosphodiesterase 5--the enzyme inhibited by sildenafil (Viagra)]
• The role of nitric oxide in erectile dysfunction: implications for medical therapy.
• Cyclic nucleotide signaling in cavernous smooth muscle.
• Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction.