Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil.
Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP; inhibitors of phosphodiesterase 5 will therefore increase and prolong the actions of endogenous substances that signal via the cyclic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves. To date, the most widely used phosphodiesterase 5 inhibitors, zaprinast and sildenafil, have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and, specifically in the case of sildenafil, have provided a major breakthrough in the treatment of erectile dysfunction in men. Although still a matter of debate, early evidence indicates that sildenafil may also be of benefit in some forms of sexual dysfunction in women. The remarkable clinical success of sildenafil has prompted the search for further novel phosphodiesterase 5 inhibitors which might be used to enhance nitrergic function in other disease states.
Gibson
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A
Messengers and Signalling Research Group, School of Biomedical Sciences, King's College London, Hodgkin Building, Guys Campus, SE1 9RT, London, UK. alan.gibson@kcl.ac.uk
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones; D009435:Synaptic Transmission / Q000187:drug effects*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C011145:zaprinast