title: Potency, selectivity, and consequences of nonselectivity of PDE inhibition.
abstract: Phosphodiesterases (PDEs) play a decisive role in cyclic nucleotide-mediated intracellular signaling. As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE inhibitor. Sildenafil, vardenafil, and tadalafil are selective for PDE5, with vardenafil exhibiting the highest potency and minimal inhibition of other PDEs, with the exception of PDE6. Tadalafil is extremely selective for PDE5, but also potently inhibits PDE11, an enzyme with unknown physiological function. As PDE1 is expressed in the brain, myocardium, and vascular smooth muscle cells, nonselectivity with respect to this enzyme (selectivity: tadalafil>vardenafil>sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil>vardenafil congruent with sildenafil), which is expressed only in retina and functions in visual transduction, can transiently disturb vision. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic guanosine monophospate levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.
authors.affiliation: Bayer Pharma Research, Bayer Healthcare Wuppertal, PH-R-EU-CV-ll, Wuppertal, Germany. erwin.bischoff.eb@bayer-ag.de
authors.forename: E
authors.initials: E
authors.lastname: Bischoff
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002243:Carbolines / Q000009:adverse effects / Q000627:therapeutic use; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D011687:Purines; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones; D013610:Tachycardia / Q000139:chemically induced; D000068581:Tadalafil; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D014664:Vasodilation / Q000187:drug effects; D014785:Vision, Ocular / Q000187:drug effects
chemical_list: D002243:Carbolines; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human