Erectile dysfunction: from biochemical pharmacology to advances in medicaltherapy

Research on penile smooth muscle physiology has increased the number of dru gs available for treating erectile dysfunction (ED. Penile erection involve s the relaxation of smooth muscle in the corpus cavernosum. The key mediato r of smooth muscle relaxation is nitric oxide (NO), which acts by increasin g the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil, An increase in cAMP and/or cGMP levels c an also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; s ildenafil is an orally active, potent and selective inhibitor of GMP-specif ic PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the co rpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fi bers through alpha(1) adrenoceptors, produces detumescence, thus malting oc adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor anta gonist that works by a dual mechanism; it facilitates sexual arousal by act ing on cut adrenoceptors in the central nervous system and blocks adrenergi c influences at peripheral level.