Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

Abstract

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing 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 can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildena®l are PDE inhibitors. Papaverine is a non-speci®c inhibitor of these enzymes; sildena®l is an orally active, potent and selective inhibitor of GMP-speci®c PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic ®bers through a 1 adrenoceptors, produces detumescence, thus making a adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed a 1 -a 2 adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on a 2 adrenoceptors in the central nervous system and blocks adrenergic in¯uences at peripheral level.

Management of erectile dysfunction by combination therapy with testosterone and sildenafil in recipients of high-dose therapy for haematological malignancies

“…9 Penile arterial insufficiency is a major cause of ED in our patients, as has been previously reported by us. Since erection is primarily a vasculogenic event controlled by neurohumoral regulation at the central and peripheral levels, 11 correction of penile vasculaopathy by a vasodilator seems to be a logical option. The selective phosphodiesterase (PDE5) inhibitor sildenafil potentiates the nitric oxide pathway via the C-GAMP mechanism.…”

Clinical applications of centrally acting agents in male sexual dysfunction

“…Yohimbine is thought to facilitate sexual arousal by acting on a2-adrenoceptors in the CNS and by blockade of adrenergic-mediated detumescence. 29 A meta-analysis of clinical trials conducted using yohimbine as a treatment for ED found it to be superior to placebo (odds ratio 3.85). 30 Data regarding other adrenergic agents such as phentolamine, doxazosin and prazosin are limited, and the putative mechanism of action of these agents on ED appears to be peripheral, not central, in nature.…”

“…30 Data regarding other adrenergic agents such as phentolamine, doxazosin and prazosin are limited, and the putative mechanism of action of these agents on ED appears to be peripheral, not central, in nature. 29 …”

Penile blood cyclic guanosin monophosphate level is associated with penile Doppler ultrasound findings

“…Phosphodiesterases are the enzymes involved in cyclic nucleotide breakdown and an increase in cyclic adenosine monophosphate (cAMP) and/or cGMP levels can be induced by inhibition of these enzymes in the smooth muscle cells of corpus cavernosum with papaverine which is a nonspecific inhibitor of these enzymes. 19 Because these enzymes do not perform their role in the cavernosal sinuses, the levels of cGMP measured from the blood circulating inside these sinuses should not be affected from the injection of this agent. Furthermore, in the screening period, we observed that taking cavernous blood sample is difficult and very painful for the patients when the penis is not erected and consequently, we excluded the patients with tumescence grades 0 and 1.…”