Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5). Inhibition of this enzyme leads to a reduction in cGMP degradation and, therefore, an accumulation of cGMP.
Increased cGMP leads to decreased intracellular calcium levels, resulting in smooth muscle relaxation in the corpus cavernosum. This allows for increased blood flow to the penis and, thus, improved erectile function. ANP and NO are endogenous hormones that bind extracellular or intracellular receptors, respectively. These receptors in turn activate the cGMP second messenger pathway via guanylate cyclase. Nitrates used in the treatment of angina work by a similar mechanism to PDE5 inhibitors; therefore, the combination of these two agents is contraindicated due to the risk of hypotensive crisis.
Heidelbaugh reviews the management of erectile dysfunction (ED) and also discusses the efficacy of PDE5 inhibitors in the treatment of ED, stating that the preferred treatment for ED includes lifestyle changes, changing drug therapy that may cause ED, and use of phosphodiesterase type 5 inhibitors. Risk factors for ED include obesity, sedentary lifestyle, and smoking. Phosphodiesterase type 5 inhibitors have been shown to be the most effective for treatment of ED overall.
Ravipati et al. review the normal cellular mechanisms that play a role in normal penile erection and are the target of PDE5 inhibitors. They state that phosphodiesterase enzymes catalyze the hydrolysis of cAMP and cGMP, the latter of which is the second messenger of NO as well as a mediator of smooth muscle relaxation and vasodilation. The mechanism of an erection is largely related to the vascular tone and blood flow within the penis.
Illustration A depicts the mechanism of action of sildenafil.
Answer 1: Elevated cGMP as a result of PDE5 inhibitor action leads to a decrease in intracellular calcium levels that causes smooth muscle relaxation.
Answer 3: Sildenafil works through inhibiting the breakdown of cGMP, not AMP.
Answers 4 & 5: NO and ANP act by increasing production of cGMP; they do not decrease the degradation of cGMP and are not directly affected by PDE5 inhibitor action.
Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010 Feb 1;81(3):305-12.
PMID:20112889 (Link to Abstract)
Ravipati G, McClung JA, Aronow WS, Peterson SJ, Frishman WH. Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease. Cardiol Rev. 2007 Mar-Apr;15(2):76-86.
PMID:17303994 (Link to Abstract)