Smooth muscle relaxation via cGMP is likely to involve several mechanisms, including inhibition of L-type Ca2+ channel,³ activation of Ca2+-dependent K+ channels resulting in hyperpolarization and, finally, inhibition of the IP3 receptors located on the sarcoplasmic reticulum.4–6 Subsequently, cGMP-specific PDE catalyze the hydrolysis of cGMP to 5GMP, leading to detumescence.

Although NO-mediated smooth muscle relaxation accounts for the predominant pathway involved in penile smooth muscle relaxation, human corpus cavernosum can also synthesize and metabolize prostanoids, of which PGE1 and PGE2 mediate smooth muscle relaxation by increasing intracellular cyclic adenosine monophosphate (cAMP) levels.

Risk Factors and the Role of Endothelial Dysfunction in Erectile Dysfunction
Erectile dysfunction is conventionally subclassified into organic and psychogenic factors. Organic factors are further subdivided into vasculogenic, neurological, and endocrine disorders, of which vasculogenic erectile dysfunction is the most common. Specific risk factors for erectile dysfunction include ageing, diabetes, smoking, hyperlipidemia, and hypertension. A longitudinal study of 401 men from the MMAS has reported that smoking in particular has been shown to be associated with disease progression.⁷

As these risk factors are also common to coronary artery disease, the concept of endothelial dysfunction has developed, which considers erectile dysfunction as another manifestation of vascular disease—albeit specific to small-vessel disease. Endothelial dysfunction due to an abnormality in the synthesis and release of NO is associated with vasoconstriction, coagulation, leucocyte adhesion, and smooth muscle cell hyperplasia, which is central to the process of atherogenesis. Endothelial NOS inhibition (via impaired hydrolysis of dimethyl arginine) and the uncoupling of eNOS activity increases the oxidative stress in the endothelial cells, with further oxidative catabolism of NO and formation of peroxynitrite.

The presence of common risk factors in erectile dysfunction and atherogenesis, combined with the proposed pathogenesis of endothelial dysfunction, has now led to clinicians describing erectile dysfunction as a predictive risk factor for coronary artery disease.⁸ The difference is that the small-calibre penile vasculature is affected before the larger coronary vessels, with endothelial dysfunction being a common denominator.