Figure 1.

Mechanism of penile erection and hormonal interactions. Nitric oxide (NO) is produced by the enzyme NO synthase (NOS), which is located inside nonadrenergic noncholinergic (NANC) nerves (nNOS) and endothelial cells (eNOS). Sexual stimulation triggers the release of NO by the NANC nerves, which is enhanced by growth hormone (GH) and testosterone. The latter also upregulates the activity of NOS in both nerves and endothelial cells. In penile smooth muscle cells, NO binds to soluble guanylyl ciclase to increase production of 3′,5′-cyclic guanosine monophosphate (cGMP) from guanosine-5′-triphosphate (GTP), which activates protein kinase G (PKG) to form a complex cGMP/PKG, which in turn inhibits the entry of extracellular calcium and promotes the shift of intracellular calcium into the endoplasmic reticulum (ER). Decreased calcium concentration leads to smooth muscle relaxation and, consequently, dilatation of the cavernous arteries and penile erection. Activity of cGMP/PKG is physiologically limited by the enzyme phosphodiesterase 5 (PDE5), which is the target of PDE5 inhibitor drugs (PDE5i), the first line of treatment for erectile dysfunction (ED). Prostaglandin 1 (PGE1), which is administered through intracavernosal injections for the treatment of ED, binds a G-protein-coupled receptor that stimulates adenylyl cyclase activity, which promotes the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). As for cGMP, cAMP activates a protein kinase (protein kinase A—PKA) and the complex cAMP/PKA reduces intracellular calcium levels and causes smooth muscle relaxation. High serum cortisol levels inhibit the response to intracavernosal injection of smooth muscle relaxants via an unknown mechanism.