The intracellular decline in Ca++ ions suppresses the activity of myosin light chain (MLC) kinase and thus increases the intracellular content of dephosphorylated MLC, which enables the smooth muscle cell to relax.^[12] It is well established that NO and cGMP are the most important transmitters for onset and maintenance of erection. In physiologic terms, 3',5'-cGMP is permanently broken down to the biologically inactive 5'-GMP by the enzyme PDE5.

Cyclic adenosine monophosphate (cAMP), a further second messenger in erectile function, plays an inferior role when compared with cGMP. When erection occurs, vasoactive intestinal polypeptide (VIP) is released at parasympathetic NANC nerve terminals, as is similarly the case with NO release. Both NO and VIP are in colocalization at the respective NANC nerve terminals and are released simultaneously with sexual arousal. VIP activates membrane-bound adenylate cyclase, which promotes cleavage of adenosine triphosphate to 3'5'-cAMP. cAMP activates protein kinase A, which phosphorylates proteins adjacent to the maxi-potassium channels, resulting in K+ ion outflow and hyperpolarization. In turn, the same biochemical actions take place as were described for 3'5'-cGMP.

Apart from these proerectile mechanisms, other biological pathways are important either for inducing or inhibiting erection. In particular, activation of the sympathetic nervous system, which occurs, for example, with performance anxiety, results in inhibition of erection. With increased sympathetic tone, norepinephrine is released at alpha1-adrenoceptors located on the cavernous smooth muscle cell. Norepinephrine activates membrane-bound phospholipase C, which induces cleavage of phosphoinositol diphosphate to inositol triphosphate and diacylglycerol. Both inositol triphosphate and diacylglycerol cause an increase in intracellular Ca++, which in turn activates MLC kinase and leads to an increase in phosphorylated MLC.^[12] This enables the smooth muscle cell to contract and thus prevent erection. In addition, endothelial vasoactive compounds, such as endothelin 1, angiotensin II, and thromboxane A2, which have smooth muscle contractile properties, can also interfere withsmooth muscle relaxation and prevent erection.