Nitric oxide erection side effects

If you go looking in the scientific literature for an explanation of why "sexual side effects" happen at all, you'll mostly encounter rather vague, unsatisfying explanations. I did a little digging on my own and came up with what I think is a fairly edifying scientific explanation of what's going on. (From here, it gets a little technical. Bear with me if you can.)

"Sexual dysfunction" covers a lot of ground, and the gaps in our knowledge of the biochemistry underlying things like arousal and orgasm could better be called knowledge in our gaps. However, we do know that nitric oxide (NO) metabolism plays a huge role in stimulatory response. Clitoral erection as well as penile erection depend on production of NO and subsequent NO-induced accumulation of cyclic guanosine monophosphate, or cGMP (see this paper).

Nitric oxide is an interesting molecule. It's a gas at room temperature; soluble in oil as well as water; extremely corrosive; penetrates cell membranes with ease; and is probably the most widely distributed free radical in the human body. For many years, researchers knew of something called the endothelium-derived relaxing factor (EDRF), a substance produced by the inner cell lining of blood vessels, capable of signalling the surrounding smooth muscle to relax (resulting in vasodilation and increasing blood flow). It turns out EDRF and nitric oxide are one and the same. When NO is produced (from arginine and a bunch of cofactors, by the action of an enzyme called, shockingly enough, NO synthase), it triggers massive production of cGMP, which in turn activates protein kinases that (in turn) cause reuptake of calcium ion, which (through a bunch more steps) results in relaxation of smooth muscle.

You wouldn't think relaxation of muscle would be the key to getting an erection going, but that's because you're thinking of the wrong "muscle." Here, we're concerned with blood-vessel smooth muscle. Relaxation of that kind of smooth muscle is crucial to allowing blood to find its way into the structures that ultimately cause a clitoris or penis to become engorged. Without an increase in NO production and all the downstream effects that lead to vasodilation, there's no arousal.