Now, as you might have noticed, I’m not male, but I am rather capable of sympathy for my Y-chromosomed brothers. I can imagine it must have been an – erm – frustrating time for men with erectile dysfunction before Pfizer developed the now eponymous Viagra pill, known as sildenafil.
Sildenafil was originally studied for the treatment of high blood pressure and heart pain associated with coronary heart disease (called angina pectoris, literally “strangling chest”), but clinical trials showed little benefits in this regard. However, it was noted to cause erections in male participants. Thus, sildenafil was researched, patented, and marketed by Pfizer as a treatment for erectile dysfunction.
To understand how the little blue pill works its wonders, we first have to analyze what exactly occurs when an erection takes place. Two particular regions of the penis, known as the corpora cavernosum, contain the majority of the blood that fills the penis during an erection. Release of nitric oxide within this region that occurs during sexual stimulus bind to guanylate cyclase enzymes, which are responsible for the synthesis of cyclic guanosine monophosphate (cGMP) from GTP (ATP’s twin brother that is known for its specificity in activating metabolic reactions). cGMP is responsible for the regulation of ion channel conductance, as well as the relaxation of smooth muscle tissues. This relaxation can lead to increased blood flow in blood vessels, such as the phenomenon previously described in the corpora cavernosum.
Logically, sildenafil helps improve this process by inhibiting the cGMP-specific phosphodiesterase type 5 (PDE5), which accepts and breaks down cGMP. Sildenafil has a similar molecular structure to that of cGMP, and so competes for the PDE5 binding sites, allowing for more cGMP to be present in the corpora cavernosum. As the sildenafil itself does not cause the Nitric oxide-cGMP reaction that causes blood flow, sildenafil does not itself cause an erection, and sexual stimulus will still be required for an erection to occur.
Interestingly enough, a similar mechanistic route of cGMP degradation occurs in the retinae. In the presence of light, phosphodiesterase is activated that degrades the cGMP. As the cGMP regulates the sodium ion channels in the photoreceptors, this allows for the modulation of the phototransduction in rods and cones, meaning that cones and rods are capable of adapting to light exposure.
Researchers have looked to interesting inspiration of a very unfamiliar nature—the toxin, Tx2-6, that is found in the venom of the Brazilian Wandering Spider, one of the most venomous spiders in the world, is also being researched in its viability as a chemical basis for erectile dysfunction. Unlike sildenafil, it operates by skipping the need for sexual stimuli for the release of nitric oxide. This effect was clear, as male victims of bites from the spider reported erections lasting for several hours. This would likely mean that a medication developed by Tx2-6 would cause erections without stimuli—which could either be beneficial or more of an inconvenience, depending on the, uhm, intents of the user. However, no marketable product utilizing this toxin has seen clinical trials yet.
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