How erections work - and what Viagra and Cialis actually do!

This too is a re-post of something I wrote on r/gettingbigger: 

 

I wrote the following originally as a reply to someone whose doctor had given him erroneous info (or maybe he just didn't understand what the doc said) about Viagra and Cialis, stating they didn't do the same thing. One was for causing an erection, the other for keeping it, according to the GP. That, of course, is complete and utter BS, so I started replying, but then I went deeper and deeper, and I realised after posting the reply that perhaps it would be of interest to more people, so here goes... I begin by describing how Cialis and Viagra work, then go into detail about the erection process step by step, from arousal to NO release to cGMP to smooth muscle relaxation, etc. .

 

Both Tadalafil (Cialis) and Sildenafil (Viagra) are phosphodiesterase type 5 (PDE5) inhibitors, and their primary mechanism of action is very similar. They do not work in fundamentally different ways in terms of one solely "keeping" an erection and the other "causing" an erection. I'll try to clarify their mechanism of action to dispel this misconception that your GPs have, or that you have read into what they say:

 

PDE5 inhibitors work by inhibiting the enzyme phosphodiesterase type 5. This enzyme is responsible for the breakdown of cyclic guanosine monophosphate (cGMP), which is a molecule that - through a couple of steps that end in Ca2+ ions - regulates blood flow to the penis (edit: I explain it in greater details below).

 

By inhibiting PDE5, these PDE5i-medications increase the levels of cGMP in the smooth muscle cells of the penis, leading to relaxation of these muscles and increased blood flow into the penile tissues. This process "facilitates the achievement and maintenance of an erection in response to sexual stimulation" - i.e. they don't "cause" erections, they facilitate them by basically turning up the volume of the cGMP signal in a manner similar to how SSRI medications (most common antidepressant) can turn up the volume of the serotonin signal in the synaptic cleft.

 

The primary misconception (yours or your GP's) seems to be about the specificity of action between "causing" versus "keeping" an erection. Both Tadalafil and Sildenafil require sexual stimulation to be effective; they do not directly cause an erection without it. Instead, they enhance the body's natural erectile response to sexual stimulation by ensuring that more blood can flow into your D and be retained there to maintain an erection. They make it easier to get an erection with a little less stimulus from nitric oxide release, and they make it easier to maintain. One does not do this better than the other (dose dependent, of course - usually 100mg Viagra is considered equivalent to 20mg Cialis).

 

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Here's a step by step walk-through of the erection process, beginning with what happens in the brain, and then moving on to what happens down below:

 

Step 0. You get sexually aroused - this happens in the brain, not in the penis. Arousal can be triggered by physical stimulation or mental - whenever you think of smelly feet or latex rubber or your middle school teacher or stepsister or hairy armpits or whatever it is you're into, pervert... :)

 

The perception of sexual stimuli activates specific regions of the brain involved in sexual function; the amygdala (emotions), hippocampus (memories), hypothalamus (the master orchestrator), prefrontal cortex (planning, social inhibition, identity), etc. The Hypothalamus is particularly important, and the three most important areas are the MPOA, INAH-3 and the PVN:

 

The "Medial Preoptic Area" (MPOA) integrates sensory inputs and coordinates the autonomic and endocrine responses necessary for sexual activity. It plays a significant role in the erection process by relaying signals that lead to the production of nitric oxide in the penile tissue.

 

INAH-3 - This nucleus is part of a cluster of neurons located in the anterior hypothalamus, an area known for its involvement in sex-typical behavior and sexual orientation. Research has suggested differences in the size of INAH-3 between heterosexual and homosexual men, implying a role in sexual orientation. The anterior hypothalamus, including INAH-3, is involved in regulating sexual behaviour and is responsive to sexual hormones. Its activation can influence sexual motivation and arousal, integrating hormonal signals with neural responses to sexual stimuli. (It's more easy to get aroused if your testosterone is high, for instance).

 

The "Paraventricular Nucleus" (PVN) is involved in the regulation of erection and ejaculation. It sends signals to the spinal cord, which then modulates the erectile response.

 

Specifically, this is transmitted through the pudendal nerve and its branches, including the dorsal nerve of the penis (the one on the top side, which you can damage or irritate by death-grip masturbation or jelqing for instance).

 

Two other important areas (that I researched in some depth when I worked on one of my erotic stories - yes, I write erotica as a hobby), are the NA and DS:

 

The NA "Nucleus Accumbens" is a critical component of the brain's reward circuitry and is involved in the concept of "incentive salience," the process by which certain stimuli are imbued with particular significance or desirability. In the context of sexual behavior, the nucleus accumbens responds to sexual stimuli by processing their reward value, thereby contributing to sexual motivation and desire. This response includes the release of dopamine, a neurotransmitter associated with pleasure and reward.

 

The DA: Comprising parts of the caudate nucleus and putamen, the dorsal striatum is involved in habit formation and the procedural learning aspects of behaviours, including those related to sexual activity. It works in concert with the nucleus accumbens to integrate reward information with action selection, thereby contributing to the motivational component of sexual behaviour. The dorsal striatum helps encode the association between sexual stimuli and pleasure, reinforcing the likelihood of engaging in sexual behaviours based on past rewarding experiences.

 

But back to the signal transmission: The autonomic nervous system (ANS), which regulates involuntary bodily functions (including sexual responses) modulates the signalling from the Hypothalamus. The parasympathetic nervous system (part of the ANS) is particularly crucial in promoting the relaxation of smooth muscle in the penis, which is necessary for an erection. The sympathetic nervous system, on the other hand, is more involved in the ejaculation and detumescence (the process of the penis returning to a flaccid state). I have written before about how maintaining an erection and achieving an ejaculation is like walking on a knife's edge, balancing parasympathetic and sympathetic tone. Get too exited (sympathetic tone) and you will lose your erection or ejaculate prematurely. Get too relaxed (parasympathetic tone) and you won't be able to stay erect (but this is where Cialis and Viagra assist).

 

The signals transmitted through the nervous system ultimately lead to the activation of endothelial cells and nerve endings in the penis to release nitric oxide (NO).

 

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Here's how that works - the rest of the process happens inside the penis itself:

 

 

Nitric oxide-cGMP pathway for relaxation and the mechanism of phosphodiesterase type 5 (PDE5) inhibition in cavernosal smooth muscle. NO, nitric oxide; GTP, guanosine triphosphate; cGMP, guanosine-3',5'-monophosphate; 5'-GMP, 5'-guanosine monophosphate; PKG, cGMP-dependent protein kinase; ATP, adenosine triphosphate; ADP, adenosine diphosphate; Ca 2+ , calcium ion; PDE5I, phosphodiesterase 5 inhibition. Modified from JD Corbin IJIR 2004

 

Step 1. Sexual Stimulation and Nitric Oxide Release

The process I described above triggers the release of nitric oxide (NO) from nerve endings and endothelial cells within the penis. Nitric oxide is a key signalling molecule that is involved in various physiological processes, including vasodilation and blood flow regulation. (This, by the way, is why we take L-Ciitrulline for PE - because it greatly assists NO production.)

 

Step 2. Activation of Guanylate Cyclase

Once released, NO diffuses into the smooth muscle cells lining the blood vessels of the corpus cavernosum (and spongiosum and glans) and binds to the enzyme soluble guanylate cyclase (sGC). The binding of NO to sGC activates the enzyme, which catalyses the conversion of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).

 

Step 3. cGMP Effects

cGMP serves as a secondary messenger that induces several downstream effects, leading to the relaxation of smooth muscle cells. One of its key roles is to reduce intracellular calcium levels, which causes muscle relaxation. The mechanism by which cGMP leads to decreased calcium levels includes:

 

A: Inhibition of Calcium Influx: cGMP closes calcium channels in the cell membrane, reducing the influx of calcium ions into the cell.

 

B: Activation of Potassium Channels: cGMP activates potassium channels, which results in potassium efflux from the cell. This efflux helps to hyperpolarise the cell membrane, making it less likely for calcium channels to open, thus indirectly contributing to reduced calcium levels within the cell.

 

C: Stimulation of cGMP-dependent Protein Kinase (PKG): cGMP activates PKG, which then phosphorylates various targets that lead to a reduction in intracellular calcium. PKG facilitates the uptake of calcium into the sarcoplasmic reticulum (a form of internal cellular storage) and increases the activity of the ATP-dependent calcium pumps that remove calcium from the cell.

 

Step 4. Muscle Relaxation

The reduction in intracellular calcium concentration is a critical step in the relaxation of smooth muscle cells. In smooth muscle, contraction is initiated by the binding of calcium to the protein calmodulin, which then activates myosin light-chain kinase (MLCK). MLCK phosphorylates myosin, allowing it to interact with actin and cause contraction. When cGMP reduces calcium levels, this cascade is inhibited, leading to a decrease in myosin phosphorylation and thus relaxation of the smooth muscle cells. Whoever said biology is complicated - this is straightforward, isn't it? Just kidding - the intracellular processes involved in muscle relaxation was something I wasn't very familiar with before today - I just thought of it as "a signal tells actin and myosin to relax".

 

Step 5. Resulting Vasodilation and Erection

The relaxation of smooth muscle cells in the corpus cavernosum allows the blood vessels to dilate, increasing blood flow into the penis. This increased blood flow, coupled with the restriction of venous outflow, leads to an erection.

 

And this is how boners work, folks.

 

The relevance for Viagra and Cialis? Well, cGMP is broken down by PDE5. By inhibiting PDE5, the medicines help cGMP remain active, and thereby keep your cavernosal smooth muscles relaxed, and thereby your D erect. The PDE5-inhibitors "turn up the volume" by preventing cGMP from being deactivated.