Sexual Stimulation & Nitric Oxide Release
Arousal signals travel down nerve fibers into penile tissue.
- NANC nerves: Trigger (non-adrenergic non-cholinergic)
- Endothelium + nerves: NO source (dual release sites)
- ~5 sec: NO half-life (extremely short-lived)
- ~100 µm: Diffusion range (reaches nearby muscle cells)
Parasympathetic activation
Sacral parasympathetic nerves fire during arousal.
Nitric oxide synthase
eNOS and nNOS convert L-arginine into nitric oxide.
NO diffuses freely across cell membranes instantly.
Guanylate Cyclase Activation & cGMP Synthesis
Nitric oxide switches on an enzyme that builds cGMP.
- Soluble GC: Target enzyme (binds NO directly)
- GTP: Substrate (converted to cGMP)
- ~200×: Activation boost (enzyme rate increase)
- 2nd messenger: cGMP role (activates PKG)
NO-GC binding
NO binds the heme group of guanylate cyclase.
cGMP accumulation
GTP is rapidly converted into cyclic GMP.
Rising cGMP is the direct trigger for relaxation.
Smooth Muscle Relaxation & Blood Inflow
cGMP relaxes cavernosal muscle, widening blood-filled spaces.
- PKG: Mediator (protein kinase G)
- ↓ intracellular Ca²⁺: Calcium effect (muscle relaxes)
- Expand: Lacunar spaces (fill with blood)
- ~8×: Flow increase (vs resting state)
Calcium lowering
PKG lowers calcium, releasing muscle tension.
Venous compression
Expanding tissue compresses outflow veins, trapping blood.
Trapped inflow sustains firmness during arousal.
PDE5 Breakdown of cGMP (Untreated)
PDE5 enzyme degrades cGMP, ending the erection naturally.
- PDE5: Enzyme (cGMP-specific phosphodiesterase)
- GMP: Product (inactive breakdown product)
- Cavernosal smooth muscle: Location (high PDE5 density)
- cGMP falls: Effect (muscle re-contracts)
Enzymatic hydrolysis
PDE5 cleaves cGMP into inactive GMP.
Muscle re-contraction
Falling cGMP lets calcium rise, muscle tightens.
Without inhibition, erections fade within minutes.
PDE5 Inhibitor Administered — Sildenafil Mechanism
Sildenafil blocks PDE5, letting cGMP stay elevated longer.
- Sildenafil: Drug (competitive PDE5 inhibitor)
- Catalytic pocket: Binding site (blocks cGMP access)
- ~30–60 min: Onset (after oral dose)
- ~4 hours: Duration (plasma half-life ~4h)
Competitive inhibition
Sildenafil occupies the site cGMP would bind.
Sustained vasodilation
Blocked PDE5 lets cGMP accumulate, muscle stays relaxed.
Erection requires stimulation; sildenafil only enables the response.