Nitric oxide → sGC → cGMP → PKG smooth-muscle relaxation cascade is the molecular basis of erection (cavernosal sinusoid filling) + pulmonary vasodilation (PAH treatment) + selected antiplatelet activity. PDE5 (phosphodiesterase type 5) is the cGMP-hydrolyzing enzyme concentrated in corpus cavernosum + pulmonary vascular smooth muscle. PDE5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) preserve cGMP → potentiated NO-dependent vasodilation; nitric oxide is the obligate upstream signal (no NO, no PDE5-i benefit). Riociguat is a sGC stimulator that works NO-independently — synergistic with low endogenous NO. Critical safety: ANY PDE5 inhibitor + organic nitrate is contraindicated (life-threatening hypotension). PDE5 inhibitors also have hearing-loss + NAION (non-arteritic anterior ischemic optic neuropathy) signals. Cross-link: vasodilator_no_endothelin (NO + endothelin antagonists) + nitric_oxide_synthesis (upstream NO production).
Organ Systems
cardiovascular
reproductive
Pathway Steps
nitric-oxide → cgmp-rise — via sGC activation by NO → cGMP from GTP (cross-link: nitric_oxide_synthesis). Nitric oxide (from nerves or endothelium) activates soluble guanylate cyclase to raise cGMP in smooth muscle. In the penis, NO from non-adrenergic non-cholinergic nerves drives this rise — the physiological trigger for erection, and the upstream half of the pathway PDE5 inhibitors act on.
cgmp-rise → smooth-muscle-relaxation — via PKG → myosin light-chain phosphatase → relaxation. cGMP activates protein kinase G, lowering intracellular calcium to relax smooth muscle — vasodilation and, in the corpus cavernosum, erection. PDE5 normally degrades cGMP to end the signal, so inhibiting it (sildenafil, tadalafil) sustains cGMP — which is why these drugs still require NO/arousal to work.
cgmp-rise → cGMP degraded by PDE5 (signal termination) — via PDE5 hydrolyzes cGMP → 5′-GMP — PDE5 inhibitors block this step → cGMP accumulates. PDE5 hydrolyzes cGMP back to 5′-GMP, terminating the relaxation signal — most prominently in the corpus cavernosum and pulmonary vasculature. Blocking PDE5 (sildenafil, tadalafil, vardenafil) sustains cGMP, which is why these drugs amplify an NO-initiated signal but still require NO/arousal to start it.
tadalafil (inhibitor) — PDE5 (long-acting). Cialis; long t½ ~17.5h enables daily low-dose + on-demand options; PAH (Adcirca 40 mg/d) + BPH indication; less food effect than sildenafil
vardenafil (inhibitor) — PDE5 (selective). Levitra/Staxyn; intermediate t½ ~4-5h; QT prolongation greater than sildenafil — caution with class III antiarrhythmics
riociguat (activator) — sGC (NO-independent stimulator). Adempas; PAH + CTEPH; works at low NO (where PDE5-i fails); pregnancy contraindicated; nitrate combination prohibited