Table 3.
Endothelial-derived vasoactive mediators, signaling pathways, and related medications for PH
| Mediator | Receptor/Target in Smooth Muscle | Postreceptor Pathways | Related Approved Medications |
|---|---|---|---|
| Vasodilators | |||
| NO | Guanylate cyclase | cGMP, PKG -PMCA, ↑Ca2+ extrusion -Phosphorylation of MLCK, ↓MLCK activity, ↓ Ca2+ sensitivity |
-Inhaled NO in acute PH -Guanylate cyclase stimulators, Riociguat -PDE5i, Sildenafil, Tadalafil, Vardenafil |
| PGI2 | IP receptor | cAMP, PKA -PMCA, ↑Ca2+ extrusion -Phosphorylation of MLCK, ↓MLCK activity, ↓Ca2+ sensitivity |
IP receptor agonists, Epoprostenol, Treprostinil, Beraprost, Iloprost, Selexipag |
| Vasoconstrictors | |||
| ET-1 | ETAR | -Ca2+ release from SR -Ca2+ influx via channels -Ca2+/CAM, activates MLCK -Rho-A/ROCK pathway, PKC pathway, inhibit MLC phosphatase |
-Nonselective ETR antagonists, Bosentan, Macitentan -Selective ETAR antagonists. Ambrisentan |
| TXA2 | TP receptor | -Ca2+ release from SR -Ca2+ influx via channels -Ca2+/CAM, activates MLCK -Rho-A/ROCK pathway, PKC pathway, inhibit MLC phosphatase |
TXA2 antagonists Need further evaluation clinically -Daltroban, Domitroban, Sulotroban, Terutroban -Vapiprost, Seratrodast |
CAM, calmodulin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ET-1, endothelin-1; ETAR, endothelin receptor type A; IP, prostacyclin receptor; MLC, myosin light chain; MLCK, MLC kinase; NO, nitric oxide; PDE5, phosphodiesterase-5; PH, pulmonary hypertension; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PMCA, plasma membrane Ca2+-ATPase, ROCK, Rho-associated protein kinase; SR, sarcoplasmic reticulum; TXA2, thromboxane A2.