Major Pathways

Three major pathways: prostacyclin, endothelin and nitric oxide are currently being used as targets for current or emerging therapies in the treatment of pulmonary arterial hypertension. The pathways are involved in the abnormal proliferation and contraction of smooth muscle cells in the pulmonary arteries in patients with pulmonary arterial hypertension. These pathways play a role in determining which four classes of drugs may be used in the treatment of pulmonary arterial hypertension.

Prostacyclin pathway. Prostaglandin I2, PGI2, is the main product of arachidonic acid conversion in the vascular endothelium. PGI2 induces vascular smooth muscle relaxation, inhibits growth of smooth muscle cells and inhibits platelet aggregation by stimulating the production of cyclic AMP, cAMP. Prostacyclin analogues stimulate the productin of cAMP. Examples of prostacyclin analogues and their mode of administration include epoprostenol (IV), treprostinil (IV, SQ, inhalation) and iloprost (inhalation).

Endothelin pathway. Endothelin 1 is produced by the conversion of preendothelin to proendothelin. Endothelin 1 stimulates the proliferation of vascular smooth muscle cells, induces fibrosis and is proinflammatory. Endothelin 1 activity is mediated through endothelin receptors A and B. Activation of endothelin A causes sustained vasoconstriction and proliferation of vascular smooth muscle. Activation of endothelin B receptors induces the production of nitric oxide and prostacyclin by endothelial cells. Examples of endothelin pathway antagonists and their mode of action and administration include bosentan - oral, non-selective alpha and beta antagonists - and ambrisentan - oral, selective alpha antagonists.

Nitric oxide pathway. Nitric oxide is endogenously produced and is a potent endothelium vasodilator that directly relaxes smooth muscle cells via stimulating cyclic guanosine monophosphate, cGMP. Pulmonary arterial hypertension is associated with a defect in the production of nitric oxide. The mode of administration is via inhalation. cGMP is inhibited by phosphodiasterase-5, PDE-5. A group of drugs known as PDE-5 inhibitors have been used to inhibit PDE-5 production. Oral examples include sildenafil, tadalafil and vardenafil.