Whether idiopathic or related to a systemic disorder, the histologic appearance of lung tissue in each of these conditions share common features which include intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion and formation of plexiform lesions. Significant advances in understanding the molecular mechanisms in PAH have delivered insight into the key role played by endothelial dysfunction in initiating and propagating the pulmonary vascular remodeling process: specifically, impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, along with chronic overproduction of vasoconstrictors such as endothelin-1 (ET-1).

The Biology of Endothelin-1 (ET-1) and Endothelin Receptors in PAH
Since its initial discovery by Yanagisawa and co-workers in 1988,ET-1 has been extensively studied and is recognized as a key mediator of pulmonary vascular biology and pathophysiology in PAH. It is a 21-amino peptide predominantly produced by endothelial cells, though it can be also produced by smooth muscle cells, leukocytes, macrophages, cardiac myocytes and mesangial cells. In PAH, not only is the plasma level of ET-1 increased, its level is inversely proportional to the magnitude of the pulmonary blood flow and cardiac output, suggesting that these hemodyanmic changes are influenced directly by this vascular effector. ET-1 exerts its vascular effects through activation of the ET_A and ET_B receptors. ET_A receptors are located on smooth muscle cells whereas ET_B receptors are found predominantly on vascular endothelial cells and to a lesser extent on smooth muscle cells.Activation of the ET_A and ET_B receptors on smooth muscle cells induces vasoconstriction and cellular proliferation and hypertrophy. In contrast, stimulation of ET_B receptors on endothelial cells results in production of vasodilators nitric oxide and prostacyclin. In addition, ET_B receptors are involved in the clearance of ET-1 from the circulatory system, particulary in the lungs and kidneys. In non-diseased state, a regulated balance is maintained between the production and clearance of ET- 1 to keep the circulating level low, a process which is mediated by ET_B.

Selective versus Dual Endothelin Receptor Antagonists in PAH
Dual ET_A and ET_B receptor blockers and selective ET_A receptor antagonist have been developed for treatment of PAH.The proposed rationale for utilizing selective ET_A receptor blockade stems from the observation that there may be advantages for selectively blocking the vasoconstrictive and proliferative effects of ET_A receptor only while maintaining the vasodilator and ET-1 clearance function of the ET_B receptors. Conversely, blocking both ET_A and ET_B receptors have been stated as necessary to completely negate all the deleterious effects of ET-1 on pulmonary vasculature since ET_B receptors have been reported to be up regulated in certain disease states. Indeed, evidence exists to support effectiveness of both strategies in animal and human studies. Studies have been performed on healthy volunteers and on those with vascular diseased states that demonstrate superiority of one type of receptor antagonist over the other.With ET_A selective antagonist sitaxsentan, the degree of vasodilation was shown to be greater with selective antagonist than dual receptor antagonist. Conversely, the dual ET_A/ET_B receptor antagonist bosentan was demonstrated to cause more percent change in forearm blood flow in hypertensive patients than the selective ET_A blockade. Further complicating the question is that the spatial distribution of the upregulated ET_B receptors in certain disease states, whether the receptors are increased in endothelial cells or smooth muscle cells, has not been well elucidated.Whether selective or dual endothelin receptor antagonism will provide the most benefit in patients with PAH remain to be seen.