Skip to main content
. 2009 Feb;84(2):191–207. doi: 10.4065/84.2.191

FIGURE 1.

FIGURE 1.

The 3 mechanistic pathways known to be disturbed in patients with pulmonary arterial hypertension (PAH). The short, thick, black arrows depict aberrations observed in these pathways in patients with PAH. The points at which drug treatment affects these mechanistic processes are shown in gray circles. AA = arachidonic acid; CCB = calcium channel blocker; ETRA = endothelin receptor antagonist (eg, bosentan [dual], ambrisentan, and sitaxsentan [receptor A selective]); PDE5i = phosphodiesterase 5 inhibitor (eg, sildenafil).

Left, The nitric oxide (NO) pathway. Nitric oxide is created in endothelial cells by type III (ie, endothelial) NO synthase (eNOS), which in pulmonary arterial smooth muscle cells (PASMCs) induces guanylate cyclase (GC) to convert guanylate triphosphate (GTP) to cyclic guanylate monophosphate (cGMP). Cyclic GMP is a second messenger that constitutively maintains PASMC relaxation and inhibition of PASMC proliferation by ultimately reducing inward flux of calcium ions (Ca++). Cyclic GMP is removed by the PDE5 enzyme to yield the inactive product 5′GMP. Patients with PAH have reduced expression and activity of eNOS.

Middle, The prostacyclin pathway. The production of prostaglandin I2 (PGI2 [ie, prostacyclin]) is catalyzed by prostacyclin synthase (PS) in endothelial cells. In PASMCs, PGI2 stimulates adenylate cyclase (AC), thus increasing production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Cyclic AMP is a second messenger that constitutively maintains PASMC relaxation and inhibition of PASMC proliferation. Patients with PAH have reduced expression and activity of PS.

Right, The endothelin (ET) pathway. Big- (ie, pro-) ET is converted in endothelial cells to ET1 (a 21-amino acid peptide) by endothelin-converting enzyme (ECE). ET1 binds to PASMC ETA and ETB receptors, ultimately leading to PASMC contraction, proliferation, and hypertrophy. Endothelin 1 also binds to endothelial cell ETB receptors (not illustrated). Patients with PAH have increased expression and activity of ECE.