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The 3 Pathophysiological Pathways in Pulmonary Arterial Hypertension: The pathophysiological pathways illustrated can be targeted using endothelin-receptor antagonists, nitric oxide, phosphodiesterase type-5 inhibitors, and prostacyclin derivatives. (Top) a transverse section of a small pulmonary artery (<500 μm diameter) from a patient with severe pulmonary arterial hypertension shows intimal proliferation and marked medial hypertrophy. Dysfunctional pulmonary-artery endothelial cells (blue)exhibit decreased production of prostacyclin and endogenous nitric oxide, with an increased production of endothelin-1, which promotes vasoconstriction and proliferation of smooth-muscle cells in the pulmonary arteries (red). Plus signsdenote an increase in the intracellular concentration; minus signsdenote a blockade of a receptor, inhibition of an enzyme, or a decrease in the intracellular concentration. | cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate. | Humbert M., Sitbon O., Simonneau G. (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436.