Phosphodiesterase inhibitors improve pulmonary hypertension by increasing intracellular levels of which messenger?

• A. Endothelin
• B. Nitric oxide
• C. Calcium
• D. cGMP

Answer: (D)

Phosphodiesterase inhibitors raise the level of cyclic GMP (cGMP) inside vascular smooth muscle. In the pulmonary arteries, blocking the breakdown of cGMP with a PDE-5 inhibitor lets NO-stimulated cGMP signaling accumulate, which activates protein kinase G and lowers intracellular calcium, causing relaxation of the smooth muscle. This vasodilation reduces pulmonary vascular resistance and improves pulmonary hypertension. Endothelin is a vasoconstrictor, and nitric oxide works upstream to increase cGMP but the inhibitor’s direct effect is to raise cGMP levels; calcium drives contraction, not the messenger whose levels are increased here.