Background—Primary pulmonary hypertension (PPH) is a rare disease of unknown cause. Although PPH and secondary pulmonary hypertension (SPH) share many clinical and pathological characteristics, their origins may be disparate. In pulmonary artery smooth muscle cells (PASMCs), the activity of voltage-gated K⁺ (K_V) channels governs membrane potential (E_m) and regulates cytosolic free Ca²⁺ concentration ([Ca²⁺]_cyt). A rise in [Ca²⁺]_cyt is a trigger of vasoconstriction and a stimulus of smooth muscle proliferation.

Methods and Results—Fluorescence microscopy and patch clamp techniques were used to measure [Ca²⁺]_cyt, E_m, and K_V currents in PASMCs. Mean pulmonary arterial pressures were comparable (46±4 and 53±4 mm Hg; P=0.30) in SPH and PPH patients. However, PPH-PASMCs had a higher resting [Ca²⁺]_cyt than cells from patients with SPH and nonpulmonary hypertension disease. Consistently, PPH-PASMCs had a more depolarized E_m than SPH-PASMCs. Furthermore, K_V currents were significantly diminished in PPH-PASMCs. Because of the dysfunctional K_V channels, the response of [Ca²⁺]_cyt to the K_V channel blocker 4-aminopyridine was significantly attenuated in PPH-PASMCs, whereas the response to 60 mmol/L K⁺ was comparable to that in SPH-PASMCs.

Conclusions—These results indicate that K_V channel function in PPH-PASMCs is inhibited compared with SPH-PASMCs. The resulting membrane depolarization and increase in [Ca²⁺]_cyt lead to pulmonary vasoconstriction and PASMC proliferation. Our data suggest that defects in PASMC K_V channels in PPH patients may be a unique mechanism involved in initiating and maintaining pulmonary vasoconstriction and appear to play a role in the pathogenesis of PPH.