Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension

Jason Xiao Jian Yuan, Ann M. Aldinger, Magdalena Juhaszova, Jian Wang, John V. Conte, Sean P. Gaine, Jonathan B. Orens, Lewis J. Rubin

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382 Scopus citations


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 (Em) 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), Em, 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 [Ca(2+)](cyt) than cells from patients with SPH and nonpulmonary hypertension disease. Consistently, PPH-PASMCs had a more depolarized Em, 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.

Original languageEnglish (US)
Pages (from-to)1400-1406
Number of pages7
Issue number14
StatePublished - Oct 6 1998

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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