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


RESULTS
Fluorescence microscopy and patch clamp techniques were used to measure [Ca2+]cyt, Em, and KV 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 Em than SPH-PASMCs. Furthermore, KV currents were significantly diminished in PPH-PASMCs. Because of the dysfunctional KV channels, the response of [Ca2+]cyt to the KV 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 KV 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 KV 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.
Yuan
J X
JX
Departments of Medicine, Physiology and Surgery, University of Maryland School of Medicine, Baltimore, Md, USA.
Aldinger
A M
AM
Juhaszova
M
M
Wang
J
J
Conte
J V
JV
Gaine
S P
SP
Orens
J B
JB
Rubin
L J
LJ
D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D017136:Ion Transport; D008297:Male; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology
D015221:Potassium Channels; D011188:Potassium; D002118:Calcium