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From the Departments of Medicine (J.X.-J.Y., A.M.A., J.W., S.P.G.,
J.B.O., L.J.R.), Physiology (J.X.-J.Y., M.J., L.J.R.), and Surgery (J.V.C.),
University of Maryland School of Medicine, Baltimore, Md.
Correspondence to Lewis J. Rubin, MD, University of Maryland School of Medicine, 10 S Pine St, Suite 800, Baltimore, MD 21201. E-mail lrubin{at}umaryland.edu
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.
Methods and 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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Dysfunctional Voltage-Gated K+ Channels in Pulmonary Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension
Key Words: potassium • electrophysiology • pulmonary heart disease
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H. C. Champion, T. J. Bivalacqua, K. Toyoda, D. D. Heistad, A. L. Hyman, and P. J. Kadowitz In Vivo Gene Transfer of Prepro-Calcitonin Gene-Related Peptide to the Lung Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in the Mouse Circulation, February 29, 2000; 101(8): 923 - 930. [Abstract] [Full Text] [PDF]
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J. E. Seiden, O. Platoshyn, A. E. Bakst, S. S. McDaniel, and J. X.-J. Yuan High K+-induced membrane depolarization attenuates endothelium-dependent pulmonary vasodilation Am J Physiol Lung Cell Mol Physiol, February 1, 2000; 278(2): L261 - L267. [Abstract] [Full Text] [PDF]
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E. D. Michelakis, E. K. Weir, D. P. Nelson, H. L. Reeve, S. Tolarova, and S. L. Archer Dexfenfluramine Elevates Systemic Blood Pressure by Inhibiting Potassium Currents in Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1143 - 1149. [Abstract] [Full Text]
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