(Circulation. 1997;96:3647-3654.)
© 1997 American Heart Association, Inc.
Articles |
Ca2+ Release From Intracellular Stores Is an Initial Step in Hypoxic Pulmonary Vasoconstriction of Rat Pulmonary Artery Resistance Vessels
From the Department of Physiology, University of Florida College of Medicine, Gainesville (C.H.G.), and the Division of Pediatric Cardiology, Department of Pediatrics, University of Miami (Fla) School of Medicine (H.G.).
Correspondence to Craig H. Gelband, Department of Physiology, University of Florida College of Medicine, PO Box 100274, Gainesville (C.H.G.), FL 32610. E-mail gelband{at}phys.med.ufl.edu
Background A reduction in oxygen tension in the lungs is believed to inhibit a voltage-dependent K+ (Kv) current, which is thought to result in membrane depolarization leading to hypoxic pulmonary vasoconstriction (HPV). However, the direct mechanism by which hypoxia inhibits Kv current is not understood.
Methods and Results Experiments were performed on rat pulmonary artery resistance vessels and single smooth muscle cells isolated from these vessels to examine the role of Ca2+ release from intracellular stores in initiating HPV. In contractile experiments, hypoxic challenge of endothelium-denuded rat pulmonary artery resistance vessels caused either a sustained or transient contraction in Ca2+-containing or Ca2+-free solution, respectively (n=44 vessels from 11 animals). When the ring segments were treated with either thapsigargin (5 µmol/L), ryanodine (5 µmol/L), or cyclopiazonic acid (5 µmol/L) in Ca2+-containing or Ca2+-free solution, a significant increase in pulmonary arterial tone was observed (n=44 vessels from 11 animals). Subsequent hypoxic challenge in the presence of each agent produced no further increase in tone (n=44 vessels from 11 animals). In isolated pulmonary resistance artery cells loaded with fura 2, hypoxic challenge, thapsigargin, ryanodine, and cyclopiazonic acid resulted in a significant increase in [Ca2+]i (n=18 cells from 6 animals) and depolarization of the resting membrane potential (n=22 cells from 6 animals). However, with prior application of thapsigargin, ryanodine, or cyclopiazonic acid, a hypoxic challenge produced no further change in [Ca2+]i (n=18 from 6 animals) or membrane potential (n=22 from 6 animals). Finally, application of an anti-Kv1.5 antibody increased [Ca2+]i and caused membrane depolarization. Subsequent hypoxic challenge resulted in a further increase in [Ca2+]i with no effect on membrane potential (n=16 cells from 4 animals).
Conclusions In rat pulmonary artery resistance vessels, an initial event in HPV is a release of Ca2+ from intracellular stores. This rise in [Ca2+]i causes inhibition of voltage-dependent K+ channels (possibly Kv1.5), membrane depolarization, and an increase in pulmonary artery tone.
Key Words: hypoxia • calcium • sarcoplasmic reticulum • potassium •
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