Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels

Craig H. Gelband, Henry Gelband

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 (h=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.

Original languageEnglish
Pages (from-to)3647-3654
Number of pages8
JournalCirculation
Volume96
Issue number10
StatePublished - Nov 18 1997
Externally publishedYes

Fingerprint

Vasoconstriction
Pulmonary Artery
Lung
Ryanodine
Thapsigargin
Membrane Potentials
Membranes
Fura-2
Smooth Muscle Myocytes
Endothelium
Anti-Idiotypic Antibodies
Oxygen
cyclopiazonic acid

Keywords

  • Calcium
  • Hypoxia
  • Potassium
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels. / Gelband, Craig H.; Gelband, Henry.

In: Circulation, Vol. 96, No. 10, 18.11.1997, p. 3647-3654.

Research output: Contribution to journalArticle

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N2 - 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 (h=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.

AB - 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 (h=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.

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