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Redox Activation of Intracellular Calcium Release Channels (Ryanodine Receptors) in the Sustained Phase of Hypoxia-Induced Pulmonary Vasoconstriction^*

^* From the Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC.

Correspondence to: Jerry Eu, MD, Division of Pulmonary, Allergy and Critical Care Medicine, PO Box 3168, Duke University Medical Center, Durham, NC 27710; e-mail: eu000001{at}duke.edu

Hypoxia-induced pulmonary vasoconstriction (HPV) is an important adaptive process that remains incompletely understood. In preconstricted rat pulmonary arteries (inner diameter, 250 to 400 µm), hypoxia (pO₂ approximately 10 mm Hg) induces an initial transient phase and a more slowly developing sustained phase of vasoconstriction. Since the release of calcium ions (Ca²⁺) from intracellular stores by redox-sensitive intracellular Ca²⁺ release channels known as ryanodine receptors (RyRs) in pulmonary arterial smooth-muscle cells (PASMCs) may play a role in HPV, and considerable evidence now supports that levels of reactive oxygen species (ROS) are paradoxically increased in PASMC under hypoxia, we investigated whether redox activation of RyRs by ROS may transduce HPV. By reverse transcriptase-polymerase chain reaction, we found that all three RyR isoforms are expressed in rat pulmonary arteries and in PASMCs. The sustained phase, but not the transient phase, of HPV can be prevented by pretreating pulmonary arteries with RyR inhibitors ryanodine (200 µmol/L) or dantrolene (50 µmol/L). The addition of dantrolene, ryanodine or the thiol-reducing agent dithiothreitol (1 mmol/L) during the sustained phase of HPV reversed the hypoxic vasoconstriction. In contrast, the superoxide scavenger nitroblue tetrazolium (500 nmol/L) prevented further hypoxic pulmonary vasoconstriction during the sustained phase of HPV but did not reverse it. Taken together, our data suggest that redox activation of RyRs by ROS has an important role in transducing the sustained contraction of pulmonary arteries under hypoxia.

Key Words: hypoxia-induced pulmonary vasoconstriction • redox regulation • ryanodine receptors