CA2-ARTERY RESISTANCE VESSELS( RELEASE FROM INTRACELLULAR STORES IS AN INITIAL STEP IN HYPOXIC PULMONARY VASOCONSTRICTION OF RAT PULMONARY)

Background A reduction in oxygen tension in the lungs is believed to i nhibit a voltage-dependent K+ (Kv) current, which is thought to result in membrane depolarization leading to hypoxic pulmonary vasoconstrict ion (HPV). However, the direct mechanism by which hypoxia inhibits Ky current is not understood. Methods and Results Experiments were perfor med on rat pulmonary artery resistance vessels and single smooth muscl e cells isolated from these vessels to examine the role of Ca2+ releas e from intracellular stores in initiating HPV. In contractile experime nts, hypoxic challenge of endothelium-denuded rat pulmonary artery res istance 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 thapsiga rgin (5 mu mol/L), ryanodine (5 mu mol/L), or cyclopiazonic acid (5 mu mol/L) in Ca2+-containing or Ca2+-free solution, a significant increa se in pulmonary arterial tone was observed (n=44 vessels from 11 anima ls). Subsequent hypoxic challenge in the presence of each agent produc ed no further increase in tone (n=44 vessels from 11 animals). In isol ated pulmonary resistance artery cells loaded with fura 2, hypoxic cha llenge, thapsigargin, ryanodine, and cyclopiazonic acid resulted in a significant increase in [Ca2+](i) (n=18 cells from 6 animals) and depo larization of the resting membrane potential (n=22 cells from 6 animal s. However, with prior application of thapsigargin, ryanodine, or cycl opiazonic 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, appli cation of an anti-Kv1.5 antibody increased [Ca2+](i) and caused membrane depolarization. Subsequent hypoxic challenge resu lted in a further increase in [Ca2+](i) with no effect on membrane pot ential (n=16 cells from 4 animals). Conclusions In rat pulmonary arter y resistance vessels, an initial event in HPV is a release of Ca2+ fro m intracellular stores. This rise in [Ca2+](i) causes inhibition of vo ltage-dependent K+ channels (possibly Kv1.5), membrane depolarization, and an increase in pulmonary artery tone.