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EDITORIAL FOCUS

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca²⁺ and nonselective cation channels

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 20 January 2005 ; accepted in final form 12 February 2005

Previous studies indicated that acute hypoxia increased intracellular Ca²⁺ concentration ([Ca²⁺]_i), Ca²⁺ influx, and capacitative Ca²⁺ entry (CCE) through store-operated Ca²⁺ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca²⁺-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl₂, and LaCl₃) on pulmonary arterial pressor responses to 2% O₂ and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca²⁺]_i responses to hypoxia in PASMC, SKF-96365 and NiCl₂ prevented and reversed HPV but did not alter pressor responses to KCl. At 10 µM, LaCl₃ had similar effects, but higher concentrations (30 and 100 µM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca²⁺-free perfusate and the voltage-operated Ca²⁺ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca²⁺ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca²⁺ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

isolated rat lung; pulmonary vascular resistance; angiotensin II; calcium signaling; vascular smooth muscle; calcium channels

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