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EDITORIAL FOCUS
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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