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

Weigand, Letitia, Joshua Foxson, Jian Wang, Larissa A. Shimoda, and J. T. Sylvester. Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store- operated Ca2+ and nonselective cation channels. Am J Physiol Lung Cell Mol Physiol 289: L5 - L13, 2005. First published February 18, 2005; doi:10.1152/ajplung.00044.2005.-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% O-2 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 mu M, LaCl3 had similar effects, but higher concentrations ( 30 and 100 mu M) 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.