Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca 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 Ca 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 Ca concentration ([Ca ]i), Ca influx, and capacitative Ca entry (CCE) through store-operated Ca 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 Ca -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 highKCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca ]i responses to hypoxia in PASMC, SKF96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 M, LaCl3 had similar effects, but higher concentrations (30 and 100 M) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca -free perfusate and the voltage-operated Ca channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca 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 Ca on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.