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1 Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: jsylv{at}jhmi.edu.
Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through storeoperated Ca2+ channels (SOCCs) in smooth muscle cells (PASMCs) from distal pulmonary arteries, 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 SOCCs and nonselective cation channels (NSCCs). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF96365, 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 PASMCs, SKF96365 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 store- and voltage-operated Ca2+ channels. 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 VOCCs.
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