IT IS KNOWN THAT hypoxic pulmonary vasoconstriction (HPV) requires an elevation in cytosolic [Ca 2ϩ ] ([Ca 2ϩ ] i ) of pulmonary arterial smooth muscle (PASM), and numerous studies in both isolated PASM cells and arteries have shown that physiological hypoxia elicits a sustained increase in [Ca 2ϩ ] i , sometimes preceded by a transient rise (2, 6, 28 -30, 32, 39, 47). There is strong evidence that this involves Ca 2ϩ entry across the cell membrane, as removal of extracellular Ca 2ϩ or blockade of Ca 2ϩ entry tends to abolish HPV and at least the sustained elevation in [Ca 2ϩ ] i (6,17,19,30,32,39). Currently, the most widely held hypothesis is that this Ca 2ϩ entry is mediated via voltage-dependent L-type channels, as a result of hypoxia-induced inhibition of K ϩ channels and consequent depolarization (1,23,46). The evidence underlying this hypothesis is convincing, as many studies have reported that L-type channel blockers suppress HPV and/or the rise in [Ca 2ϩ ] i (7,17,19,32,37,39), and hypoxia has been shown to inhibit K ϩ channels and cause depolarization in both pulmonary artery and PASM cells (2,14,(23)(24)(25)49).However, the K ϩ channel hypothesis is not unassailable, as some reports have shown either no or only partial block of HPV with L-type channel blockers (8,9,30,31), and others have suggested that hypoxia causes insufficient depolarization to activate L-type channels in the absence of some form of priming stimulus (24,33,38). In particular, Robertson et al. (30) showed that both the elevation in [Ca 2ϩ ] i and HPV in small intrapulmonary arteries (IPA) were unaffected by simultaneous L-type channel blockade and depolarization with 80 mM K ϩ and suggested that hypoxia activates a voltage-independent Ca 2ϩ entry pathway through unidentified nonselective cation channels (NSCC) (30).There is now a significant body of work suggesting that hypoxia-induced Ca 2ϩ release from intracellular stores is an early and essential requirement for HPV (11,16,20,32,47). Store release activates store-operated channels (SOC) and capacitative Ca 2ϩ entry (CCE) in many cell types (27), including PASM (18,30,34,40,48). Interestingly, CCE seems to have an unusually prominent role in distal IPA, since activation of CCE elicits vasoconstriction in distal IPA, but not in small systemic arteries (34). These factors all support the suggestion that CCE might contribute to the elevation in PASM [Ca 2ϩ ] i during hypoxia (30, 43), and indeed in two recent papers hypoxia has been shown to activate CCE as a consequence of store release and thus elevate [Ca 2ϩ ] i in freshly isolated (22) and cultured PASM cells (41). Nevertheless, changes in [Ca 2ϩ ] i are not necessarily associated with vasoconstriction (e.g., Ref. 34), and these reports on their own cannot conclusively prove a physiological role for CCE in HPV. The decisive study by Weigand et al., the current article in focus (Ref. 45, see p. L5 in this issue), extends their previous work (41) to examine the role of CCE and NSCC in HPV of isolated perfused lungs of rats. The...