Unlike systemic arteries, which dilate in response to hypoxia, the arteries of the pulmonary circulation constrict under hypoxic conditions. The mechanisms underlying this process, termed hypoxic pulmonary vasoconstriction, or HPV, remain controversial. Initial work by Post et al. (1992) suggested that hypoxia inhibited K⁺ channels in pulmonary artery smooth muscle cells, causing depolarization and Ca²⁺ influx via L-type Ca²⁺]channels. However, later work from our laboratory (Robertson et al. 2000) showed that HPV in isolated intrapulmonary arteries (IPA) was little affected by simultaneous depolarization and treatment with L-type channel blockers, indicating that voltage-independent Ca²⁺ influx was likely to play a pivotal role in raising [Ca²⁺]_i during HPV. Moreover, both rho kinase-mediated Ca²⁺ sensitization and the endothelium make important contributions to HPV (Aaronson et al. 2002). In an effort to define the voltage-independent Ca²⁺ influx pathways present in rat IPA, we have recently investigated the mechanisms by which agonists raise [Ca²⁺]_i in these arteries, focusing mainly on PGF_2α which causes a powerful vasoconstriction. Our experiments show that low concentrations (0.1μM) of PGF_2α or the FP receptor agonist fluprostenol cause a transient rise in [Ca²⁺]_i associated with Ca²⁺ release, followed by a sustained rise in [Ca²⁺]_i which is abolished by pretreatment with 3μM U73122, 10μM La³⁺, 75μM 2-APB and or 1μM thapsigargin. Conversely, a higher concentration (10μM PGF_2α and the TP receptor agonist U46619 (0.1μM) cause a sustained rise in [Ca²⁺]_i which is relatively insensitive to each of these drugs, and to the L-type Ca²⁺ channel blocker diltiazem. In addition, the Ca²⁺ influx pathway activated by U46619, but not the pathway activated by fluprostenol, is permeable to Sr²⁺. These results suggest that FP receptor activation stimulates store-operated Ca²⁺ entry, whereas TP receptor activation stimulates Ca²⁺entry through a receptor operated channel. In order to determine whether these pathways are also involved in the response to hypoxia, we have examined the effects on HPV of agents acting to modify or block either Ca²⁺ release or Ca²⁺ influx through non-voltage-gated Ca²⁺ entry pathways. HPV consists of an initial transient contraction (phase 1), followed by a sustained constriction (phase 2). Phase 1 HPV is abolished by 1μM La³⁺ or 1μM cyclopiazonic acid, but is less sensitive to dantrolene (50 μM) and 2-APB, whereas phase 2 is strongly inhibited by 2-APB and dantrolene and is partially inhibited by cyclopiazonic acid, but is insensitive to 1 μM La³⁺. These results suggest that non-voltage-gated Ca²⁺ influx pathways are important in raising [Ca²⁺]_i in pulmonary artery smooth muscle during HPV, and that separate pathways probably contribute to each phase.