Mechanisms of the prostaglandin F2α-induced rise in [Ca2+]i in rat intrapulmonary arteries

The mechanisms by which prostaglandin F-2 alpha (PGF(2 alpha)) increases intracellular Ca2+ concentration [Ca2+](i) in vascular smooth muscle remain unclear. We examined the role of store-, receptor- and voltage-operated Ca2+ influx pathways in rat intrapulmonary arteries (IPA) loaded with Fura PE-3. Low concentrations (0.01-1 mu M) of PGF(2 alpha) caused a transient followed by a plateau rise in [Ca2+](i). Both responses became maximal at 0.1 mu M PGF(2 alpha). At higher concentrations of PGF(2 alpha), a further slower rise in [Ca2+](i) was superimposed on the plateau. The [Ca2+](i) response to 0.1 mu M PGF(2 alpha) was mimicked by the FP receptor agonist fluprostenol, whilst the effect of 10 mu M PGF(2 alpha) was mimicked by the TP receptor agonist U-46619. The plateau rise in [Ca2+](i) in response to 0.1 mu M PGF(2 alpha) was insensitive to diltiazem, and was abolished in Ca2+-free physiological salt solution, and by pretreatment with La3+, 2-APB, thapsigargin or U-73122. The rises in [Ca2+](i) in response to 10 mu M PGF(2 alpha) and 0.01 mu M U-46619 were partially inhibited by diltiazem. The diltiazem-resistant components of both of these responses were inhibited by 2-APB and La3+ to an extent which was significantly less than that seen for the response to 0.1 mu M PGF(2 alpha), and were also much less sensitive to U-73122. The U-46619 response was also relatively insensitive to thapsigargin. When Ca2+ was replaced with Sr2+, the sustained increase in the Fura PE-3 signal to 0.1 mu M PGF(2 alpha) was abolished, whereas 10 mu M PGF(2 alpha) and 0.05 mu M U-46619 still caused substantial increases. These results suggest that low concentrations of PGF(2 alpha) act via FP receptors to cause IP3-dependent Ca2+ release and store operated Ca2+ entry (SOCE). U-46619 and 10-100 mu M PGF(2 alpha) cause a TP receptor-mediated Ca2+ influx involving both L-type Ca2+ channels and a receptor operated pathway, which differs from SOCE in its susceptibility to La3+, 2-APB and thapsigargin, does not require phospholipase C activation, and is Sr2+ permeable.