Abstract
The aim of this study was to explore the effect of 0NO-54918-07, a stable prostacyclin analogue, on the current–voltage (IV) curve and the intracellular Ca2+ concentration [Ca2+]i of NG108-15 neuroblastoma × glioma hybrid cells. The IV curve was measured with ramp pulses from −70 to 0 mV, and [Ca2+]i was determined with Fura 2. Bath application of 0.2 μM ONO-54918-07 reversibly increased the holding current at −70 mV by −81.1 ± 14.8 pA (mean ± SEM, n = 35) and the slope of the IV curve between −70 and −50 mV by the factor 2.24 ± 0.24. The effect of 0.2 μM prostaglandin PGE1 was similar (ΔI hold = −96.1 ± 29.9 pA, g/g control = 2.72 ± 0.44, n = 9). ONO-54918-07 concentrations of 0.04, 2 and 6 μM were also effective. From the dose–response curve, the concentration for the half maximal effect was obtained as 0.054 μM. When cells did not respond to ONO-54918-07, an effect could sometimes be elicited by a ramp pulse or by a second ONO-54918-07 application 30–50 min after the first. The effect of ONO-54918-07 was not affected by pre-treatment with the EP1 antagonists ONO-8713 or SC-51089. However, a 14–40 min pre-treatment with 1 μM RO3244794, a selective prostacyclin receptor (IP) antagonist, abolished the effect of 0.2 μM PGE1. The effect of 0.2 μM ONO-54918-07 vanished completely in the presence of 5 μM RO32446794. ONO-54918-07 and PGE1 produced a slow increase in [Ca2+]i that lasted at least 6 min. Δ[Ca2+]i induced by both substances reached approximately 12% of the peak Δ[Ca2+]i induced by application of bradykinin. In only a few cells, PGE1 produced a brief, transient rise of [Ca2+]i. Using reverse transcriptase polymerase chain reaction, a prominent expression of the IP was detected in NG108-15 cells. It is concluded that ONO-54918-07 mimics the effect of PGE1, supporting the notion that the PGE1 effect on NG108-15 cells is mediated by IP receptors.
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Acknowledgements
The authors thank Ono Pharmaceutical (Osaka, Japan) for a generous gift of ONO-54918-07 and ONO-8713. They are also indebted to Roche Palo Alto LLC (Palo Alto, CA, USA) for a kind gift of RO3244794. The authors thank Dr. Mary-Frances Jett (Roche Palo Alto LLC) for critically reading the manuscript. They are grateful to Dr. M. Nirenberg (Bethesda, MD, USA) for providing the NG108-15 cells and to the Deutsche Forschungsgemeinschaft for financial support (SFB 530).
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Cavalié, A., Philipp, S.E. & Meves, H. ONO-54918-07, a stable prostacyclin analogue, mimics the effect of prostaglandin PGE1 on NG108-15 cells. Naunyn-Schmied Arch Pharmacol 376, 165–173 (2007). https://doi.org/10.1007/s00210-007-0186-2
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DOI: https://doi.org/10.1007/s00210-007-0186-2