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Coordination of calcium signalling by endothelial-derived nitric oxide in the intact liver

Nature Cell Biology volume 1, pages 467–471 (1999)Cite this article

Abstract

Calcium ions (Ca2+) and nitric oxide (NO) are key signalling molecules that are implicated in the regulation of numerous cellular processes. Here we show that, in the intact liver, stimulation of endothelial cells by bradykinin coordinates the propagation of vasopressin-dependent intercellular Ca2+ waves across hepatic plates, and markedly increases the frequency of Ca2+ oscillations in individual hepatocytes. Modulation of Ca2+ oscillations by bradykinin is lost following isolation of hepatocytes, but restored in co-cultures of hepatocytes and endothelial cells. The sensitizing effects of bradykinin are mimicked by NO donors and abrogated by NO inhibitors. Thus, crosstalk between NO and Ca2+ signalling pathways through the microvasculature is probably an important mechanism for the coordination of liver function and may have a function in other organs.

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Figure 1: Ca2+ signals in the intact liver and their modulation by bradykinin.
Figure 2: Effect of bradykinin on Ca2+ concentration in the intact liver.
Figure 3: Effect of bradykinin on Ca2+ concentration in isolated hepatocytes and cultured endothelial cells.
Figure 4: Modulation of Ca2+ oscillations by bradykinin in co-cultures of isolated hepatocytes and endothelial cells.
Figure 5: Effect of desensitization of hepatocyte purinergic receptors on the modulation of Ca2+ oscillations by bradykinin in the intact liver.
Figure 6: Effects of l-NAME, cPTIO and spermine NONOate on Ca2+ signals in isolated hepatocytes.
Figure 7: Effects of l-NAME and cPTIO on bradykinin-induced sensitization of hepatic Ca2+ signals in the intact liver and in hepatocyte/endothelial co-cultures.

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Acknowledgements

We thank A.D. Michel, B.M. Hantash, L.S. Jouaville, W.N. Duran, G.C. Churchill and A. Galione for helpful comments; and M.J. Woolkalis for initial provision of CPAE cells. This work was supported by grants from the NIH (to A.P.T.) and a Wellcome Prize Travel Research Fellowship (to S.P.).

Correspondence and requests for materials should be addressed to A.P.T.

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Author notes

  1. Sandip Patel

    Present address: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

  2. Sandip Patel and Lawrence D. Robb-Gaspers: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, 07103, New Jersey, USA

    Sandip Patel, Lawrence D. Robb-Gaspers, Kerri Anne Stellato, Mimi Shon & Andrew P. Thomas

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Correspondence to Andrew P. Thomas.

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Patel, S., Robb-Gaspers, L., Stellato, K. et al. Coordination of calcium signalling by endothelial-derived nitric oxide in the intact liver. Nat Cell Biol 1, 467–471 (1999). https://doi.org/10.1038/70249

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