Direct cytotoxic effects of radiocontrast (RC) agents have been implicated in radiocontrast nephropathy (RCIN). The interaction between extracellular calcium, which plays a central role in intercellular contacts, and the in vitro toxicity of RC was tested in Madin-Darby canine kidney (MDCK) cell monolayers grown on permeable supports. Cell viability was determined by trypan blue exclusion. The function of intercellular junctions was assessed by measuring the electrical transmonolayer resistance (TMR). The cell contacts were examined with indirect immunofluorescence microscopy using antibodies against the junctional proteins E-cadherin, ZO-1 and occludin. The ionic RC agents diatrizoate and ioxaglate (74 mg iodine/ml), but not the nonionic compounds iohexol or iodixanol, decreased ionized calcium (Ca2+) in the incubation media from 1.48 ± 0.04 mM (control) to 0.89 ± 0.06 mM (diatrizoate), respectively to 1.05 ± 0.08 mM (ioxaglate). Diatrizoate, and to a lesser extent ioxaglate, reduced the number of viable MDCK cells and showed a redistribution of the E-cadherin, ZO-1 and occludin immunofluorescence signal with a parallel decrease of the TMR indicating an impaired monolayer integrity. A similar reduction of extracellular Ca2+ through EGTA failed to reproduce these effects. Conversely, raising Ca2+ in diatrizoate-containing media to control levels did not abrogate its toxicity. In conclusion, the ionic RC agents diatrizoate and ioxaglate, but not the nonionic compounds iohexol or iodixanol, reduce extracellular Ca2+ in vitro. However, this reduction of Ca2+ does not explain their cytotoxic effects which could contribute to the pathogenesis of RCIN in vivo by opening intercellular junctions.

Keywords:
Radiocontrast, Calcium, Junctions, Transmonolayer resistance, Cytotoxicity
1.
Berns AS: Nephrotoxicity of contrast media. Kidney Int 1989;36:730–740.
2.
Heyman SN, Brezis M, Epstein FH, Spokes K, Silva P, Rosen S: Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991;40:632–642.
3.
Andersen KJ, Christensen EI, Vik H: Effects of iodinated X-ray contrast media on renal epithelial cells in culture. Invest Radiol 1994;11:955–962.
4.
Haller C, Schick CS, Zorn M, Kübler W: Cytotoxicity of radiocontrast agents on polarized renal epithelial cell monolayers. Cardiovasc Res 1997;33:655–665.
5.
Hizoh S, Sträter J, Schick CS, Kübler W, Haller C: Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: Role of hypertonicity. Nephrol Dial Transplant 1999;13:911–918.
6.
Schick CS, Haller C: Comparative cytotoxicity of ionic and non-ionic radiocontrast agents on MDCK cell monolayers in vitro. Nephrol Dialysis Transplant 1999;14:342–347.
7.
Eloy R, Corot C, Belleville J: Contrast media for angiography: Physicochemical properties pharmacokinetics and biocompatibility. Clin Mater 1991;7:89–197.
8.
Schrader R, Hoeft A, Hoeft T, Korb H, Wolpers HG, Kober G, Hellige G: Acute cardiac side effects of iodecol, a new nonionic dimer roentgen contrast medium, in intracoronary injection. Z Kardiol 1985;74:604–610.
9.
Wolpers HG, Baller D, Hoeft A, Korb H, Schrader R, Zipfel J, Hellige G: The effect of ion composition on cellular membrane potentials during selective coronary arteriography. Invest Radiol 1984;19:291–295.
10.
Dawson P: Cardiovascular effects of contrast agents. Am J Cardiol 1989;64:2E–9E.
11.
Gumbiner B: Cadherins: A family of Ca2+-dependent adhesion molecules. Trends Biochem Sci 1988;13:75–76.
12.
Kartenbeck J, Schmelz M, Franke WW: Endocytosis of junctional cadherins in bovine kidney epithelial (MDBK) cells cultured in low Ca2+ ion medium. J Cell Biol 1991;113:881–892.
13.
Thadhani R, Pascual M, Bonventre J: Acute renal failure. N Engl J Med 1996;334:1448–1460.
14.
Molitoris BA: New insights into the cell biology of ischemic acute renal failure. J Am Soc Nephrol 1991;1:1263–1270.
15.
Barrett BJ, Carlisle EJ: Meta-analysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188:171–178.
16.
Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA, Winniford M, Cohen MB, VanFossen DB: Nephrotoxicity of ionic and nonionic contrast media in 1,196 patients: A randomized trial. Kidney Int 1995;47:254–261.
17.
Humes HD, Hunt DA, White MD: Direct toxic effect of the radiocontrast agent diatrizoate on renal proximal tubule cells. Am J Physiol 1987;252:F246–F255.
18.
Baliga R, Ueda N, Walker PD, Shah SV: Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis 1997;29:465–477.
19.
Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oostuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, deRuiter MC, Gittenberger-deGroot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E: Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1999;98:147–157.
20.
Vleminckx K, Kemler R: Cadherins and tissue formation: Integrating adhesion and signaling. Bioassays 1999;21:211–220.
21.
Behrens J: Cadherins and catenins: Role in signal transduction and tumor progression. Cancer Metastasis Rev 1999;18:15–30.
22.
Cronin RE: Renal failure following radiologic procedures. Am J Med Sci 1989;298:342–356.
23.
Russo D, Minutolo R, Cianciaruso B, Memoli B, Conte G, Nicola LD: Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol 1995;6:1451–1458.
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2002
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