Abstract
This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured endothelium derived from capillaries of human brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl− cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ETA but not ETB receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ETA receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC.
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REFERENCES
Inoue, A. M., Yanagisawa, M., Kimura, S., Kasuya, V., Miyachi, T., Goto, K., and Masaki, T. 1989. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc. Natl. Acad. Sci. USA 86:2853-2867.
Rubanyi, G. M. and Polokoff, M. A. 1994. Endothelins: molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmcol. Rev. 46:325-415.
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., and Masaki, T. 1988. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (London) 332:411-415.
Bacic, F., Uematsu, S., McCarron, R. M., and Spatz, M. 1992. Secretion of immunoreactive endothelin-1 by capillary and microvascular endothelium of human brain. Neurochem. Res. 17:699-702.
Giaid, A., Gibson, S. J., Herrero, M. T., Gentleman, S., Legon, S., Yanagisawa, M., Masaki, T., Ibrahim N. B. N., Roberts, G. W., Rossi, M. L., and Polak, J. M. 1991. Topographical localization of endothelin mRNA and peptide immunoreactivity in neurons of the human brain. Histochemistry 95:303-314.
MacCumber, M. W., Ross, C. A., and Snyder, S. H. 1990. Endothelin in brain: Receptors, mitogenesis, and biosynthesis in glial cells. Proc. Natl. Acad. Sci. USA 87:2359-2363.
Spatz, M., Kawai, N., Merkel, N., Bembry, J., and McCarron, R. M. 1997. Functional properties of cultured endothelial cells derived from large microvessels of human brain. Am. J. Physiol. 41:C231-C239.
Yoshimoto, S., Ishizaki, Y., Kurihara, H., Sasaki, T., Yoshizumi, M., Yanagisawa, M., Yazaki, Y., Masaki, T., Takakura, K., and Murota, S. 1990. Cerebral microvessel endothelium is producing endothelin. Brain Res. 508:283-285.
Kawai, N., McCarron, R. M., and Spatz, M. 1995. Endothelins stimulate sodium uptake into rat brain capillary endothelial cells through endothelin A-like receptors. Neurosci. Lett. 190:85-88.
Kawai, N., Yamamoto, T., Yamamoto, H., McCarron, R. M., and Spatz, M. 1995. Endothelin 1 stimulates Na+, K+-ATPase and Na+-K+-Cl− cotransport through ETA receptors and protein kinase C-dependent pathway in cerebral capillary endothelium. J. Neurochem. 65:1588-1596.
Kawai, N., McCarron, R. M., and Spatz, M. 1996. Na+-K+-Cl-cotransport system in brain capillary endothelial cells: Response to endothelin and hypoxia. Neurochem. Res. 21:1259-1266.
Renterghem, C. V., Vigne, P., and Frelin, C. 1995. A charybdotoxin-sensitive, Ca2+-activated K+ channel with inward rectifying properties in brain microvascular endothelial cells: properties and activation by endothelins. J. Neurochem. 65:1274-1281.
Vigne, P., Landoux, A., and Frelin, C. 1991. Endothelins activate Na+/H+ exchange in brain capillary endothelial cells via a high affinity endothelin-3 receptor that is not coupled to phospholipase C. J. Biol. Chem. 266:5925-5928.
Vigne, P., Desmarets, J., Guedin, D., and Frelin, C. 1996. Properties of an endothelin-3-sensitive ETA-like endothelin receptor in brain capillary endothelial cells. Biochem. Biophys. Res. Comm. 220:839-842.
Stanimirovic, D. B., Yamamoto, T., Uematsu, S., and Spatz, M. 1994. Endothelin-1 receptor binding and cellular signal transduction in cultured human brain endothelial cells. J. Neurochem. 62:592-601.
Muldoon, L. L., Enslen, H., Rodland, K. D., and Magun, B. E. 1991. Stimulation of Ca2+ influx by endothelin-1 is subject to negative feedback by elevated intracellular Ca2+ Am. J. Physiol. 260:C1273-C1281.
Stanimirovic, D. B., Nikodijevic, B., Nikodijevic-Kedeva, D., McCarron, R. M., and Spatz, M. 1994. Signal transduction and calcium uptake activated by endothelins in rat brain endothelial cells. Eur. J. Pharmacol. 288:1-8.
Vigne, P., Farre, A. L., and Frelin, C. 1994. Na+-K+-Cl− cotransporter of brain capillary endothelial cells. J. Biol. Chem. 269:19925-19930.
Zlokovic, B. V., Mackic, J. B., Wang, L., McComb, J. G., and McDonough, A. 1993. Differential expression of Na, K-ATPase α and β subunit isoforms at the blood-brain barrier and the choroid plexus. J. Biol. Chem. 268:8019-8025.
Betz, A. L., Keep, R. F., Beer, M. E., and Ren, X. 1994. Blood-brain barrier permeability and brain concentration of sodium, potassium, and chloride during focal ischemia. J. Cereb. Blood Flow Metab. 14:29-37.
Ehrenreich, H., Lange, M., Near, K. A., Aneser, F., Schoeller, L. A., Schmid, R., Winkler, P. S., Kehrl, J. H., Schmiedek, P., and Goebel, F. D. 1992. Long-term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-hr urine of patients with subarachnoid hemorrhage. Res. Exp. Med. 192:257-268.
Mrsulja, B. B., Djuricic, B. M., Cvejic, V., Mrsulja, B. J., Abe, K., Spatz, M., and Klatzo, I. 1980. Biochemistry of experimental ischemic brain edema. In Advances in neurology, Vol. 28, Cervos-Navarro, J. and Fersz, R. (ed), pp 217-230. Raven Press, New York.
Mrsulja, B. B., Micic, D. V., and Djuricic, B. M. 1983. Gerbil stroke model: an approach to the study of therapeutic aspects of postischemic brain edema. Pages 45-62, in Stefanovich, V. (ed.), Advances in the Biosciences, Vol. 43, Stroke: Animal Models, Oxford, Pergamon Press.
Barone, F. C., Globus, M.Y-T., Price, W. J., Storer, B. L., Feuerstein, G. Z., Busto, R., and Ohlstein, E. H. 1994. Endothelin levels increase in rat focal and global ischemia. J Cereb. Blood Flow Metab. 14:337-342.
Spatz, M., Yasuma, Y., Strasser, A., and McCarron, R. M. 1996. Cerebral postischemic hypoperfusion is mediated by ETA receptors. Brain Res. 726:242-246.
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Spatz, M., Kawai, N., Bembry, J. et al. Human Brain Capillary Endothelium: Modulation of K+ Efflux and K+, Ca2+ Uptake by Endothelin. Neurochem Res 23, 1125–1132 (1998). https://doi.org/10.1023/A:1020772422266
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DOI: https://doi.org/10.1023/A:1020772422266