Endothelins stimulate sodium uptake into rat brain capillary endothelial cells through endothelin A-like receptors

Abstract

The effect of endothelins (ETs) on sodium/hydrogen (Na +/H +) antiport system was examined in cultured rat brain capillary endothelium (RBEC). ET 1, ET 2, and ET -3 stimulated Na + upptake into RBEC with similar half-maximal stimulation (EC 50) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na +/H + antiport inhibitor, N-(ethyl- N-isopropyl)-amiloride (EIPA). The selective endothelin A (ET A) receptor-antagonist (cyclo- d-Trp- d-Asp-Pro- d-Val-Leu (BQ123)), but not endothelin B (ET B) receptor-antagonists ((Cys 11, Cys 15)-ET l (IRL1038) or N-cis-2,6-dimethylpiperidinocarbonyl- l-γMeLeu- d-Trp(000Me)- d-Nle-ONa (BQ788)), inhibited both ET-1- and ET-3-stimulated Na + uptake, indicating ET A-receptor mediation. The protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA)) failed to stimulate Na + uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1-stimulated Na + uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of the Na +/H + antiport system is linked to a CaM-dependent and PKC-independent pathway.