We report that the endothelins, a newly described family of vasoactive peptides, have a profound effect on intracellular calcium levels of cultured rat hippocampal astrocytes that resembles the effect of endothelin (ET) on vascular smooth muscle cells (VSMCs) in many respects. The astrocyte's response has two components that can be distinguished by their extracellular calcium requirement and time course. Within seconds of application, ET induces a transient calcium spike that corresponds to a release of calcium from internal stores. The second component follows immediately, is dependent upon extracellular calcium, and maintains an elevated intracellular calcium level for many minutes. Sustained elevations of intracellular calcium can dramatically alter astrocyte morphology and induce cell division in many other cell types. ET may serve these functions, and thus form a communication link between blood vessels and neurons through astrocytes.