At least three endothelin receptor types may be characterized pharmacologically, ETA and ETB being most prominent in the heart. Cardiac cell types express ETA and ETB receptors differentially, as do comparable cells amongst species. ET receptors can couple to Gq and Gi-linked signaling pathways; thus, the primary effects of endothelin are activation of phosphoinositide hydrolysis via stimulation of the Gq-PLC pathway and activation of G¡ leading to inhibition of adenylyl cyclase; subunits of activated G¡ may also alter the properties of ion channels. As a consequence of endothelin’s effects on the Gq-PLC pathway, endothelin may secondarily activate numerous Ca++- dependent pathways in cells and cause the activation of autocrine and paracrine signaling systems, such as production of nitric oxide/cGMP, eicosanoids and cAMP and secretion of atrial natriuretic peptide. The interaction of endothelin with ETA receptors is quasi-irreversible, as are endothelin’s primary effects. Irreversibility and refractoriness to ET suggest a model in which the actions of endothelin are terminated by the development of an inaccessible ligand-ETA receptor complex rather than by simple dissociation. In addition to immediate effects, endothelin promotes gene induction and hypertrophic responses via activation of both G¡ and Gq-linked pathways.