Ubiquitously expressed volume‐regulated anion channels (VRACs) are chloride channels which are permeable to a variety of small organic anions, including the excitatory amino acids (EAAs) glutamate and aspartate. Broad spectrum anion channel blockers strongly reduce EAA release in cerebral ischaemia and other pathological states associated with prominent astrocytic swelling. However, it is uncertain whether VRAC serves as a major pathway for EAA release from swollen cells. In the present study, we measured swelling‐activated release of EAAs as d‐[³H]aspartate efflux, and VRAC‐mediated Cl⁻ currents by whole‐cell patch clamp in cultured rat astrocytes. We compared the pharmacological profiles of the swelling‐activated EAA release pathway and Cl⁻ currents. The expression of candidate Cl⁻ channels was confirmed by RT‐PCR. The maxi Cl⁻ channel (p‐VDAC) blocker Gd³⁺, the ClC‐2 inhibitor Cd²⁺, and the MDR‐1 blocker verapamil did not affect EAA release or VRAC currents. An antagonist of calcium‐sensitive Cl⁻ channels (CaCC), niflumic acid, had little effect on EAA release and only partially inhibited swelling‐activated Cl⁻ currents. The phorbol ester PDBu, which blocks ClC‐3‐mediated Cl⁻ currents, had no effect on VRAC currents and up‐regulated EAA release. In contrast, DCPIB, which selectively inhibits VRACs, potently suppressed both EAA release and VRAC currents. Two other relatively selective VRAC inhibitors, tamoxifen and phloretin, also blocked the VRAC currents and strongly reduced EAA release. Taken together, our data suggest that (i) astrocytic volume‐dependent EAA release is largely mediated by the VRAC, and (ii) the ClC‐2, ClC‐3, ClC‐4, ClC‐5, VDAC, CaCC, MDR‐1 and CFTR gene products do not contribute to EAA permeability.

High salt consumption contributes to the development of hypertension and is considered an independent risk factor for vascular remodeling, cardiac hypertrophy, and stroke incidence. In this review, we discuss the molecular origins of primary sensors involved in the phenomenon of salt sensitivity. Based on the analysis of literature data, we conclude that the kidneys and central nervous system (CNS) are two major sites for salt sensing via several distinct mechanisms: 1) [Cl⁻] sensing in renal tubular fluids, primarily by Na⁺-K⁺-Cl⁻cotransporter (NKCC) isoforms NKCC2B and NKCC2A, whose expression is mainly limited to macula densa cells; 2) [Na⁺] sensing in cerebrospinal fluid (CSF) by a novel isoform of Na⁺channels, Na_x, expressed in subfornical organs; 3) sensing of CSF osmolality by mechanosensitive, nonselective cation channels (transient receptor potential vanilloid type 1 channels), expressed in neuronal cells of supraoptic and paraventricular nuclei; and 4) osmolarity sensing by volume-regulated anion channels in glial cells of supraoptic and paraventricular nuclei. Such multiplicity of salt-sensing mechanisms likely explains the differential effects of Na⁺and Cl⁻loading on the long-term maintenance of elevated blood pressure that is documented in experimental models of salt-sensitive hypertension.