Swelling‐activated cation channels mediate depolarization of rat cerebrovascular smooth muscle by hyposmolarity and intravascular pressure

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Abstract
Increases in intravascular pressure depolarize vascular smooth muscle cells. Based on the attenuating effects of Cl− channel antagonists, it has been suggested that swelling-activated Cl− channels may be integral to this response. Consequently, this study tested for the presence of a swelling-activated Cl− conductance in both intact rat cerebral arteries and isolated rat smooth muscle cells. A 50 mosmol l−1 hyposmotic challenge (300 to 250 mosmol l−1) constricted rat cerebral arteries. This constriction contained all the salient features of a pressure-induced response including smooth muscle cell depolarization and a rise in intracellular Ca2+ that was blocked by voltage-operated Ca2+ channel antagonists. The hyposmotically induced depolarization was attenuated by DIDS (300 μm) and tamoxifen (1 μm), a response consistent with the presence of a swelling-activated Cl− conductance. A swelling-activated current was identified in cerebral vascular smooth muscle cells. This current was sensitive to Cl− channel antagonists including DIDS (300 μm), tamoxifen (1 μm) and IAA-94 (100 μm). However, contrary to expectations, the reversal potential of this swelling-activated current shifted with the Na+ equilibrium potential and not the Cl− equilibrium potential, indicating that the swelling-activated current was carried by cations and not anions. The swelling-activated cation current was blocked by Gd3+, a cation channel antagonist. Gd3+ also blocked both swelling- and pressure-induced depolarization of smooth muscle cells in intact cerebral arteries. These findings suggest that swelling- and pressure-induced depolarization arise from the activation of a cation conductance. This current is inhibited by DIDS, tamoxifen, IAA-94 and gadolinium.