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Cell volume is frequently down‐regulated by the activation of anion channels. The role of cell swelling‐activated chloride channels in cell volume regulation has been studied using the patch‐clamp technique and a non‐invasive microspectrofluorimetric assay for changes in cell volume. The rate of activation of these chloride channels was shown to limit the rate of regulatory volume decrease (RVD) in response to hyposmotic solutions. Expression of the human MDR1 or mouse mdr1a genes, but not the mouse mdr1b gene, encoding the multidrug resistance P‐glycoprotein (P‐gp), increased the rate of channel activation and the rate of RVD. In addition, P‐gp decreased the magnitude of hyposmotic shock required to activate the channels and to elicit RVD. Tamoxifen selectively inhibited both chloride channel activity and RVD. No effect on potassium channel activity was elicited by expression of P‐gp. The data show that, in these cell types, swelling‐activated chloride channels have a central role in RVD. Moreover, they clarify the role of P‐gp in channel activation and provide direct evidence that P‐gp, through its effect on chloride channel activation, enhances the ability of cells to down‐regulate their volume.

Glycoside-induced cardiac inotropy has traditionally been attributed to direct Na2+ -free solution) and in Na + -free solution (replaced by Li + ) the inotropic effects of DIG and ACS were completely prevented. In voltage-clamped cat myocytes, OUA increased Ca 2+ transients by 48 ± 4% but OUA had no effect in Na + -depleted cells (replaced by N -methyl-D-glucamine). In permeabilized cat myocytes, OUA did not change Ca 2+ spark frequency, amplitude or spatial spread (although spark duration was slightly prolonged). We conclude that the acute inotropic effects of DIG, ACS and OUA (and the effects on RyRs) depend on the presence of Na + and a functional NCX in ferret and cat myocytes (rather than alternate Na + -independent mechanisms).

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