Screening for novel drug effects with a microphysiometer: A potent effect of clofilium unrelated to potassium channel blockade

Changes in cellular metabolism in response to pharmacological compounds can be detected using a biosensor known as a microphysiometer, which measures the rate at which cells release acidic metabolites. We have applied this technique to screen for effects of cation channel blockers on the metabolism of a variety of human and murine cell lines. At concentrations sufficient for cation channel blockade, most of these drugs have little or no effect on cellular metabolism as measured by acid release. In contrast, the potassium channel blocker clofilium triggers sustained increases in acid release at low (> or = 3 microM) concentration. Acid release persists in media containing high (150 mM) extracellular potassium. This release is not triggered by chemically similar potassium channel blockers. Thus these metabolic effects reflect a potent and specific function of clofilium which is unrelated to potassium channel blockade. Attempts to identify physiological correlates to this response revealed that low concentrations of clofilium but not other potassium channel blockers cause lymphoma apoptosis. These findings demonstrate that effects of clofilium found in other studies may not be due to changes in plasma membrane potassium conductance.