Dexfenfluramine increases pulmonary smooth muscle intracellular Ca2+ independent of membrane potential

The anorexic agent dexfenfluramine causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism that may include changes in K+-channel activity and intracellular Ca2+ concentration ([Ca2+](i)). We investigated the dose-dependent effects of dexfenfluramine on [Ca2+](i), K+ current, and membrane potential in freshly dispersed rat pulmonary artery smooth muscle cells, Dexfenfluramine caused a dose-dependent (1-1,000 mu M) increase in [Ca2+](i), even at concentrations lower than those necessary to inhibit K+ currents (100 mu M) and cause membrane depolarization (100 PM) The [Ca2+](i) response to 1 and 10 mu M dexfenfluramine was completely abolished by pretreatment of the cells with 0.1 mu M thapsigargin; whereas the response to 100 mu M dexfenfluramine was reduced. CoCl2 (1 mM), removal of extracellular Ca2+, and pretreatment with caffeine (1 mM) reduced but did not abolish the response to 100 mu M dexfenfluramine. We conclude that dexfenfluramine increases [Ca2+](i) in rat pulmonary artery smooth muscle cells by both release of Ca2+ from the sarcoplasmic reticulum and influx of extracellular Ca2+.