Fluoxetine and venlafaxine cause K+ current inhibition but minimal membrane depolarization in rat Pulmonary Artery Smooth Muscle Cells (PASMCs). A contrast to dexfenfluramine (Dex)

Dex, a serotonin-releasing agent and reuptake inhibitor, is associated with an increased risk for primary pulmonary hypertension (PPH), unlike fluoxetine, a serotonin reuptake inhibitor and venlafaxine, an inhibitor of both serotonin and norepinephrine reuptake. Since Dex inhibits voltage-dependent K+ channels and causes membrane depolarization in PASMCs, we investigated the effects of fluoxetine and venlafaxine on K+ currents (IK) and membrane potential recorded from freshly dispersed PASMCs. Fluoxetine caused dose-dependent inhibition of IK, with 79.8±3% of the current inhibited by 30μM at +50mV (n=6). At the same potential, 30μM Dex inhibited IK by 25.6±6% (n=6). Despite marked inhibition of IK, 100μM fluoxetine depolarized cells from their resting membrane potential (RMP ∼-50mV) by only 3.6±1mV (n=7). In contrast, when cells were held at a more positive potential of -30mV, 100μM fluoxetine caused 18.3±3mV depolarization (n=3). Dex (100μM) depolarized the cell membrane from its RMP by 14.2±3mV. Venlafaxine also caused dose-dependent inhibition of IK but was less effective than fluoxetine with only 22.7±1% of IK inhibited at 30μM (n=3, +50mV). It also had little effect on RMP (5.0±2mV depolarization by 100μM, n=4).These data suggest that fluoxetine and venlafaxine differ from Dex in their ability to inhibit IK at RMP and thus cause membrane depolarization in PASMC and initiate vasoconstriction. This difference may explain the apparent lack of PPH with reuptake inhibitors, despite their widespread use as antidepressants.