Relationship Between Norepinephrine Transporter (NET) Potency and Hemodynamic Responses to Monoamine Reuptake Inhibitors in an Anesthetized Rat Model

Monoamine reuptake inhibitors (MRI) that inhibit transporters for serotonin (SERT) and/or norepinephrine (NET) produce hemodynamic effects of varying magnitudes in the clinic. Here, we used an anesthetized rat model to compare the potency to increase heart rate (HR) and mean arterial pressure (MAP) and to inhibit tyramine pressor response (TPR) of intraperitoneally‐dosed MRIs with a range of SERT and NET potencies and selectivities. In vitro SERT and NET potencies (IC50) were determined using a [3H]neurotransmitter uptake assay with rat synaptosomal preparations. With parallel pharmacokinetic studies, we estimated the plasma free drug concentrations required to produce 50% inhibition of TPR (Tyr EC50) or to induce a 10 mm Hg increase in MAP (MAP PC10) and a 25 bpm increase in HR (HR PC25). Esreboxetine, desipramine, atomoxetine, milnacipran, duloxetine and venlafaxine produced dose‐dependent decreases in TPR and increases in MAP and HR. TPR EC50 positively correlated (r2 = 0.9) with in vitro NET IC50 but not SERT IC50 (r2 = 0). Moreover, NET IC50 of the molecules also positively correlated with their HR PC25 (r2= 0.9) but not MAP PC10 (r2= 0.6). Milnacipran was an exception in that NET potency correlated with TPR EC50, but not with HR PC25. This model offers a simple and sensitive in vivo method for assessing the potency of MRIs to evoke mechanism‐based hemodynamic effects and to inhibit NE transporters in the periphery.