Activation of inwardly‐rectifying potassium (KIR) channels and Na+/K+‐ATPase regulates muscle blood flow during mild exercise; whether these pathways are involved in the blunting of sympathetic α‐adrenergic vasoconstriction in active muscle is unknown. We tested the hypothesis that α1‐adrenergic vasoconstriction (phenylephrine; PE) is augmented during exercise after inhibition of KIR channels and Na+/K+‐ATPase. Young adults (n=11) were instrumented with a brachial artery catheter (drug infusions and blood pressure) and forearm blood flow (Doppler ultrasound) was measured and vascular conductance (FVC) calculated at rest, during minute 4 of steady‐state hyperemic conditions (moderate handgrip exercise or adenosine; ADO), and after 2 min of PE in these conditions: control (saline), combined inhibition of nitric oxide (NO; L‐NMMA) and prostaglandins (PGs; ketorolac) and combined inhibition of NO, PGs, KIR channels and Na+/K+‐ATPase (L‐NMMA+ketorolac+BaCl2+ouabain). In control, exercise blunted PE‐mediated vasoconstriction (%ΔFVC) compared to ADO (‐21±3% vs ‐46±6%; P<0.05) and this was unchanged with L‐NMMA+ketorolac (‐24±3% vs ‐47±5%). The addition of BaCl2+ouabain had no effect on vasoconstriction during exercise (‐27±3%), indicating that activation of KIR channels and Na+/K+‐ATPase is not obligatory to blunt sympathetic vasoconstriction in contracting human muscle.Support HL102720