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The sympathetic reflex response to mechanical ventilation with PEEP was studied in conscious human volunteers (n = 8). Muscle sympathetic nerve activity (MSNA) was measured from the peroneal nerve, calf blood flow, forearm venous plasma catecholamines, blood pressure, heart rate, airway pressure, and end-tidal CO2 (%) during spontaneous breathing and during mechanical ventilation with 0-20 cmH2O PEEP. MSNA increased (P less than 0.01) during PEEP ventilation, from 22 bursts.min-1 at spontaneous breathing to 39 bursts.min-1 at 20 PEEP. This increase in MSNA was accompanied by an increase (P less than 0.01) in calf vascular resistance (CVR) from 35 PRU100 at spontaneous breathing to 48 PRU100 at 15 PEEP with no further increase at 20 PEEP. Venous plasma norepinephrine concentrations increased (P less than 0.01) during PEEP ventilation from 0.19 ng.ml-1 at spontaneous breathing to 0.31 ng.ml-1 at 20 PEEP, whereas plasma epinephrine and dopamine were less than 0.03 ng.ml-1 during the experiment. Blood pressure and heart rate were not affected by PEEP ventilation except at 20 PEEP, where blood pressure and heart rate increased (P less than 0.01). The results show that PEEP ventilation induces a considerable reflex increase of MSNA, reflected also by an increase in CVR and venous plasma norepinephrine. It is proposed that the main mechanism responsible for these reflex adjustments is caused by a decreased activity of the cardiopulmonary low-pressure baroreceptors, in turn resulting from a decrease in cardiac transmural pressures due to PEEP ventilation.