The aim of the present study was to investigate the impact of isoflurane on regional neurogenic mechanisms in the control of vascular tone. Therefore, regional determinations of sympathetic activity and hemodynamics were made in chloralose-anesthetized swine before and during administration of 1.4% isoflurane. Sympathetic activity was examined from spillover of norepinephrine (NE) into the circulation using an isotope dilution technique. Administration of isoflurane caused a marked decrease in mesenteric (65 ± 9 pmol · min-1 · 100 g-1; P < 0.05) NE spillover. Renal NE spillover was moderately decreased (25 ± 6 pmol · min-1 · 100 g-1; P < 0.05), whereas liver NE spillover did not change significantly during isoflurane administration, suggesting that liver sympathetic activity is maintained at this level of isoflurane anesthesia. Total body NE spillover decreased (13 ± 2 pmol · min-1 · 100 g-1, P < 0.05). Thus, isoflurane affected sympathetic outflow in a regionally differentiated pattern. Significant correlations were found between total body, mesenteric, and renal NE spillovers and vascular resistances, supporting the concept that the observed reductions in vascular resistances in these circulations during isoflurane administration were in part a consequence of reduced sympathetic outflow. In the liver circulation, no correlation was found between NE spillover and liver portal or liver arterial vascular resistances. Liver arterial resistance was significantly reduced during isoflurane administration while liver portal resistance was unchanged. Administration of isoflurane caused reductions in cardiac output, renal, portal, hepatic arterial, and total hepatic blood flows, whereas mesenteric blood flow was unchanged. To summarize, isoflurane decreased mesenteric and renal NE spillover with concomitant reductions in vascular resistances. Liver NE spillover was, however, not changed, and no correlations to hepatic arterial and hepatic portal resistances were found. Thus, the effect of 1.4% isoflurane on sympathetic discharge and hemodynamics showed a differential pattern.