Cutaneous vascular conductance (CVC) declines in response to local cooling (LC). Previous work indicates that at least part of the vasoconstrictor response to LC may be through an inhibitory effect on nitric oxide synthase (NOS) activity. In this study we further tested that notion. A total of eight (6 male, 2 female) subjects participated (Part 1 n= 7; Part 2 n= 5, 4 of whom participated in Part 1). Skin blood flow was monitored by laser-Doppler flowmetry. Control of local skin and body temperatures was achieved with Peltier cooler/heater probe holders and water perfused suits, respectively. Microdialysis fibres were inserted aseptically. Saline, L-NAME (20 mM; to inhibit NOS activity) and sodium nitroprusside (SNP 10 μM) were infused by microdialysis. Bretylium tosylate (BT), to block adrenergic function, was administered by iontophoresis. CVC was calculated from blood flow and blood pressure. Part 1 was designed to determine the relative roles of the NO and the adrenergic systems. The infusion of L-NAME elicited a 35 ± 4% decrease in CVC at the L-NAME and BT +L-NAME sites (P < 0.05); subsequent slow LC (34–24°C) for 35 min caused a significant (P < 0.05) decrease in CVC at control sites (68 ± 4%) and at the BT treated sites (39 ± 5%). LC caused a further 23 ± 5% of initial baseline decrease in CVC at the L-NAME treated sites (P < 0.05). Importantly, CVC at the BT +L-NAME sites was unaffected by LC (P > 0.05). Part 2 was designed to test whether LC influences were specific to the NOS enzymes. Two sites were pretreated with both BT and L-NAME. After 50 min, SNP was added as an NO donor to restore baseline CVC at one site. The same LC process as in Part 1 was applied. There was a 24 ± 10% decrease (P < 0.05) in CVC at sites with baseline CVC restored, while, as in Part 1, there was no change (P > 0.05) at sites treated with BT +L-NAME only. These data suggest that the vasoconstriction with slow LC is due to a combination of increased noradrenaline release and decreased activity of both NOS per se and of process(es) downstream of NOS.