Cutaneous vascular conductance (CVC) increases in response to local skin heating. While attenuation of vasoconstrictor responsiveness due to local heating has been demonstrated, the mechanism(s) responsible for this attenuation remain unclear. Nitric oxide has been shown to at least partially contribute to this response, but other mechanisms also may be involved. The purpose of this study was to test the hypothesis that local heating diminishes cutaneous vasoconstrictor responsiveness through a nitric oxide independent mechanism by altering post-synaptic reactivity to norepinephrine. A follow-up protocol tested the hypothesis that local heating attenuates the pre-synaptic release of neurotransmitters that cause vasoconstriction, also via non-nitric oxide mechanisms. Protocol I: in 8 subjects, CVC was assessed while increasing doses of norepinephrine (via intradermal microdialysis) were administered at adjacent sites separately heated to 34 and 40 °C. Protocol II: in an identical but separate protocol, in 7 subjects, CVC was assessed while increasing doses of tyramine, which causes release of neurotransmitters from adrenergic nerves, were administered. At each site for both protocols, nitric oxide synthesis was inhibited (via microdialysis administration of N ^G-nitro-L-arginine methyl ester) and flow was matched (via microdialysis administration of adenosine), leaving temperature as the only variable different between sites. For both protocols, non-linear regression analysis revealed no difference (P > 0.05) in the effective drug concentration causing 50% of the vasoconstrictor response. Minimum CVC (protocol I, mean ± SD: 6.3 ± 2.0 and 9.0 ± 4.0 %CVC_peak; protocol II: 19.3 ± 9.3 and 20.5 ± 11.9 %CVC_peak at the 34 and 40 °C sites, respectively) was not different between sites. Independent of nitric oxide, local skin heating to 40 °C does not attenuate adrenergically-mediated cutaneous vasoconstriction through pre- or post-synaptic mechanisms.