It is widely accepted that sympathetic vasoconstriction is blunted in skeletal muscle during muscle contraction. This phenomenon is known as functional sympatholysis. It has been attributed to a particular vulnerability of the α₂ adrenoreceptor component of sympathetic stimulation that arises because local hypoxia can open the KATP channels on vascular smooth muscle that are closed by α₂-adrenoceptor stimulation, and to the action of nitric oxide (NO) that is generated by neuronal NO synthase (nNOS) expressed on the skeletal muscle fibres (Thomas & Segal, 2004). An apparently similar phenomenon occurs in skeletal muscle during systemic hypoxia. Thus, systemic hypoxia induces an increase in muscle sympathetic nerve activity (MSNA), attributable to peripheral chemoreceptor stimulation, but the predominant response is muscle vasodilatation (see Ray et al, 2004). We have attempted to elucidate these local-sympathetic interactions in experiments that were approved under current UK Home Office Legislation. By applying intravital microscopy to the spinotrapezius muscle of anaesthetised rats, we showed that although many arterioles dilate during systemic hypoxia, others constrict and local α-adrenoceptor blockade accentuates the dilatator, and reverses the constrictor responses. Thus, sympathetic vasoconstriction is not completely blunted during systemic hypoxia. We have since developed the spinotrapezius muscle preparation to allow focal recordings of MSNA from the surface of identified muscle arterial vessels. These recordings show the typical cardiac- and respiratory-related rhymicity of MSNA. During graded levels of systemic hypoxia these rhythmicities persist, concomitant with hypoxia-evoked increase in respiration and fall in arterial pressure. Moreover, the frequency of MSNA increased in a graded manner such that instantaneous frequencies in discriminated single fibres reached as high as 20-40Hz. And yet, blood flow recorded from the main artery that supplies the spinotrapezius, showed a graded increase in muscle vascular conductance indicating progressive vasodilatation (Hudson, 2008) as occurs in hindlimb muscle (Ray et al, 2004). In other experiments we used activity recorded from sympathetic fibres on arterial vessels, or patterns of impulses modelled on specific components of this activity, to stimulate the lumbar sympathetic chain (LSC). By using appropriate pharmacological antagonists, we showed that in normoxia, the vasoconstriction evoked in hindlimb muscle by low and high frequencies and by short and longer trains of impulses is mediated by the actions of noradrenaline and ATP which act synergistically and that at frequencies >20Hz, NPY acting on Y1 receptors contributes (Johnson et al, 2001). However when the LSC was stimulated continuously at 2Hz or with bursts of impulses at 20 or 40 Hz so as to deliver the same number of pulses in 1 minute, the evoked vasoconstrictor response was blunted in a graded manner by graded systemic hypoxia, the vasoconstriction evoked by constant, low frequency stimulation being most vulnerable (Coney & Marshall, 2003). Although ~50% of the muscle vasodilatation induced by systemic hypoxia is mediated by adenosine acting on A1 receptors via a pathway that involves PGI₂ and depends on the new synthesis of NO (Ray et al, 2004), blockade of A₁ or A_2A receptors did not reverse the hypoxia-induced blunting of sympathetic vasoconstriction (Coney & Marshall, 2003). Moreover the blunting was unchanged after NOS blockade, providing the tonic dilator influence of NO was restored by infusion of NO donor. Notably, there was no evidence that NO generated by nNOS contributed to the blunting of sympathetic vasoconstriction associated with systemic hypoxia (Coney et al, 2004). However, we recently found that the component of sympathetic vasoconstriction that approximately 50% of the blunting of sympathetic vasoconstriction that occurs during systemic hypoxia is attributable to loss of the α₂-adrenoceptor component, whereas the component mediated by NPY on Y1 receptors during burst at 20 or 40 Hz, persists, more or less unchanged (Coney & Marshall, 2007). Thus, it seems that the blunting of sympathetic vasoconstriction that occurs in muscle during systemic hypoxia does not involve the actions of the major dilators that are released during hypoxia; adenosine or NO, but does involve a particular vulnerability of the α₂-adrenoceptor component of the actions of noradrenaline. On the other hand, the component of sympathetic vasoconstriction that is attributable to NPY is resistant to systemic hypoxia, so ensuring that muscle vascular resistance can contribute to the regulation of arterial pressure when MSNA reaches high frequencies.