Objective:To test whether the activation of the sympathetic nervous system that is common in essential hypertension derives from subcortical noradrenergic neuronal excitation.Design and methods:We performed a radionuclide cerebral venous sinus scan, using technetium-99m, to establish which internal jugular vein predominantly drained the cortical (the major jugular vein) and which the subcortical (minor jugular vein) brain regions. Blood samples were then collected simultaneously from catheters placed percutaneously in the brachial artery or radial artery and high in the internal jugular vein in 11 untreated hypertensive patients and 18 normotensive subjects, for determination of the plasma concentrations of noradrenaline, its precursor dihydroxyphenylalanine (DOPA) and its metabolite dihydroxyphenylglycol (DHPG) to calculate their rates of overflow into the cerebrovascular circulation.Results:In normotensive subjects blood flow determined by thermodilution was significantly higher in the major than in the minor jugular vein. The noradrenaline spillovers into the major and minor jugular veins calculated during infusions of L-[3H]-7-noradrenaline were similar in healthy subjects. The noradrenaline spillover from subcortical regions into the minor jugular vein was significantly higher in the hypertensives than in the normal subjects, as was the overflow of DHPG. In contrast, cortical noradrenaline and DHPG overflows into the major jugular vein were similar in hypertensive and normotensive subjects. Overflow of DOPA into the minor jugular vein, which derives largely from precursor turnover in dopaminergic neurons, was similar in hypertensive and normotensive subjects. Subcortical noradrenaline spillover correlated with neurochemical indices of sympathetic nervous system activity, with total body noradrenaline spillover (r=0.56,P<0.05) in normal and hypertensive subjects combined, and with renal noradrenaline spillover in the six hypertensive patients tested (r=0.91,P<0.05).Conclusion:These results suggest that increased subcortical noradrenaline release is a possible cause of peripheral sympathetic activation in essential hypertension.