Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans

Abstract

A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n = 6), central sympathetic inhibition (clonidine, n = 4) and neuronal noradrenaline uptake blockade (desipramine, n = 13) and in a group of patients (n = 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 +/- 1.8, and 186.4 +/- 25 ng min(-1), respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min(-1) +/- 34.4 ng min(-1). As expected, trimethaphan infusion lowered brain noradrenaline spillover (P = 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P = 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P = 0.004), without changing brain metabolite overflow (P = 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P = 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P = 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P = 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow from the brain under these different circumstances indicates that the two measures arise from different sources, i.e. noradrenaline spillover originates from the cerebral vasculature outside the blood-brain barrier, and the noradrenaline metabolites originate primarily from brain noradrenergic neurons. We suggest that measurements of transcranial plasma noradrenaline spillover have utility as a method for assessing the sympathetic nerve activity of the cerebral vasculature.

Figure 1. Jugular venous noradrenaline spillover and whole body noradrenaline spillover

A, jugular venous noradrenaline spillover; *Trimethaphan intervention (P= 0.03); **clonidine intervention (P= 0.004). B, whole body noradrenaline spillover; **Healthy subjects vs. PAF (P < 0.001); **Trimethaphan (P= 0.01); **Clonidine (P= 0.008). When noradrenaline spillover rates from the brain (A) and for the whole body (B) was compared, both responded concordantly to the same interventions and study groups. Trimethaphan and clonidine infusions both lowered regional brain noradrenaline spillover and whole body noradrenaline spillover. Healthy subjects at rest had higher noradrenaline spillover from the brain and whole body noradrenaline spillover than PAF patients. All values are expressed as means ±s.e.m. PAF, pure autonomic failure.

Figure 2. Tritiated noradrenaline extraction across the cerebrovascular circulation in healthy subjects, PAF patients and with desipramine administration

Healthy vs. PAF (P= 0.4); **Desipramine intervention (P= 0.001). Tritiated noradrenaline extraction across the cerebral circulation was lowered significantly by desipramine infusion. In contrast, [³H]noradrenaline fractional extraction was only marginally lower in PAF patients, and not significantly so. Values are expressed as means ±s.e.m. All units are decimal fractions. PAF, pure autonomic failure.

Figure 3. Internal jugular venous metabolite overflow (MHPG and DHPG combined) from the brain in healthy and PAF subjects, and with trimethaphan administration

*Healthy vs. PAF (P= 0.3); **Trimethaphan (P= 0.01). Jugular venous noradrenaline metabolite overflow is discordant with the previously illustrated brain noradrenaline spillover rates and noradrenaline whole body spillover rates (Fig. 1), specifically trimethaphan infusion significantly elevated noradrenaline metabolite brain overflow, and noradrenaline metabolite overflow in PAF patients was not significantly different from that of healthy patients. Clonidine, not shown, did not alter noradrenaline metabolite overflow from the brain. All data are given in ng min⁻¹. PAF, pure autonomic failure.