Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentrationtime curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p<0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p<0.001), whereas the spillover rate of NE increased from 33±5 to 63±11 pmolmln"' (p<0.05). Nitroprussideinduced increments in blood flow increased the spillover of NE from 18±4 to 35±6 pmolmin" 1 (/7<0.01); the clearance of circulating NE also increased (by 58%, p<0.05), and the intrinsic clearance capacity remained unchanged. This demonstrates that regional spillover of NE is markedly influenced by local changes in clearance and flow. The new parameter plasma appearance rate of NE is proposed. Although also derived from isotope dilution, this parameter may better approximate the regional entry of NE into the blood pool than spillover. This is corroborated by the nonsignificant changes of plasma appearance rate of NE during our desipramine and nitroprusside infusions. {Hypertension 1991;18:56-66) S ympathetic outflow may occur in a differentiated rather than in a global pattern. For instance, in the early stages of essential hypertension indications for a preferential increase in sympathetic nerve activity to the heart and kidneys have been found. 1 Therefore, adequate measures for organ sympathetic activity are needed. Venous plasma norepinephrine can provide only limited information of organ sympathetic nerve activity 12 because it reflects the balance between the sum of the input of norepinephrine (NE) into the organ via 1) the arterial inflow of NE and 2) the local release of NE and the organ clearance of locally From the Departments of Nephrology (P.CC, E.K., P.B.) and Pharmacology (J.A.K.), University of Leiden, The Netherlands.Supported by grant 84.082 of the Netherlands Heart Fo...

SUMMARY The relevance of local removal and release of norepinephrine (NE) for antecubital venous plasma NE concentration was studied in 22 healthy subjects. Arterial and venous plasma NE and forearm blood flow were measured during 1) intra-arterial infusion of two doses of NE, 2) intraarterial NE infusion with two doses of sodium nitroprusside, 3) intravenous infusion of NE with intraarterial infusion of four doses of sodium nitroprusside, and 4) lower body negative pressure of -2 0 mm Hg for 15 minutes. The venous plasma NE concentration-time curves during the infusions of the two doses of NE indicated first-order kinetics for forearm extraction: forearm NE extraction rate during the low dose infusion was 67 ± 4.1% (SEM) and correlated with basal forearm blood flow (r= -0.64, p<0.03, n= 12). Local sodium nitroprusside-induced vasodilatation during the intraarterial and intravenous NE infusions was accompanied by dose-dependent decreases in forearm extraction rates for NE and epinephrine. During lower body negative pressure, taking into account the high basal forearm extraction rate for NE, local and systemic release of NE was indicated by increases in arterial and venous plasma and the venous-arterial plasma NE concentration difference (p<0.05 for all). These data show that removal of NE from forearm circulation is a process with a high extraction ratio obeying first-order kinetics and that this extraction process inversely relates to forearm blood flow. Thus, antecubital venous plasma NE is likely to be derived mainly from local release and not from the arterial plasma NE input. (Hypertension 8: 801-809, 1986) KEY WORDS * plasma norepinephrine • plasma epinephrine • norepinephrine release norepinephrine extraction • epinephrine extraction • forearm blood flow • sodium nitroprusside • lower body negative pressure T HE plasma norepinephrine (PNE) concentration in blood taken from a forearm vein is a widely used estimate of overall sympathetic nervous system activity. Although several studies have shown a correlation between venous PNE and the activity of the sympathetic nervous system, 1 " 3 this approach has also been criticized. 4 -5 For instance, Mancia et al. 6 showed that alterations in sympathetic tone and blood pressure induced by manipulating the baroreflex were not reflected by alterations in plasma catecholamine concentrations. Also, during experimental mental stress, changes in sympathetic nerve activity are not paralleled by changes in venous PNE. From the Depts. of Nephrology

1. To define the role of circulating noradrenaline in cardiovascular regulation, threshold concentrations for haemodynamic effects were determined in arterial and venous plasma of eight healthy volunteers. 2. Five doses of noradrenaline, 0-54 ng min-1 kg-1, were infused intravenously in random order and single-blind for 15 min per dose. Changes in intra-arterial blood pressure, heart rate, forearm blood flow and forearm vascular resistance were determined, and plasma noradrenaline was measured in arterial and venous blood samples. 3. Significant increases in systolic and diastolic blood pressure were found at arterial and venous plasma noradrenaline concentrations (means +/- SEM) of 3.00 +/- 0.23 and 1.35 +/- 0.12 nmol/l, respectively. A significant decrease in heart rate was found at arterial and venous plasma noradrenaline concentrations of 8.99 +/- 0.69 and 3.09 +/- 0.60 nmol/l, respectively. The lower doses of noradrenaline tended to increase forearm blood flow and to decrease forearm vascular resistance, whereas the higher doses had no consistent effect on forearm haemodynamics. 4. During the noradrenaline infusions 73 +/- 5% of the increase in arterial plasma noradrenaline concentration was extracted in the forearm. 5. The venous plasma noradrenaline threshold concentration was found to be much lower than previously reported. It is concluded that arterial and venous plasma noradrenaline concentrations which are readily encountered in physiological circumstances elicit haemodynamic effects.

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Increases in plasma norepinephrine (NE) concentration induced by beta-agonist infusion have been taken as evidence for the existence of peripheral presynaptic beta-adrenoceptors, facilitating NE release. Concomitant hemodynamic changes, however, could invoke reflex mechanisms and thus hamper the interpretation of the results. We studied the presence of peripheral presynaptic beta-adrenoceptors by giving intra-arterial infusions of EPI in the forearm before and during uptake inhibition, and the effects of systemic infusions of very low-dose epinephrine (EPI) and isoproterenol (ISO) on hemodynamics and arterial and venous plasma NE concentrations. An i.a. infusion of EPI, 0.1 ng.kg-1.min-1, increased the net overflow of NE from 0.3 +/- 1.0 to 5.4 +/- 1.8 pmol.min-1 (M +/- SEM, p less than 0.05) and raised the calculated arterial plasma EPI concentration to 0.92 +/- 0.22 nmol.l-1. The uptake inhibition increased the net overflow of NE to 15.4 +/- 2.4 pmol.min-1 and during addition of EPI, 0.1 ng.kg-1.min-1, it further increased to 23.0 +/- 4.1 pmol.min-1 (p less than 0.05), while it decreased during addition of an effective beta-blocking dose of propranolol, 50 ng.kg-1.min-1 i.a., to 18.2 +/- 4.1 pmol.min-1 (n.s.). Systemic infusions of EPI and ISO increased blood pressure, heart rate, and forearm blood flow before significant changes in arterial or venous plasma NE concentrations were found. It is concluded that the increases in net NE overflow from the forearm during local EPI infusions indicate the presence of peripheral presynaptic beta-adrenoceptors which are responsive to physiologic concentrations of EPI. Systemic infusions of EPI or ISO elicit hemodynamic effects, and thus may invoke reflex mechanisms, before an influence on arterial or venous plasma NE concentration is found.