Hypertension, Vol 18, 56-66, Copyright © 1991 by American Heart Association
PC Chang, E Kriek, JA van der Krogt and P van Brummelen
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 concentration-time 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 less than 0.01) during neuronal uptake
blockade by desipramine; the forearm clearance decreased by 59% (p less
than 0.001), whereas the spillover rate of NE increased from 33 +/- 5 to 63
+/- 11 pmol.min-1 (p less than 0.05). Nitroprusside-induced increments in
blood flow increased the spillover of NE from 18 +/- 4 to 35 +/- 6
pmol.min-1 (p less than 0.01); the clearance of circulating NE also
increased (by 58%, p less than 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.
ARTICLES
Does regional norepinephrine spillover represent local sympathetic activity?
Department of Nephrology, University of Leiden, The Netherlands.
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