AJP - Regulatory, Integrative and Comparative Physiology, Vol 268, Issue 6 1429-R1441, Copyright © 1995 by American Physiological Society
Sympatholytic effect of tricyclic antidepressants: site and mechanism of action in anesthetized rats
D. Huangfu, W. B. Goodwin and P. G. Guyenet
Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
Intravenous desipramine (DMI) and amitriptyline, but not fluoxetine, dose
dependently inhibited splanchnic sympathetic nerve discharge (sSND; -64 +/-
3% after 4 mg/kg iv DMI, 172 ng/ml plasma) in urethan-anesthetized
debuffered rats. Inhibition was reversed or prevented by microinjection of
the alpha 2-adrenergic receptor (alpha 2-AR) antagonist 2-methoxyidazoxan
(MOI) into the rostral ventrolateral medulla (RVLM, 1 nmol/side). sSND
inhibition (-58 +/- 12%) by baclofen (8 mg/kg iv, a gamma-aminobutyric
acid-B receptor agonist) was unaffected by MOI. MOI alone raised sSND 46
+/- 9%. Microinjection of 6-hydroxydopamine into the RVLM (2
micrograms/side, 10-13 days, to destroy noradrenergic terminals) did not
change the effect of intravenous DMI or MOI on sSND. Slow-firing
presympathetic neurons of the RVLM were activated by iontophoretic MOI (26
+/- 4%) and inhibited by 4 mg/kg iv DMI (-44 +/- 12%, effect reversed by
alpha 2-AR antagonists iv). We interpret these findings as follows: 1)
alpha 2-ARs in the RVLM are activated at rest, probably by catecholamines
released by C1 adrenergic cells, 2) this activation reduces sSND, 3) DMI
and amitriptyline reduce sSND by increasing alpha 2-AR activation in the
RVLM, and 4) these effects are due to neither serotonin uptake inhibition
nor blockade of norepinephrine uptake by noradrenergic fibers.
