title: Sympatholytic effect of tricyclic antidepressants: site and mechanism of action in anesthetized rats.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
authors.forename: D
authors.initials: D
authors.lastname: Huangfu
authors.forename: W B
authors.initials: WB
authors.lastname: Goodwin
authors.forename: P G
authors.initials: PG
authors.lastname: Guyenet
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001931:Brain Mapping; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D019329:Idazoxan / Q000031:analogs & derivatives; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D008771:Nordefrin / Q000494:pharmacology; D016627:Oxidopamine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013153:Splanchnic Nerves / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000929:Antidepressive Agents, Tricyclic; D004146:Dioxanes; D007093:Imidazoles; D013565:Sympatholytics; D005473:Fluoxetine; C050701:atipamezole; D000639:Amitriptyline; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; C058525:2-methoxyidazoxan; D001418:Baclofen; D008771:Nordefrin; D003891:Desipramine; D019329:Idazoxan