Inhibition of uptake 1 by (+)-oxaprotiline reveals a differential central regulation of noradrenaline and adrenaline release.
Inhibition of uptake 1 in the central nervous system leads to a decrease of sympathetic outflow to many tissues; central alpha 2-adrenoceptors are involved in this decrease. The aim of the present study was to compare the effects of the selective uptake 1 inhibitor (+)-oxaprotiline on the plasma kinetics of noradrenaline and adrenaline in anaesthetized and in conscious rabbits. [3H]Noradrenaline and [3H]adrenaline were infused i.v. The arterial plasma concentrations of endogenous and radiolabelled noradrenaline and adrenaline were measured, and the clearance from and spillover into the plasma of noradrenaline and adrenaline were calculated. Results obtained in conscious and anaesthetized rabbits were similar. (+)-Oxaprotiline 0.2, 0.6 and 1.8 mg kg-1 i.v. dose-dependently reduced the clearance of [3H]noradrenaline from the plasma. The clearance of [3H]adrenaline was reduced less. The spillover of endogenous noradrenaline was decreased by up to 35%. In contrast, the spillover of adrenaline tended to be enhanced. Prazosin 0.1 and 1 mg kg-1 was injected i.v. in a second part of each experiment. It lowered the blood pressure and caused a marked increase in noradrenaline spillover but no increase or even a decrease in adrenaline spillover. The results are compatible with the following hypothesis. The sympathetic outflow from the central nervous system is subject to a twofold alpha-adrenoceptor-mediated modulation: alpha 2-adrenoceptor-mediated inhibition and alpha 1-adrenoceptor-mediated excitation. In the control of the sympathetic outflow to many extra-adrenal tissues, the alpha 2-adrenergic inhibition prevails. Uptake 1 inhibitors depress sympathetic outflow to such tissues by enhancing the alpha 2-adrenergic inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Szabo
B
B
Pharmakologisches Institut, Albert-Ludwigs-Universität, Freiburg, Germany.
Auberle
T
T
Starke
K
K
D000758:Anesthesia; D000818:Animals; D000928:Antidepressive Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood / Q000378:metabolism*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008376:Maprotiline / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects
D000928:Antidepressive Agents; D018341:Receptors, Adrenergic, alpha-2; D008376:Maprotiline; C027299:hydroxymaprotilin; D009638:Norepinephrine; D011224:Prazosin; D004837:Epinephrine