Characterization of the inhibitory effect of some antidepressant drugs on the outward transport of norepinephrine in the ischemic myocardium.
The noradrenergic amine carrier has an important role in mediating the local release of norepinephrine (NE) during myocardial ischemia. The effects of the antidepressant or putative antidepressant drugs desipramine, 2-hydroxy desipramine, nisoxetine, (S)-oxaprotiline and (R)-oxaprotiline with respect to this release mechanism were investigated in the isolated rat heart submitted to total stop-flow ischemia and subsequent reperfusion. During the reperfusion phase a massive efflux of NE was observed, which was reduced in a concentration-dependent manner in the presence of the antidepressant drugs. The potency (pIC50) of the antidepressants in inhibiting the ischemia-induced NE release varied between 9.16 (desipramine) and 6.17 [(R)-oxaprotiline]. On the other hand, lidocaine (10 microM) or clonidine (1 microM) did not reduce the magnitude of the NE efflux. No attenuation in NE efflux could be detected when desipramine (0.1 microM) was present only during the reperfusion period. During repeated periods (3 x 20 min) of ischemia, desipramine (0.1 microM) reduced markedly the loss of NE. In another experiment in the isolated guinea pig heart, desipramine (0.1 microM) was also found to attenuate the ischemia-induced mobilization of NE to the same significant extent as in the isolated perfused rat heart. Chronic treatment (3 weeks) of rats with desipramine as well as acute administration of desipramine to rats (2 hr before the initiation of perfusion) caused a pronounced reduction in the ischemia-induced release of NE in the isolated perfused heart. In conclusion, these experiments strongly suggest that a major part of the ischemia-induced release of NE is mediated by the amine carrier associated with the noradrenergic nerve terminal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Carlsson
L
L
Department of Pharmacology, University of Göteborg, Sweden.
Abrahamsson
T
T
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000494:pharmacology; D003327:Coronary Disease / Q000378:metabolism*; D003891:Desipramine / Q000031:analogs & derivatives / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007536:Isomerism; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008376:Maprotiline / Q000031:analogs & derivatives / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D000928:Antidepressive Agents; D005473:Fluoxetine; C011386:nisoxetine; D008376:Maprotiline; C027299:hydroxymaprotilin; D008012:Lidocaine; D003000:Clonidine; D003891:Desipramine; C028653:2-hydroxydesipramine; D009638:Norepinephrine