From the Medizinische Klinik and Poliklinik I, Klinikum Großhadern,
Ludwig-Maximilian-University (U.W.-L., C.S., R.M.A.) and the II. Medizinische
Klinik and Poliklinik, Department of Toxicology, Klinikum rechts der Isar,
Technical University (T.Z.), Munich, Germany.
Correspondence to Dr Rainer M. Arendt, Med. I, Klinikum Großhadern, University of Munich, Marchioninistr 15, 81366 Munich, Germany. E-mail rainer.arendt{at}med1.med.uni-muenchen.de
Background—Cocaine-associated
vascular events are not completely explained by adrenergic stimulation.
The purposes of this study were to investigate whether
vasoconstrictive endothelin-1 is released by cocaine
and to elucidate the mechanisms involved.
Methods and Results—Endothelin-1 was measured by radioimmunoassay
and high-performance liquid chromatography (1)
in the supernatant of porcine aortic endothelial cells
after treatment with cocaine (10-7 to 10-4
mol/L) and a
Conclusions—The data suggest that cocaine increases the
endothelin-1 release in vitro and in vivo. The cocaine-induced
vasoconstriction/vasospasm may therefore be facilitated by the release
of endothelin-1. Cocaine appears to be an exogenous stimulator at
endothelial
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Cocaine Increases the Endothelial Release of Immunoreactive Endothelin and Its Concentrations in Human Plasma and Urine
Reversal by Coincubation With
-Receptor Antagonists
-receptor antagonist, haloperidol
(10-6 mol/L) or ditolylguanidine (10-5 mol/L)
and (2) in plasma and urine of 12 cocaine-intoxicated patients and 13
healthy control subjects. Radioligand binding assays were
performed on endothelial membrane preparations. In cell
culture, cocaine significantly increased endothelin accumulation above
baseline at 3 to 24 hours; endothelin release rates per hour increased
dose-dependently, reaching a plateau of 175±23% of control at hour 4
to 5. Coincubation of cocaine with haloperidol or ditolylguanidine
abolished or reduced cocaine-induced endothelin release.
Endothelial membrane preparations specifically and
displaceably bound the highly selective -ligand
[3H]ditolylguanidine (25x10-9 mol/L), with
1400 binding sites estimated per cell. Endothelin-1 levels in plasma
(22.7±5.6 versus 7.3±0.8 pmol/L) and urine (41.5±10.1 versus
12.7±3.8 pmol/L) of cocaine-intoxicated patients were significantly
increased compared with control values. -receptors. The endogenous
ligands of this antiopioid system may prove to play a role in
vasospastic angina, acute myocardial infarction, and sudden cardiac
death.
Key Words: cocaine • endothelin • receptors, sigma • death, sudden • vasospasm
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