Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: reversal by coincubation with sigma-receptor antagonists.
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.


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 sigma-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 sigma-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.


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 sigma-receptors. The endogenous ligands of this antiopioid system may prove to play a role in vasospastic angina, acute myocardial infarction, and sudden cardiac death.
Medizinische Klinik and Poliklinik I, Klinikum Grosshadern, Ludwig-Maximilian-University, Munich, Germany.
U
U
Wilbert-Lampen
C
C
Seliger
T
T
Zilker
R M
RM
Arendt
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D017480:Receptors, sigma / Q000819:agonists* / Q000187:drug effects*; D013552:Swine; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D019332:Endothelin-1; D017480:Receptors, sigma; D014662:Vasoconstrictor Agents; D003042:Cocaine