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

Article; Proceedings Paper

关键词: NORMAL CORONARY-ARTERIES;    CENTRAL-NERVOUS-SYSTEM;    SUDDEN CARDIAC DEATH;    MYOCARDIAL-INFARCTION;    ABUSE;    DISEASE;    HEART;    MECHANISMS;    SPASM;    COMPLICATIONS;   

DOI  :  10.1161/01.CIR.98.5.385

来源: SCIE

【 摘 要 】

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 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 a-ligand [H-3]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.

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