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

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 (1027 to 1024 mol/L) and a s-receptor antagonist, haloperidol (1026 mol/L) or ditolylguanidine (1025 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 175623 % 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 s-ligand [3H]ditolylguanidine (2531029 mol/L), with 1400 binding sites estimated per cell. Endothelin-1 levels in plasma (22.765.6 versus 7.360.8 pmol/L) and urine (41.5610.1 versus 12.763.8 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-induce