endothelin-1 and Cocaine-Related-Disorders

Stroke is the third most common cause of death in developed countries. In England and Wales, 1000 people under the age of 30 have a stroke each year. Cocaine is the most commonly used class A drug, and the first report of cocaine-induced stroke was in 1977. Since the development of alkaloidal "crack" cocaine in the 1980s, there has been a significant rise in the number of case reports describing both ischaemic and haemorrhagic stroke associated with cocaine use. Cocaine is a potent central nervous system stimulant, and acts by binding to specific receptors at pre-synaptic sites preventing the reuptake of neurotransmitters. The exact mechanism of cocaine-induced stroke remains unclear and there are likely to be a number of factors involved including vasospasm, cerebral vasculitis, enhanced platelet aggregation, cardioembolism, and hypertensive surges associated with altered cerebral autoregulation. The evidence surrounding each of these factors will be considered here.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Endothelin-1; Humans; Stroke; Vasospasm, Intracranial

Cocaine is commonly used among HIV-infected people and may worsen HIV disease progression. In addition, existing evidence suggests a link between antiretroviral regimens and endothelial dysfunction. This study aimed to examine whether the associations of antiretroviral therapy (ART) regimens with endothelial dysfunction may be modified by cocaine use in adults with HIV infection. Between 2003 and 2014, 466 HIV-positive participants residing in Baltimore, Maryland, were enrolled in a study investigating comorbidities associated with HIV/ART. The associations between various risk factors and endothelial dysfunction indicators were examined by robust regression models fitted for the overall subjects and cocaine subgroups, separately. Duration of nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy was negatively associated with plasma vWF:Ag levels in cocaine non-users (β = -.715, SE = .220, P < .05). However, cocaine users on longer-term NNRTI-based regimens had greater plasma endothelin-1 (ET-1) concentrations than their counterparts (β = .003, SE = .001, P < .05). In addition, current cigarette smoking was significantly positively associated with ET-1 concentrations in both cocaine non-users (β = .609, SE = .164, P < .05) and cocaine users (β = .331, SE = .086, P < .05). In conclusion, cocaine use modified the potential effects of NNRTI-based therapy on biomarkers of endothelial dysfunction. These findings suggested that reduction in cocaine use may improve endothelial function in HIV-infected cocaine users.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Biomarkers; CD4 Lymphocyte Count; Cocaine; Cocaine-Related Disorders; Drug Interactions; Endothelin-1; Endothelium; Female; HIV Infections; Humans; Male; Middle Aged; Viral Load; von Willebrand Factor

Clinical and epidemiological evidence suggests that HIV infection and cocaine use are associated with an increased risk of premature atherosclerosis. The underlying mechanisms linking HIV infection and cocaine use with early atherosclerosis remain elusive.. Endothelin-1 (ET-1) levels in 360 African American participants in Baltimore, Maryland were measured. Quantile regression analysis was performed to examine the associations between ET-1, HIV infection, cocaine use, and other relevant clinical factors. The median of ET-1 in plasma, (1.05 pg/mL with interquartile range: 0.73, 1.40) for those with HIV infection was significantly higher than values for those without HIV infection (0.74 pg/mL with interquartile range: 0.61, 0.93). The median of ET-1 was markedly higher in chronic cocaine users (0.96 pg/mL with interquartile range: 0.71, 1.36) than that in non-cocaine users (0.72 pg/mL with interquartile range: 0.58, 1.06). Multivariate quantile regression suggested that HIV infection and duration of cocaine use were independently associated with plasma ET-1 levels after controlling for potential confounding factors.. This study may provide insight into the mechanism of premature atherosclerosis in HIV-infected cocaine users and suggest that measurement of ET-1 in plasma can be used as a marker of early atherosclerosis in HIV infected patients and cocaine users.

Topics: Adult; Atherosclerosis; Black or African American; Cocaine-Related Disorders; Endothelin-1; Endothelium, Vascular; Female; HIV Infections; Humans; Male; Middle Aged

Cocaine use has been related with the development of accelerated atherosclerosis and with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood, although thrombus formation and altered vascular function are prominent findings.. Our aim was to evaluate markers of endothelial dysfunction in chronic cocaine consumers before and after drug withdrawal.. We determined circulating endothelial cells (CECs) and plasma levels of stromal cell-derived factor-1 (SDF-1), monocyte chemotactic protein-1(MCP-1), soluble intracellular adhesion molecule (sICAM), high-sensitivity C reactive protein (hsCRP) and endothelin-1(ET-1), in DSM-IV cocaine addicts at baseline and after one month of cocaine abstinence.. Cocaine users showed a strikingly higher numbers of CEC (62.35 ± 18.4 vs 8.25 ± 13.8 CEC/mL) and significantly elevated plasma levels for all the markers evaluated as compared to the control group. After cocaine withdrawal, patients improved SDF-1, ET-1, hsCRP and sICAM levels. However, CEC number and MCP-1 plasma levels remained significantly elevated. All the results were adjusted for blood levels of cholesterol and triglycerides and for smoking habit.. Our results demonstrated that chronic cocaine consumption alters several functions of the endothelium towards a pro-thrombotic condition and that some of those functions remain abnormal even after short-term drug withdrawal. These observations support the notion that endothelial dysfunction may play a key role in the pathogenesis of ischemic vascular disease observed in cocaine abusers.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Cell Count; Chemokine CXCL12; Chile; Chronic Disease; Cocaine-Related Disorders; Endothelial Cells; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Substance Withdrawal Syndrome; Time Factors; Up-Regulation; Young Adult

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.. 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.. 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.

Topics: Acute Disease; Adolescent; Adult; Animals; Cells, Cultured; Cocaine; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Receptors, sigma; Swine; Time Factors; Vasoconstrictor Agents