Effect of cocaine on endothelial function: Role of nitric oxide and endothelin-1
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Description
Cardiovascular events commonly associated with acute and chronic cocaine abuse include coronary vasospasm, arrhythmias, myocardial infarction and sudden death. Acutely, cocaine inhibits the reuptake of monoamines in the adrenergic nerve terminal and potentiates their peripheral vascular effects. It has been suggested that chronic cocaine causes endothelial dysfunction and vasoconstriction by inhibiting local production of nitric oxide (NO) and that endothelial dysfunction may be involved in the cardiovascular events associated with cocaine use. The present study was designed to investigate the effect of acute and chronic cocaine treatment on endothelial function and the adrenergic pathway. The hypothesis that cocaine can lead to endothelial dysfunction was tested by performing in vivo and in vitro experiments. The results of the acute in vivo study suggest that single intravenous cocaine dose potentiates the vasopressor response to norepinephrine and blocks vasopressor responses to tyramine but does not change the vasodepressor response to endothelial dependent vasodilator, acetylcholine and endothelium independent vasodilator sodium nitroprusside suggesting that acutely cocaine does not cause endothelial dysfunction. For the chronic study, cocaine was administered intraperitoneally and blood flow responses were measured in the hindlimb vascular bed of the male Sprague Dawley rats. Chronically, cocaine decreased the blood flow responses to mixed adrenergic agonist norepinephrine, alpha-adrenergic agonist phenylephrine and beta adrenergic agonist isoproterenol suggesting that chronic cocaine treatment may lead to adrenergic pathway desensitization. The blood flow responses to acetylcholine were reduced and the blood flow responses to sodium nitroprusside were not altered. Chronic cocaine treatment significantly reduced total plasma nitrate-nitrite levels which are indicative of the plasma NO levels and significantly increased endothelin-1 levels. To delineate the mechanisms by which cocaine can lead to endothelial dysfunction, in vitro study was performed using human aortic endothelial cells (HAECs). Cocaine treatment of HAECs decreased NO production and increased endothelin-1 production. This decrease in NO was suppressed by co-treating the cells with endothelin-1 receptor blocker BQ123. Cocaine also increased adhesion of U937 premonocytes to HAECs. This increase in adhesion was reversed by BQ123 and SNP. In conclusion, chronic cocaine abuse can lead to endothelial dysfunction and eventually cardiovascular disease by impairing the endothelial NO-endothelin-1 pathway