Cardiovascular Toxicology

, Volume 8, Issue 4, pp 161–171 | Cite as

Molecular Analysis of Cocaine-Induced Endothelial Dysfunction: Role of Endothelin-1 and Nitric Oxide

  • Leena Pradhan
  • Debasis Mondal
  • Surabhi Chandra
  • Mussa Ali
  • Krishna C. Agrawal
Article

Abstract

Cocaine remains the most frequently used illicit substance. Although cocaine-induced atherosclerosis is well documented, its mechanism of action on human vascular endothelial cells has not been determined. Nitric oxide (NO) and endothelin-1 (ET-1) are involved in endothelial cell activation and leukocyte recruitment. The present study monitored the effects of cocaine on NO and ET-1 production in human aortic endothelial cells (HAECs) and the effects of sodium nitroprusside (SNP) and BQ-123 on leukocyte adhesion to HAECs. Acute exposure to cocaine (1 and 3 μM) significantly increased ET-1 production (2-fold) and ET-1 receptor type-A (ETAR) protein expression, within 6–12 h. Cocaine exposure for a longer duration (24–72 h) showed a temporal decrease in both NO production and endothelial NO-synthase (eNOS) expression. The cocaine-mediated suppression of NO was ameliorated by co-treatment of cells with the ETAR blocker, BQ-123 (5 μM). Furthermore, both short-term (24 h) and long-term (72 h) exposure to cocaine increased endothelial adhesion of monocytes (U937 cells) by 20% and 40%, respectively, which were also suppressed by BQ-123 and SNP co-treatment. These data suggest that a concomitant increase in both ET-1 and ETAR expression in cocaine exposed HAECs may enhance signaling via the ETAR which decreases eNOS expression and NO production, and ultimately results in endothelial activation and leukocyte adhesion. Our findings implicate a molecular mechanism of action of cocaine and a therapeutic effect of ETAR-specific inhibitor in suppressing the cocaine-induced endothelial dysfunction.

Keywords

Cocaine Endothelial dysfunction HAECs Leukocyte adhesion Endothelin-1 Endothelin receptors Nitric oxide 

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Copyright information

© Humana Press 2008

Authors and Affiliations

  • Leena Pradhan
    • 1
    • 2
  • Debasis Mondal
    • 1
  • Surabhi Chandra
    • 1
  • Mussa Ali
    • 1
  • Krishna C. Agrawal
    • 1
  1. 1.Department of PharmacologyTulane University School of MedicineNew OrleansUSA
  2. 2.Department of Surgery, Division of Vascular SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA

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