title: Efavirenz induces interactions between leucocytes and endothelium through the activation of Mac-1 and gp150,95.
abstract: OBJECTIVE
  The potential cardiovascular (CV) toxicity associated with combined antiretroviral therapy (cART) has been attributed mainly to the nucleoside reverse transcriptase inhibitors abacavir and didanosine. However, the other two components of cART--non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)--may also be implicated, either directly or by influencing the action of the other drugs. This study evaluates the acute direct effects of the NNRTIs efavirenz and nevirapine and one of the most widely employed PIs, lopinavir, on leucocyte-endothelium interactions, a hallmark of CV disease.
  
  
  METHODS
  Drugs were analysed in vitro in human cells (interactions of peripheral blood polymorphonuclear or mononuclear cells with human umbilical vein endothelial cells) using a flow chamber system, and in vivo in rat mesenteric vessels by means of intravital microscopy. The expression of adhesion molecules in leucocytes and endothelial cells was studied by flow cytometry, and the role of these molecules in white cell recruitment was evaluated by pre-treating human cells or rats with blocking antibodies.
  
  
  RESULTS
  Efavirenz and nevirapine, but not lopinavir, increased the rolling flux and adhesion of leucocytes in vitro and in vivo while inducing emigration in rat venules. Efavirenz, but not nevirapine, augmented the levels of CD11b, CD11c and CD18 in neutrophils and monocytes. The actions of efavirenz, but not of nevirapine, were reversed by antibodies against Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18) or ICAM-1 (CD54).
  
  
  CONCLUSIONS
  NNRTIs, but not PIs, interfere with leucocyte-endothelial interactions. However, differences between efavirenz and nevirapine suggest a specific CV profile for each compound.
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Orden
authors.forename: Carmen
authors.initials: C
authors.lastname: De Pablo
authors.forename: Cesar
authors.initials: C
authors.lastname: Rios-Navarro
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Martinez-Cuesta
authors.forename: Jose E
authors.initials: JE
authors.lastname: Peris
authors.forename: Maria D
authors.initials: MD
authors.lastname: Barrachina
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D048588:Benzoxazines / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003521:Cyclopropanes; D004727:Endothelium / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D061466:Lopinavir / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008297:Male; D019829:Nevirapine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D061466:Lopinavir; D019829:Nevirapine; C098320:efavirenz
keywords: cardiovascular; leucocyte–endothelium interactions; lopinavir; nevirapine