title: Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase.
abstract: OBJECTIVE
  To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction.
  
  
  METHODS
  Drug effects were studied with biochemical and cellular assays.
  
  
  METHODS
  Human platelets were incubated with nucleoside analogue drugs ex vivo. Platelet activation stimulated by ADP was studied by measuring surface P-selectin with flow cytometry. Inhibition of purified soluble guanylyl cyclase was quantified using an ELISA to measure cGMP production.
  
  
  RESULTS
  Pre-incubation of platelets in abacavir significantly increased activation in response to ADP in a time and dose-dependent manner. The active anabolite of abacavir, carbovir triphosphate, competitively inhibited soluble guanylyl cyclase activity with a K(i) of 55 μmol/l.
  
  
  CONCLUSIONS
  Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyperreactivity. This may explain the observed increased risk of myocardial infarction in HIV patients taking abacavir.
authors.affiliation: Division of Experimental Medicine, Department of Medicine bVeterans Affairs Medical Center, University of California San Francisco, San Francisco, California 94143-1234 , USA. paul.baum@ucsf.edu
authors.forename: Paul D
authors.initials: PD
authors.lastname: Baum
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sullam
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D001792:Blood Platelets / Q000187:drug effects*; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D006801:Humans; D009203:Myocardial Infarction / Q000139:chemically induced; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000071756:Soluble Guanylyl Cyclase; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D006162:Guanylate Cyclase; D019007:P-Selectin; D018160:Receptors, Cytoplasmic and Nuclear; D018894:Reverse Transcriptase Inhibitors; D000071756:Soluble Guanylyl Cyclase; D000099227:Abacavir