Paul D Baum1, Paul M Sullam, Cheryl A Stoddart, Joseph M McCune. 1. 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
Abstract
OBJECTIVE: To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction. DESIGN: 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. CONCLUSION: Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyperreactivity. This may explain the observed increased risk of myocardial infarction in HIV patients taking abacavir. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
OBJECTIVE: To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction. DESIGN: 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. CONCLUSION:Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyperreactivity. This may explain the observed increased risk of myocardial infarction in HIVpatients taking abacavir. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
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