Abstract
BackgroundThe use of abacavir has been linked with increased cardiovascular risk in patients with human immunodeficiency virus infection; however, the mechanism involved remains unclear. We hypothesize that abacavir may impair endothelial function. In addition, based on the structural similarity between abacavir and adenosine, we propose that abacavir may affect vascular contractility through endogenous adenosine release or adenosine receptors in blood vessels.MethodsThe relaxation effect of abacavir on rat basilar arteries was studied using the myograph technique. Cyclic GMP and AMP levels were measured by immunoassay. The effects of abacavir on nucleoside transporters were studied using radiolabeled nucleoside uptake experiments. Ecto-5′ nucleotidase activity was determined by measuring the generation of inorganic phosphate using adenosine monophosphate as the substrate.ResultsAbacavir induced the relaxation of rat basilar arteries in a concentration-dependent manner. This relaxation was abolished when endothelium was removed. In addition, the relaxation was diminished by the nitric oxide synthase inhibitor, L-NAME, the guanylyl cyclase inhibitor, ODQ, and the protein kinase G inhibitor, KT5820. Abacavir also increased the cGMP level in rat basilar arteries. Abacavir-induced relaxation was also abolished by adenosine A2 receptor blockers. However, abacavir had no effect on ecto-5’ nucleotidase and nucleoside transporters. Short-term and long-term treatment of abacavir did not affect acetylcholine-induced relaxation in rat basilar arteries.ConclusionAbacavir induces acute endothelium-dependent relaxation of rat basilar arteries, probably through the activation of adenosine A2 receptors in endothelial cells, which subsequently leads to the release of nitric oxide, resulting in activation of the cyclic guanosine monophosphate/protein kinase G-dependent pathway in vascular smooth muscle cells. It is speculated that abacavir-induced cardiovascular risk may not be related to endothelial dysfunction as abacavir does not impair relaxation of blood vessels. The most likely explanation of increased cardiovascular risk may be increased platelet aggregation as suggested by other studies.
Highlights
Use of the nucleoside reverse transcriptase inhibitor (NRTI), abacavir, in the treatment of patients infected with the human immunodeficiency virus (HIV) may be associated with increased cardiovascular risk [1]
Abacavir-induced relaxation was abolished by adenosine A2 receptor blockers
Abacavir induces acute endothelium-dependent relaxation of rat basilar arteries, probably through the activation of adenosine A2 receptors in endothelial cells, which subsequently leads to the release of nitric oxide, resulting in activation of the cyclic guanosine monophosphate/protein kinase G-dependent pathway in vascular smooth muscle cells
Summary
Use of the nucleoside reverse transcriptase inhibitor (NRTI), abacavir, in the treatment of patients infected with the human immunodeficiency virus (HIV) may be associated with increased cardiovascular risk [1]. Didanosine and tenofovir have no effect on coronary endothelial cell gene transcription and protein expression of proinflammatory molecules such as vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemotactic protein-1 and interleukin-6. These agents do not affect gene expression of the intracellular reactive oxygen species producing enzyme, NADPH oxidase, and the apoptosis regulating molecules [17]. Similar conflicting results were observed in a single study in which the levels of vascular cell adhesion molecule-1 were decreased, while those of interleukin-6 were elevated during abacavir treatment [18]. Based on the structural similarity between abacavir and adenosine, we propose that abacavir may affect vascular contractility through endogenous adenosine release or adenosine receptors in blood vessels
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