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Relaxation effect of abacavir on rat basilar arteries.

Li RW, Yang C, Chan SW, Hoi MP, Lee SM, Kwan YW, Leung GP - PLoS ONE (2015)

Bottom Line: 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.It is speculated that abacavir-induced cardiovascular risk may not be related to endothelial dysfunction as abacavir does not impair relaxation of blood vessels.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacy, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

ABSTRACT

Background: The 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.

Methods: The 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.

Results: Abacavir 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.

Conclusion: 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. 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.

No MeSH data available.


Related in: MedlinePlus

Effect of abacavir on the relaxation of rat basilar arteries.Abacavir-induced relaxation of rat basilar arteries was measured in the presence (+EC) or absence (–EC) of endothelial cells. (A) Changes in tension were expressed as the percentage decrease in response to contraction caused by endothelin-1 (ET-1; 1–10 nM). (B) Sample trace showing the effect of endothelium removal on abacavir-induced relaxation. Values are means ± S.E.M of six to eight sets of experiments and statistical comparisons were made using ANOVA. ** P<0.01 compared with control.
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pone.0123043.g001: Effect of abacavir on the relaxation of rat basilar arteries.Abacavir-induced relaxation of rat basilar arteries was measured in the presence (+EC) or absence (–EC) of endothelial cells. (A) Changes in tension were expressed as the percentage decrease in response to contraction caused by endothelin-1 (ET-1; 1–10 nM). (B) Sample trace showing the effect of endothelium removal on abacavir-induced relaxation. Values are means ± S.E.M of six to eight sets of experiments and statistical comparisons were made using ANOVA. ** P<0.01 compared with control.

Mentions: Abacavir had no contractile effect on rat basilar arteries with basal tone (data not shown). However, abacavir induced the relaxation of rat basilar arteries in a concentration-dependent manner with an IC50 value of 5.46 μM (Fig 1). This abacavir-induced relaxation was greatly diminished when the endothelium was removed from rat basilar arteries. It is well known that the major relaxing factors released from endothelial cells are nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF). To study which factors were responsible for the abacavir-induced relaxation response, the effects of L-NAME (100 μM; an endothelial NO synthase inhibitor), indomethacin (10 μM; a cyclooxygenase inhibitor) and TRAM-34 plus UCL 1684 (both at 1 μM; inhibitors of EDHF-mediated responses) were studied. Abacavir-induced relaxation of rat basilar arteries was not affected when arteries were pretreated with indomethacin or TRAM-34 plus UCL 1684 (Fig 2). In contrast, abacavir-induced relaxation was abolished by L-NAME.


Relaxation effect of abacavir on rat basilar arteries.

Li RW, Yang C, Chan SW, Hoi MP, Lee SM, Kwan YW, Leung GP - PLoS ONE (2015)

Effect of abacavir on the relaxation of rat basilar arteries.Abacavir-induced relaxation of rat basilar arteries was measured in the presence (+EC) or absence (–EC) of endothelial cells. (A) Changes in tension were expressed as the percentage decrease in response to contraction caused by endothelin-1 (ET-1; 1–10 nM). (B) Sample trace showing the effect of endothelium removal on abacavir-induced relaxation. Values are means ± S.E.M of six to eight sets of experiments and statistical comparisons were made using ANOVA. ** P<0.01 compared with control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390379&req=5

pone.0123043.g001: Effect of abacavir on the relaxation of rat basilar arteries.Abacavir-induced relaxation of rat basilar arteries was measured in the presence (+EC) or absence (–EC) of endothelial cells. (A) Changes in tension were expressed as the percentage decrease in response to contraction caused by endothelin-1 (ET-1; 1–10 nM). (B) Sample trace showing the effect of endothelium removal on abacavir-induced relaxation. Values are means ± S.E.M of six to eight sets of experiments and statistical comparisons were made using ANOVA. ** P<0.01 compared with control.
Mentions: Abacavir had no contractile effect on rat basilar arteries with basal tone (data not shown). However, abacavir induced the relaxation of rat basilar arteries in a concentration-dependent manner with an IC50 value of 5.46 μM (Fig 1). This abacavir-induced relaxation was greatly diminished when the endothelium was removed from rat basilar arteries. It is well known that the major relaxing factors released from endothelial cells are nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF). To study which factors were responsible for the abacavir-induced relaxation response, the effects of L-NAME (100 μM; an endothelial NO synthase inhibitor), indomethacin (10 μM; a cyclooxygenase inhibitor) and TRAM-34 plus UCL 1684 (both at 1 μM; inhibitors of EDHF-mediated responses) were studied. Abacavir-induced relaxation of rat basilar arteries was not affected when arteries were pretreated with indomethacin or TRAM-34 plus UCL 1684 (Fig 2). In contrast, abacavir-induced relaxation was abolished by L-NAME.

Bottom Line: 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.It is speculated that abacavir-induced cardiovascular risk may not be related to endothelial dysfunction as abacavir does not impair relaxation of blood vessels.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacy, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

ABSTRACT

Background: The 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.

Methods: The 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.

Results: Abacavir 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.

Conclusion: 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. 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.

No MeSH data available.


Related in: MedlinePlus