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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

Effects of short-term treatment with abacavir on acetylcholine-induced relaxation of rat basilar arteries.Basilar arterial rings were treated with abacavir (10 μM) for 24 h. Rings not treated with abacavir served as controls. Acetylcholine (Ach)-induced relaxation of basilar arteries was then measured. Changes in tension were expressed as a percentage decrease in response to contraction caused by endothelin-1 (ET-1 1–10 nM). Values are means ± S.E.M. of five to eight sets of experiments and statistical comparisons were made using ANOVA.
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pone.0123043.g011: Effects of short-term treatment with abacavir on acetylcholine-induced relaxation of rat basilar arteries.Basilar arterial rings were treated with abacavir (10 μM) for 24 h. Rings not treated with abacavir served as controls. Acetylcholine (Ach)-induced relaxation of basilar arteries was then measured. Changes in tension were expressed as a percentage decrease in response to contraction caused by endothelin-1 (ET-1 1–10 nM). Values are means ± S.E.M. of five to eight sets of experiments and statistical comparisons were made using ANOVA.

Mentions: Acetylcholine-induced endothelium-dependent relaxation was not altered when basilar arteries were pre-incubated with abacavir for 24 h (10 μM) (Fig 11). For long-term treatment, rats were fed abacavir (16 mg/kg/day or 160 mg/kg/day) for 4 weeks. The weight of the rats was 537.4 ± 12.5 g (control) vs 488.6 ± 5.9 g (treated with abacavir 16 mg/kg); and 484.3 ± 5.064 g (control) vs 479.5 ± 15.02 g (treated with abacavir 160 mg/kg). There was no significant difference between the controls and abacavir treatment groups. Acetylcholine-induced endothelium-dependent relaxation in rat basilar arteries was unaffected when rats were treated with both dosages of abacavir (Fig 12A and 12B). Endothelium-independent relaxation was also studied using sodium nitroprusside. 10 nM of sodium nitroprusside induced a relaxation response of 64.4 ± 6.3% and 66.8 ± 8.5% in control arteries and arteries incubated with abacavir for 24 h, respectively. Sodium nitroprusside-induced relaxation was 48.9 ± 7.4% and 52.3 ± 8.2% in control rats and rats treated with 160 mg/kg of abacavir, respectively.


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)

Effects of short-term treatment with abacavir on acetylcholine-induced relaxation of rat basilar arteries.Basilar arterial rings were treated with abacavir (10 μM) for 24 h. Rings not treated with abacavir served as controls. Acetylcholine (Ach)-induced relaxation of basilar arteries was then measured. Changes in tension were expressed as a percentage decrease in response to contraction caused by endothelin-1 (ET-1 1–10 nM). Values are means ± S.E.M. of five to eight sets of experiments and statistical comparisons were made using ANOVA.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123043.g011: Effects of short-term treatment with abacavir on acetylcholine-induced relaxation of rat basilar arteries.Basilar arterial rings were treated with abacavir (10 μM) for 24 h. Rings not treated with abacavir served as controls. Acetylcholine (Ach)-induced relaxation of basilar arteries was then measured. Changes in tension were expressed as a percentage decrease in response to contraction caused by endothelin-1 (ET-1 1–10 nM). Values are means ± S.E.M. of five to eight sets of experiments and statistical comparisons were made using ANOVA.
Mentions: Acetylcholine-induced endothelium-dependent relaxation was not altered when basilar arteries were pre-incubated with abacavir for 24 h (10 μM) (Fig 11). For long-term treatment, rats were fed abacavir (16 mg/kg/day or 160 mg/kg/day) for 4 weeks. The weight of the rats was 537.4 ± 12.5 g (control) vs 488.6 ± 5.9 g (treated with abacavir 16 mg/kg); and 484.3 ± 5.064 g (control) vs 479.5 ± 15.02 g (treated with abacavir 160 mg/kg). There was no significant difference between the controls and abacavir treatment groups. Acetylcholine-induced endothelium-dependent relaxation in rat basilar arteries was unaffected when rats were treated with both dosages of abacavir (Fig 12A and 12B). Endothelium-independent relaxation was also studied using sodium nitroprusside. 10 nM of sodium nitroprusside induced a relaxation response of 64.4 ± 6.3% and 66.8 ± 8.5% in control arteries and arteries incubated with abacavir for 24 h, respectively. Sodium nitroprusside-induced relaxation was 48.9 ± 7.4% and 52.3 ± 8.2% in control rats and rats treated with 160 mg/kg of abacavir, respectively.

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