title: Relaxation effect of abacavir on rat basilar arteries.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology and Pharmacy, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors: Rachel Wai Sum
authors: RW
authors: Li
authors: Key Laboratory of Ethnic Medicine Resource Chemistry (Yunnan University of Nationalities), State Ethnic Affairs Commission & Ministry of Education, School of Chemistry & Biotechnology, Yunnan University of Nationalities, Kunming, China.
authors: Cui
authors: C
authors: Yang
authors: State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
authors: Shun Wan
authors: SW
authors: Chan
authors: Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Maggie Pui Man
authors: MP
authors: Hoi
authors: Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Simon Ming Yuen
authors: SM
authors: Lee
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Yiu Wa
authors: YW
authors: Kwan
authors: Department of Pharmacology and Pharmacy, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors: George Pak Heng
authors: GP
authors: Leung
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D015224:Dideoxynucleosides / Q000008:administration & dosage*; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009213:Myography; D051381:Rats; D012307:Risk Factors; D014665:Vasodilator Agents / Q000008:administration & dosage*; D000099227:Abacavir
chemical_list: D000255:Adenosine Triphosphate; D006152:Cyclic GMP; D015224:Dideoxynucleosides; D014665:Vasodilator Agents; D000099227:Abacavir