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CARDIOVASCULAR

Two "Knockout" Mouse Models Demonstrate That Aortic Vasodilatation Is Mediated via _2A-Adrenoceptors Located on the Endothelium

Autonomic Physiology Unit, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland (M.M., C.D., A.W., J.M., C.J.D., J.C.M.); and Sari Medical Faculty, Mazandaran, Iran (M.M.S.)

UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine]-mediated vasodilator responses were studied on wire myograph-mounted mouse aorta to determine the cells involved, mechanisms of action, and subtypes of ₂-adrenoceptors. In the presence of induced tone, UK-14,304 produced concentration-related vasodilatation that was abolished by rauwolscine, N-nitro-L-arginine methyl ester (L-NAME), or endothelium removal, indicating that endothelial ₂-adrenoceptors can release nitric oxide. In the _2A-adrenoceptor knockout mouse and the D79N mouse, a functional knockout of the _2A-adrenoceptor, these relaxant effects of UK-14,304 were lost, indicating the involvement of the _2A-adrenoceptor. UK-14,304 could also contract aorta: a small contraction occurred at high concentrations, was enhanced by L-NAME, and was absent in the _1D-adrenoceptor knockout mouse, indicating activation of the _1D-adrenoceptor. There was no evidence for a contractile ₂-adrenoceptor-mediated response. A fluorescent ligand, quinazoline piperazine bodipy, antagonized the relaxant action of UK-14,304. This compound could be visualized on aortic endothelial cells, and its binding could be prevented by rauwolscine, providing direct evidence for the presence of ₂-adrenoceptors on the endothelium. Norepinephrine reduced tone in the _1D-adrenoceptor knockout and controls, an effect blocked by rauwolscine and L-NAME but not by prazosin. This suggests that norepinephrine activates endothelial ₂-adrenoceptors. In conclusion, the endothelium of mouse aorta has an _2A-adrenoceptor that responds to norepinephrine; promotes the release of nitric oxide, causing smooth muscle relaxation; and that can be directly visualized. Knockout or genetic malfunction of this receptor should increase arterial stiffness, exacerbated by raised catecholamines, and contribute to heart failure.

Address correspondence to: Professor J. C. McGrath, Autonomic Physiology Unit, Institute of Biomedical and Life Sciences, West Medical Bldg., University of Glasgow, Glasgow G12 8QQ, UK. E-mail: i.mcgrath{at}bio.gla.ac.uk

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