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Shafaroudi MM, McBride M, Deighan C, Wokoma A, Macmillan J, Daly CJ, McGrath JC: Two "knockout" mouse models demonstrate that aortic vasodilatation is mediated via alpha2a-adrenoceptors located on the endothelium. J Pharmacol Exp Ther. 2005 Aug;314(2):804-10. Epub 2005 May 5.
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 alpha (2)-adrenoceptors. In the presence of induced tone, UK-14,304 produced concentration-related vasodilatation that was abolished by rauwolscine, N (omega)-nitro-L-arginine methyl ester (L-NAME), or endothelium removal, indicating that endothelial alpha (2)-adrenoceptors can release nitric oxide. In the alpha (2A)-adrenoceptor knockout mouse and the D79N mouse, a functional knockout of the alpha (2A)-adrenoceptor, these relaxant effects of UK-14,304 were lost, indicating the involvement of the alpha (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 alpha (1D)-adrenoceptor knockout mouse, indicating activation of the alpha (1D)-adrenoceptor. There was no evidence for a contractile alpha (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 alpha (2)-adrenoceptors on the endothelium. Norepinephrine reduced tone in the alpha (1D)-adrenoceptor knockout and controls, an effect blocked by rauwolscine and L-NAME but not by prazosin. This suggests that norepinephrine activates endothelial alpha (2)-adrenoceptors. In conclusion, the endothelium of mouse aorta has an alpha (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. |
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