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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 5, 2005; DOI: 10.1124/jpet.105.085944

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Received for publication March 8, 2005.
Revised May 3, 2005.
Accepted for publication May 3, 2005.

Two "knockout" mouse models demonstrate that aortic vasodilatation is mediated via {alpha}2A- adrenoceptors located on the endothelium

Majid Malekzadeh Shafaroudi 1, Melissa McBride 2, Clare Deighan 2, Alexis Wokoma 2, Joyce Macmillan 2, Craig J. Daly 2, John C. McGrath 2*

1 Sari Medical Faculty 2 University of Glasgow

* Address correspondence to: E-mail: i.mcgrath{at}bio.gla.ac.uk

Abstract

UK14304-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, UK14304 produced concentration-related vasodilatation that was abolished by rauwolscine, 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 UK14304 were lost, indicating the involvement of the {alpha}2A-adrenoceptor. UK14304 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 (QAPB), antagonised the relaxant action of UK14304. This compound could be visualised 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 which can be directly visualised. Knockout or genetic malfunction of this receptor should increase arterial stiffness, exacerbated by raised catecholamines, and contribute to heart failure.


Key words: {alpha}2-adrenoceptors, arteries, endothelium, nitric oxide, receptor imaging, receptor knockout


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[Abstract] [Full Text] [PDF]


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