The α1B/D-adrenoceptor knockout mouse permits isolation of the vascular α1A-adrenoceptor and elucidates its relationship to the other subtypes

Methven, L., McBride, M. , Wallace, G.A. and McGrath, J.C. (2009) The α1B/D-adrenoceptor knockout mouse permits isolation of the vascular α1A-adrenoceptor and elucidates its relationship to the other subtypes. British Journal of Pharmacology, 158(1), pp. 209-224. (doi: 10.1111/j.1476-5381.2009.00269.x) (PMID:19572943) (PMCID:PMC2795267)

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Background and purpose: Mesenteric and carotid arteries from the a1B/D-adrenoceptor knockout (a1B/D-KO) were employed to isolate a1A-adrenoceptor pharmacology and location and to reveal these features in the wild-type (WT) mouse.Experimental approach: Functional pharmacology by wire myography and receptor localization by confocal microscopy, using the fluorescent a1-adrenoceptor ligand BODIPY FL-Prazosin (QAPB), on mesenteric (an 'a1A-adrenoceptor' tissue) and carotid (an 'a1D-adrenoceptor' tissue) arteries.Key results: a1B/D-KO mesenteric arteries showed straightforward a1A-adrenoceptor agonist/antagonist pharmacology. WT had complex pharmacology with a1A- and a1D-adrenoceptor components. a1B/D-KO had a larger a1A-adrenoceptor response suggesting compensatory up-regulation: no increase in fluorescent ligand binding suggests up-regulation of signalling. a1B/D-KO carotid arteries had low efficacy a1A-adrenoceptor responses. WT had complex pharmacology consistent with co-activation of all three subtypes. Fluorescent binding had straightforward a1A-adrenoceptor characteristics in both arteries of a1B/D-KO. Fluorescent binding varied between cells in relative intracellular and surface distribution. Total fluorescence was reduced in the a1B/D-KO due to fewer smooth muscle cells showing fluorescent binding. WT binding was greater and sensitive to a1A- and a1D-adrenoceptor antagonists.Conclusions and implications: The straightforward pharmacology and fluorescent binding in the a1B/D-KO was used to interpret the properties of the a1A-adrenoceptor in the WT. Reduced total fluorescence in a1B/D-KO arteries, despite a clear difference in the functionally dominant subtype, indicates that measurement of receptor protein is unlikely to correlate with function. Fewer cells bound QAPB in the a1B/D-KO suggesting different cellular phenotypes of a1A-adrenoceptor exist. The a1B/D-KO provides robust assays for the a1A-adrenoceptor and takes us closer to understanding multi-receptor subtype interactions.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McBride, Dr Martin and McGrath, Professor John and Methven, Dr Laura
Authors: Methven, L., McBride, M., Wallace, G.A., and McGrath, J.C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:British Journal of Pharmacology
Publisher:John Wiley & Sons, Inc.
ISSN (Online):1476-5381
Published Online:30 June 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
418761Isolation & analysis of each of the three vascular alpha-1 adrenoceptor subtypes - double alpha-1 adrenoceptor knockout mice "monosubtype"John McgrathBritish Heart Foundation (BHF)PG/05/140/20094LS - LIFE SCIENCES HUMAN BIOLOGY
380471Endothelial Alpha 1B AdrenoceptorsJohn McgrathBritish Heart Foundation (BHF)FS/04/035LS - LIFE SCIENCES HUMAN BIOLOGY