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

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Abstract
Background and purpose: Mesenteric and carotid arteries from the α1B/D‐adrenoceptor knockout (α1B/D‐KO) were employed to isolate α1A‐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 α1‐adrenoceptor ligand BODIPY FL‐Prazosin (QAPB), on mesenteric (an ‘α1A‐adrenoceptor’ tissue) and carotid (an ‘α1D‐adrenoceptor’ tissue) arteries.Key results: α1B/D‐KO mesenteric arteries showed straightforward α1A‐adrenoceptor agonist/antagonist pharmacology. WT had complex pharmacology with α1A‐ and α1D‐adrenoceptor components. α1B/D‐KO had a larger α1A‐adrenoceptor response suggesting compensatory up‐regulation: no increase in fluorescent ligand binding suggests up‐regulation of signalling. α1B/D‐KO carotid arteries had low efficacy α1A‐adrenoceptor responses. WT had complex pharmacology consistent with co‐activation of all three subtypes. Fluorescent binding had straightforward α1A‐adrenoceptor characteristics in both arteries of α1B/D‐KO. Fluorescent binding varied between cells in relative intracellular and surface distribution. Total fluorescence was reduced in the α1B/D‐KO due to fewer smooth muscle cells showing fluorescent binding. WT binding was greater and sensitive to α1A‐ and α1D‐adrenoceptor antagonists.Conclusions and implications: The straightforward pharmacology and fluorescent binding in the α1B/D‐KO was used to interpret the properties of the α1A‐adrenoceptor in the WT. Reduced total fluorescence in α1B/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 α1B/D‐KO suggesting different cellular phenotypes of α1A‐adrenoceptor exist. The α1B/D‐KO provides robust assays for the α1A‐adrenoceptor and takes us closer to understanding multi‐receptor subtype interactions.

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