α1A/B‐Knockout mice explain the native α1D‐adrenoceptor's role in vasoconstriction and show that its location is independent of the other α1‐subtypes

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Abstract
Background and purpose: Theoretically, three α1‐adrenoceptor subtypes can interact at the signalling level to alter vascular contraction or at the molecular level to alter each other's cellular location. The α1A/B‐adrenoceptor knockout mouse (α1A/B‐KO) was used to study the isolated α1D‐adrenoceptor to consider these potential interactions in native tissue.Experimental approach: Pharmacological analysis of carotid and mesenteric arteries employed wire myography and fluorescent ligand binding (α1‐adrenoceptor ligand BODIPY FL‐prazosin, QAPB).Key results: α1A/B‐KO carotid had clear α1D‐adrenoceptor‐induced contractions. In WT carotid α1D‐adrenoceptor dominated but all three α1‐subtypes participated. α1A/B‐KO mesenteric had α1D‐adrenoceptor responses with high sensitivity and small maximum, explaining how α1D‐adrenoceptor could determine agonist sensitivity in WT. In both arteries α1A/B‐KO fluorescence levels were reduced but pharmacologically more consistent with ‘pure’α1D‐adrenoceptors. α1D‐Adrenoceptor binding in α1A/B‐KO was observed on the cell surface and intracellularly and was present in a high proportion of smooth‐muscle cells in both strains, regardless of artery type.Conclusions and implications: ‘Pure’α1D‐adrenoceptor pharmacology in α1A/B‐KO provides a quantitative standard. Functionally, the α1D‐ and α1A‐adrenoceptors produce additive responses and do not significantly compensate for each other. α1D‐Adrenoceptor contributes to sensitivity even in resistance arteries. In α1A/B‐KO, the loss of α1A‐ and α1B‐adrenoceptors is reflected by a general decrease in fluorescence, but similar binding distribution to WT indicates that the α1D‐adrenoceptor location in native smooth‐muscle cells is not influenced by other α1‐adrenoceptors. Equivalent levels of receptors did not correspond to equivalent responses. In conclusion, α1‐subtypes do not interact but provide independent alternative signals for vascular regulation.

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