The three members of the α1-adrenoceptor family (α1A α1B α1D) are present and functional on both vascular endothelium and smooth muscle.
Year: 2025
Type: preprint
Abstract: Background and Purpose: α 1 -adrenoceptor agonists can cause endothelium-dependent arterial dilatation; no direct evidence of an endothelial α 1 -adrenoceptor receptor location exists. Are any/all the three α 1 -adrenoceptors (α 1A α 1B α 1D ) located on arterial endothelium? Could this explain potentiation of catecholamine-mediated vasoconstriction by NOS blockade and/or the putative vasodilator effect of α 1D -adrenoceptor agonism? Experimental Approach: α 1 -adrenoceptors were located by a fluorescent ligand, Bodipy-FL prazosin (QAPB) employing confocal microscopy. Receptors were identified in two ways: using α 1 -adrenoceptor knockout mice (single, double and triple KOs) and competition with non-fluorescent antagonists. Contractile effects were analysed pharmacologically using wire myography. Key results: Prazosin-sensitive fluorescent ligand binding was found in endothelial cells of all mouse strains possessing one, two or three α 1 -AR subtypes. Selective antagonists RS100-329 and BMY7378 reduced binding when the mice possessed the gene for α 1A -AR or α 1D -AR; together they abolished fluorescence except when the α 1B -AR gene was present. Thus, all three subtypes are present on endothelium whenever the mouse possesses the appropriate gene. Sub-nanomolar concentrations of Phenylephrine could cause dilatation of preconstricted arteries in “α 1D -AR-only” mice but not WT. L-NAME potentiated vasoconstriction to phenylephrine and A-61603 (relatively selective for α 1D -AR and α 1A -AR, respectively) but not to 5-HT, in all strains possessing the relevant α 1 -AR genes. Conclusions and Implications - The three α 1 -adrenoceptor types are present on carotid arterial endothelium and smooth muscle. Endothelial α 1D - or α 1A -adrenoceptor agonism produces a NO-mediated counter-contractile effect that opposes vasoconstriction within the α 1 -adrenoceptor agonists’ concentration/contraction ranges. In a more limited study, α 1B -adrenoceptor localisation in endothelium and vascular smooth muscle; its mediation of vasoconstriction and vasodilatation were revealed directly for the first time. A reassessment of the balance between vasoconstriction and vasodilatation of catecholamines via the α 1 -adrenoceptor family, and of the consequences of their non-smooth muscle location, is indicated.
Authors: Laura Scott, John (Ian) McGrath
Institution: University of Glasgow
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4414206362
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