A knockout approach indicates a minor vasoconstrictor role for vascular α 1B-adrenoceptors in mouse

Abstract

Pharmacological analysis alone has failed to clarify the role of the three α1-adrenoceptor subtypes in modulating vascular tone, due to a lack of sufficiently selective antagonists, particularly for the α 1B-adrenoceptor, and the complexity when three receptor subtypes are potentially activated by the same agonist. We adopted a combined genetics/ pharmacology strategy based on the α1B-adrenoceptor knockout (KO) mouse. The potency of three α1-adrenoceptor antagonists vs. phenylephrine was tested in aorta, carotid, mesenteric, and caudal isolated arteries from KO and wild-type (WT) mice. In the KO mouse the pharmacology became straightforward, showing α1D in two major conducting arteries (aorta and carotid) and α1A in two distributing arteries (mesenteric and caudal). By combining antagonist pharmacology and genetics, we provide a simplified analysis of α1-mediated vasoconstriction, demonstrating that α1D and α1A are the major subtypes involved in vasoconstriction, with a minor but definite contribution from α1B in every vessel.