Correlation between vasoconstrictor roles and mRNA expression of α1‐adrenoceptor subtypes in blood vessels of genetically engineered mice

We examined the contribution of each α1-adrenoceptor (AR) subtype in noradrenaline (NAd)-evoked contraction in the thoracic aortas and mesenteric arteries of mice. Compared with the concentration–response curves (CRCs) for NAd in the thoracic aortas of wild-type (WT) mice, the CRCs of mutant mice showed a significantly lower sensitivity. The pD2 value in rank order is as follows: WT mice (8.21)>α1B-adrenoceptor knockout (α1B-KO) (7.77)>α1D-AR knockout (α1D-KO) (6.44)>α1B- and α1D-AR double knockout (α1BD-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and α1B-KO mice (7.12) or α1D-KO (6.19) and α1BD-KO (6.29) mice. However, the CRC maximum responses to NAd in α1D- and α1BD-KO mice were significantly lower than those in WT and α1B-KO mice. Except in the thoracic aortas of α1BD-KO mice, the competitive antagonist prazosin inhibited the contraction response to NAd with high affinity. However, prazosin produced shallow Schild slopes in the vessels of mice lacking the α1D-AR gene. In the thoracic aorta, pA2 values in WT mice for KMD-3213 and BMY7378 were 8.25 and 8.46, respectively, and in α1B-KO mice they were 8.49 and 9.13, respectively. In the mesenteric artery, pA2 values in WT mice for KMD-3213 and BMY7378 were 8.34 and 7.47, respectively, and in α1B-KO mice they were 8.11 and 7.82, respectively. These pharmacological findings were in fairly good agreement with findings from comparison of CRCs, with the exception of the mesenteric arteries of WT and α1B-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each α1-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each α1-AR subtype in mediating vascular contraction. The rank order of each α1-AR subtype in terms of its vasoconstrictor role was in fairly good agreement with the level of expression of mRNA of each subtype, that is, α1D-AR>α1B-AR>α1A-AR in the thoracic aorta and α1D-AR>α1A-AR>α1B-AR in the mesenteric artery. No dramatic compensatory change of α1-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis. British Journal of Pharmacology (2005) 146, 456–466. doi:10.1038/sj.bjp.0706325