Correlation between vasoconstrictor roles and mRNA expression of α 1-adrenoceptor subtypes in blood vessels of genetically engineered mice

Abstract

We examined the contribution of each α 1-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 pD 2 value in rank order is as follows: WT mice (8.21)>α 1B-adrenoceptor knockout (α 1B-KO) (7.77)>α 1D-AR knockout (α 1D-KO) (6.44)>α 1B- and α 1D-AR double knockout (α 1BD-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and α 1B-KO mice (7.12) or α 1D-KO (6.19) and α 1BD-KO (6.29) mice. However, the CRC maximum responses to NAd in α 1D- and α 1BD-KO mice were significantly lower than those in WT and α 1B-KO mice. Except in the thoracic aortas of α 1BD-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 α 1D-AR gene. In the thoracic aorta, pA 2 values in WT mice for KMD-3213 and BMY7378 were 8.25 and 8.46, respectively, and in α 1B-KO mice they were 8.49 and 9.13, respectively. In the mesenteric artery, pA 2 values in WT mice for KMD-3213 and BMY7378 were 8.34 and 7.47, respectively, and in α 1B-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 α 1B-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each α 1-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each α 1-AR subtype in mediating vascular contraction. The rank order of each α 1-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, α 1D-AR>α 1B- AR>α 1A-AR in the thoracic aorta and α 1D- AR>α 1A-AR>α 1B-AR in the mesenteric artery. No dramatic compensatory change of α 1-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis. © 2005 Nature Publishing Group All rights reserved.