title: Correlation between vasoconstrictor roles and mRNA expression of alpha1-adrenoceptor subtypes in blood vessels of genetically engineered mice.
abstract: We examined the contribution of each alpha(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) > alpha(1B)-adrenoceptor knockout (alpha(1B)-KO) (7.77) > alpha(1D)-AR knockout (alpha(1D)-KO) (6.44) > alpha(1B)- and alpha(1D)-AR double knockout (alpha(1BD)-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and alpha(1B)-KO mice (7.12) or alpha(1D)-KO (6.19) and alpha(1BD)-KO (6.29) mice. However, the CRC maximum responses to NAd in alpha(1D)- and alpha(1BD)-KO mice were significantly lower than those in WT and alpha(1B)-KO mice. Except in the thoracic aortas of alpha(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 alpha(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 alpha(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 alpha(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 alpha(1B)-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each alpha(1)-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each alpha(1)-AR subtype in mediating vascular contraction. The rank order of each alpha(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, alpha(1D)-AR > alpha(1B)-AR > alpha(1A)-AR in the thoracic aorta and alpha(1D)-AR > alpha(1A)-AR > alpha(1B)-AR in the mesenteric artery. No dramatic compensatory change of alpha(1)-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hosoda
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
authors.forename: Mari
authors.initials: M
authors.lastname: Shibano
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masami
authors.initials: M
authors.lastname: Hiroyama
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Koshimizu
authors.forename: Susanna
authors.initials: S
authors.lastname: Cotecchia
authors.forename: Tadaichi
authors.initials: T
authors.lastname: Kitamura
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Katsuo
authors.initials: K
authors.lastname: Koike
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C547717:Adra1b protein, mouse; C547720:Adra1d protein, mouse; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D010879:Piperazines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; C095285:silodosin; C053428:BMY 7378; D009638:Norepinephrine; D011224:Prazosin