α1D-Adrenoceptor regulates the vasopressor action of α1A-adrenoceptor in mesenteric vascular bed of α1D-adrenoceptor knockout mice

Abstract

1 The pressor action of the α_1A-adrenoceptor (α_1A-AR) agonist A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulfonamide) and the α₁-ARs agonist phenylephrine and their blockade by selective α₁-ARs antagonists in the isolated mesenteric vascular bed of wild-type (WT) mice and α_1D-AR knockout (KO α_1D-AR) mice were evaluated.

2 The apparent potency of A61603 to increase the perfusion pressure in the mesenteric vascular bed of WT and KO α_1D-AR mice is 86 and 138 times the affinity of phenylephrine, respectively.

3 A61603 also enhanced the perfusion pressure by ≈1.7 fold in the mesenteric vascular bed of WT mice compared with KO α_1D-AR mice.

4 Because of its high affinity, low concentrations of the α_1A-AR selective antagonist RS100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione) shifted the agonist concentration–response curves to the right in the mesenteric vascular bed of WT and KO α_1D-AR mice.

5 The α_1D-AR selective antagonist BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dione) did not modify the A61603 or the phenylephrine-induced pressor effect.

6 The α_1B/D-ARs alkylating antagonist chloroethylclonidine (CEC) shifted the agonist concentration–response curves to the right and decreased the maximum phenylephrine-induced vascular contraction in KO α_1D-AR mice when compared to WT mice; however, CEC only slightly modified the contraction induced by A61603.

7 The results indicate that the isolated mesenteric vascular bed of WT and KO α_1D-AR mice expresses α_1A-AR, that the pressor action of α_1A-AR is up-regulated for α_1D-AR in WT mice and suggest an important role of α_1B-AR in the vascular pressure evoked by phenylephrine in KO α_1D-AR mice.