The antipsychotic drug sertindole is a specific inhibitor of alpha1A-adrenoceptors in rat mesenteric small arteries.

We have investigated the adrenergic antagonist effect of the antipsychotic sertindole in rat resistance vessels and in membranes of HEK293 cells transfected with alpha1-adrenoceptors. Segments of rat mesenteric small arteries or rat aorta were mounted on a myograph for isometric tension recording. In mesenteric small arteries, specific alpha1A-adrenoceptor antagonists (5-methyl urapidil and WB-4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane)) inhibited phenylephrine responses with high affinity (pA2 9.1 and 9.5, respectively). Chlorethylclonidine (alpha1B- and alpha1D-adrenoceptor antagonist) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5] decane-7,9-dione dihydrochloride, alpha1D-adrenoceptor antagonist) had little effect. This indicated that the adrenoceptor subtype in the mesenteric small arteries was of the alpha1A subtype. Sertindole inhibited the phenylephrine response of mesenteric small arteries (pA2 9.0), but had little effect on the phenylephrine response of aorta (which lacks alpha1A-adrenoceptors). The specific action of sertindole on alpha1A-adrenoceptors was supported by experiments with membranes of HEK293 (human embryonic kidney) cells transfected with the alpha1A-, alpha1B- and alpha1D-adrenoceptors. Here, with concurrent incubation, sertindole showed selective competitive inhibition of BE2254 (2-beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralone) binding to alpha1A-adrenoceptors (Ki 8.9), compared to alpha1B-adrenoceptors (Ki 7.1) and alpha1D-adrenoceptors (Ki 6.8). Despite the apparent competitive action sertindole, it was not possible to wash out its antagonist effect within 6 h in the functional phenylephrine concentration-response experiments. Furthermore, in the membranes of HEK293 cells transfected with the alpha1A-adrenoceptors, binding of [125I]BE2254 was reduced by 45% following preincubation with sertindole (1 nM). We conclude that the alpha-adrenoceptors of rat mesenteric small arteries are of the alpha1A-type, and that sertindole is a specific pseudo-irreversible competitive antagonist of this adrenoceptor subtype.