Identification of alpha sub(1L)-adrenoceptor in mice and its abolition by alpha sub(1A)-adrenoceptor gene knockout

Background and purpose: The alpha sub(1L)-adrenoceptor has pharmacological properties that distinguish it from three classical alpha sub(1)-adrenoceptors ( alpha sub(1A), alpha sub(1B) and alpha sub(1D)). The purpose of this was to identify alpha sub(1L)-adrenoceptors in mice and to examine their relationship to classical alpha sub(1)-adrenoceptors. Experimental approach: Radioligand binding and functional bioassay experiments were performed on the cerebral cortex, vas deferens and prostate of wild-type (WT) and alpha sub(A)-, alpha sub(1B)- and alpha sub(1D)-adrenoceptor gene knockout (AKO, BKO and DKO) mice. Key results: The radioligand [ super(3)H]-silodosin bound to intact segments of the cerebral cortex, vas deferens and prostate of WT, BKO and DKO but not of AKO mice. The binding sites were composed of two components with high and low affinities for prazosin or RS-17053, indicating the pharmacological profiles of alpha sub(1A)-adrenoceptors and alpha sub(1L)-adrenoceptors. In membrane preparations of WT mouse cortex, however, [ super(3)H]-silodosin bound to a single population of prazosin high-affinity sites, suggesting the presence of alpha sub(1A)-adrenoceptors alone. In contrast, [ super(3)H]-prazosin bound to two components having alpha sub(1A)-adrenoceptor and alpha sub(1B)-adrenoceptor profiles in intact segments of WT and DKO mouse cortices, but AKO mice lacked alpha sub(1A)-adrenoceptor profiles and BKO mice lacked alpha sub(1B)-adrenoceptor profiles. Noradrenaline produced contractions through alpha sub(1L)-adrenoceptors with low affinity for prazosin in the vas deferens and prostate of WT, BKO and DKO mice. However, the contractions were abolished or markedly attenuated in AKO mice. Conclusions and implications: alpha sub(1L)-Adrenoceptors were identified as binding and functional entities in WT, BKO and DKO mice but not in AKO mice, suggesting that the alpha sub(1L)-adrenoceptor is one phenotype derived from the a sub(1A)-adrenoceptor gene.