Hepatocytes from α 1B ‐adrenoceptor knockout mice reveal compensatory adrenoceptor subtype substitution

α 1 ‐Adrenoceptors (ARs) play an important functional role in the liver; yet little is known about their cellular location. We identified the subtypes present in wild‐type (WT) and α 1B ‐AR knockout (KO) mice livers at 3 and 4 months of age, and investigated their distribution in hepatocytes. The fluorescent α 1 ‐AR antagonist quinazolinyl piperazine borate‐dipyrromethene (QAPB) was used to visualise hepatic α 1 ‐ARs and radioligand binding with [ 3 H]‐prazosin was used to quantify the α 1 ‐AR population. QAPB and [ 3 H]‐prazosin bound specifically to hepatic α 1 ‐ARs with nanomolar affinity. The cellular distribution of α 1 ‐ARs was similar in WT and α 1B ‐AR KO hepatocytes; QAPB binding was distributed diffusely throughout the cell with no binding evident on the plasma membrane. Radioligand binding produced B max values as follows: 3‐month WT – 76±3.3 fmol mg −1 ; 4‐month WT – 50±3.1 fmol mg −1 ; 3‐month α 1B ‐AR KO – 7.4±0.73 fmol mg −1 ; 4‐month α 1B ‐AR KO – 30±2.0 fmol mg −1 . In 3‐ and 4‐month WT liver, all antagonists acted competitively. RS100329 ( α 1A ‐selective) and BMY7378 ( α 1D ‐selective) bound with low affinities, indicating the presence of α 1B ‐ARs. In 4‐month α 1B ‐AR KO liver prazosin produced a biphasic curve, whereas RS100329 and BMY7378 produced monophasic curves of high and low affinity, respectively, indicating the presence of α 1A ‐ARs. In conclusion, we have made the novel observation that α 1 ‐ARs can compensate for one another in the absence of the endogenously expressed receptor; yet there appears to be no subtype‐specific subcellular location of α 1 ‐ARs; the WT livers express α 1B ‐ARs, while α 1B ‐AR KO livers express α 1A ‐ARs. This study provides new insights into both hepatocyte and α 1 ‐AR biology.British Journal of Pharmacology (2004) 142 , 1031–1037. doi: 10.1038/sj.bjp.0705872