Insights into the functional roles of α 1 ‐adrenoceptor subtypes in mouse carotid arteries using knockout mice

1 α 1 ‐Adrenoceptor (AR) subtypes in mouse carotid arteries were characterised using a combination of agonist/antagonist pharmacology and knockout (KO) mice. 2 Phenylephrine (PE) was most potent in the α 1B ‐KO (pEC 50 =6.9±0.2) followed by control (pEC 50 =6.3±0.06) and α 1D ‐KO (pEC 50 =5.5±0.07). Both N ‐[5‐(4,5‐dihydro‐1 H ‐imidazol‐2yl)‐2‐hydroxy‐5,6,7,8‐tetrahydronaphthalen‐1‐yl] methanesulphonamide hydrobromide (A‐61603) and 5‐hydroxytryptamine (5‐HT) were more potent in the α 1D ‐KO (pEC 50 =7.4±0.27 and 7.4±0.05, respectively) than the control (pEC 50 =6.9±0.09 and 6.9±0.08, respectively) and equipotent with the control in the α 1B ‐KO (pEC 50 =6.7±0.07 and 6.8±0.04). Maximum responses to PE and A‐61603 were reduced in the α 1D ‐KO compared to control; there was no difference in maximum responses to 5‐HT. 3 In control arteries, prazosin and 5‐methylurapidil acted competitively with p A 2 of 9.6 and 7.5, respectively. BMY7378 produced antagonism only at the highest concentration used (100 n M ; p K B 8.3). 4 Prazosin, 5‐methylurapidil and BMY7378 acted competitively in α 1B ‐KO carotid arteries with p A 2 of 10.3, 7.6 and 9.6, respectively. 5 In the α 1D ‐KO, against PE, 5‐methylurapidil produced a p A 2 of 8.1. p K B values were calculated for prazosin (10.6) and BMY7378 (7.0). Against A‐61603, 5‐methylurapidil had a p A 2 of 8.5, prazosin 8.6, while BMY7378 had no effect. 6 In conclusion, the α 1B ‐KO mediates contraction solely through α 1D ‐ARs and the α 1D ‐KO through α 1A ‐ARs. Extrapolating back to the control from the knockout data suggests that all three subtypes could be involved in the responses, but we propose that the α 1D ‐AR causes the contractile response and that the role of the α 1B ‐AR is mainly regulatory.British Journal of Pharmacology (2005) 144 , 558–565. doi: 10.1038/sj.bjp.0706089