Insights into the functional roles of alpha; 1-adrenoceptor subtypes in mouse carotid arteries using knockout mice

Abstract

? 1-Adrenoceptor (AR) subtypes in mouse carotid arteries were characterised using a combination of agonist/antagonist pharmacology and knockout (KO) mice. Phenylephrine (PE) was most potent in the ? 1B-KO (pEC 50 = 6.9 آ± 0.2) followed by control (pEC 50 = 6.3 آ± 0.06) and ? 1D-KO (pEC 50 = 5.5 آ± 0.07). Both N-[5-(4,5-dihydro-1H-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 ? 1D-KO (pEC 50 = 7.4 آ± 0.27 and 7.4 آ± 0.05, respectively) than the control (pEC 50 = 6.9 آ± 0.09 and 6.9 آ± 0.08, respectively) and equipotent with the control in the ? 1B-KO (pEC 50 = 6.7 آ± 0.07 and 6.8 آ± 0.04). Maximum responses to PE and A-61603 were reduced in the ? 1D-KO compared to control; there was no difference in maximum responses to 5-HT. In control arteries, prazosin and 5-methylurapidil acted competitively with pA 2 of 9.6 and 7.5, respectively. BMY7378 produced antagonism only at the highest concentration used (100 nMl; pK B 8.3). Prazosin, 5-methylurapidil and BMY7378 acted competitively in ? 1B-KO carotid arteries with pA 2 of 10.3, 7.6 and 9.6, respectively. In the ? 1D-KO, against PE, 5-methylurapidil produced a pA 2 of 8.1. pK B values were calculated for prazosin (10.6) and BMY7378 (7.0). Against A-61603, 5-methylurapidil had a pA 2 of 8.5, prazosin 8.6, while BMY7378 had no effect. In conclusion, the ? 1B-KO mediates contraction solely through ? 1D-ARs and the ? 1D-KO through ? 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 ? 1D-AR causes the contractile response and that the role of the ? 1B-AR is mainly regulatory. آ© 2005 Nature Publishing Group All rights reserved.