b1-Adrenoceptors compensate for b3-adrenoceptors in ileum from b3-adrenoceptor knock-out mice

1 This study examines b1-, b2and b3-adrenoceptor (AR)-mediated responses, mRNA levels and radioligand binding in ileum from b3-AR knock-out (7/7) (KO) and wild type (+/+) (FVB) mice. 2 In KO and FVB mice, SR59230A (100 nM) (b3-AR antagonist) antagonized responses to (7)isoprenaline in both KO and FVB mice. (7)-Isoprenaline mediated relaxation of ileum was antagonized weakly by ICI118551 (100 nM) (b2-AR antagonist). Responses to (7)-isoprenaline were more strongly antagonized by CGP20712A (100 nM) (b1-AR antagonist), propranolol (1 mM) (b1-/ b2-AR antagonist), carvedilol (100 nM) (non-speci®c b-AR antagonist), and CGP12177A (100 nM) (b1-/b2-AR antagonist) in ileum from KO than in FVB mice. 3 Responses to CL316243 (b3-AR agonist) in ileum from FVB mice were antagonized by SR59230A (100 nM) but not by propranolol (1 mM) or carvedilol (100 nM). CL316243 was ine€ective in relaxing ileum from KO mice. 4 CGP12177A had no agonist actions in ileum from either KO or FVB mice. 5 b1-AR mRNA levels were increased 3 fold in ileum from KO compared to FVB mice. This was associated with an increased maximum number of b1-/b2-AR binding sites (Bmax). b2-AR mRNA levels were una€ected while no b3-AR mRNA was detected in KO mice. 6 In mouse ileum, b3-ARs and to a lesser extent b1-ARs are the predominant adrenoceptor subtypes mediating relaxation in ileum from FVB mice. In KO mice b1-ARs functionally compensate for the lack of b3-ARs, and this is associated with increased b1-AR mRNA and levels of binding. British Journal of Pharmacology (2001) 132, 433 ± 442