α1‐Adrenoceptor antagonist properties of CGP 12177A and other β‐adrenoceptor ligands: evidence against β3‐ or atypical β‐adrenoceptors in rat aorta

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Abstract
The α1‐adrenoceptor antagonist properties of the β‐adrenoceptor nonconventional partial agonist, CGP 12177A, was investigated in functional assays in rat aorta and in radioligand binding assays in rat cerebral cortical membranes. In addition, binding affinities of other β‐adrenoceptor ligands were measured to investigate any correlation between α1‐adrenoceptor affinity and relaxant potency in phenylephrine‐constricted rings. In functional studies, CGP 12177A produced parallel rightward shifts of the phenylephrine CRC with no reduction in the maximum responses. Schild regression analysis gave a straight line with a slope of 0.95 (95% CL: 0.87–1.04), suggesting reversible competitive antagonism, and gave a pKB value of 5.26. In contrast, CGP 12177A (300 μM) had no effect on contraction induced by the thromboxane‐mimetic, U46619. In binding studies, CGP 12177A competed monophasically with [3H]prazosin binding (Hill slope, 0.95, 95% CL: 0.76–1.13), giving a pKi value of 5.48, in good agreement with the pKB from functional studies. Competition experiments with various other β‐adrenoceptor ligands showed that they all displaced [3H]prazosin in a manner consistent with one‐site competition. pKi values were as follows: SR 59230A, 6.25; cyanopindolol, 6.33; bupranolol, 6.35; alprenolol, 5.90; propranolol, 5.80; BRL 37344, 5.50; ICI 118551, 5.55; CGP 20712A, 5.26. The pKi values correlated well with the pEC50 values for relaxation of phenylephrine‐constricted rat aorta obtained previously (r2=0.984, Pβ‐adrenoceptor ligands in phenylephrine‐constricted rat aorta can be attributed to α1‐adrenoceptor blockade and are unrelated to effects at β3‐adrenoceptors or atypical β‐adrenoceptors. British Journal of Pharmacology (2004) 142, 781–787. doi:10.1038/sj.bjp.0705840