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α 1 ‐Adrenoceptor antagonist properties of CGP 12177A and other β ‐adrenoceptor ligands: evidence against β 3 ‐ or atypical β ‐adrenoceptors in rat aorta
Author(s) -
Brahmadevara Nataraj,
Shaw Angus M,
MacDonald Allan
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705840
Subject(s) - rauwolscine , prazosin , phenylephrine , chemistry , radioligand , antagonist , agonist , medicine , schild regression , endocrinology , potency , intrinsic activity , partial agonist , propranolol , alprenolol , stereochemistry , receptor , biology , biochemistry , blood pressure , in vitro
The α 1 ‐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 α 1 ‐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 p K B value of 5.26. In contrast, CGP 12177A (300 μ M ) had no effect on contraction induced by the thromboxane‐mimetic, U46619. In binding studies, CGP 12177A competed monophasically with [ 3 H]prazosin binding (Hill slope, 0.95, 95% CL: 0.76–1.13), giving a p K i value of 5.48, in good agreement with the p K B from functional studies. Competition experiments with various other β ‐adrenoceptor ligands showed that they all displaced [ 3 H]prazosin in a manner consistent with one‐site competition. p K i 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 p K i values correlated well with the pEC 50 values for relaxation of phenylephrine‐constricted rat aorta obtained previously ( r 2 =0.984, P <0.0001). In conclusion, relaxant effects of CGP 12177A and other β ‐adrenoceptor ligands in phenylephrine‐constricted rat aorta can be attributed to α 1 ‐adrenoceptor blockade and are unrelated to effects at β 3 ‐adrenoceptors or atypical β ‐adrenoceptors.British Journal of Pharmacology (2004) 142 , 781–787. doi: 10.1038/sj.bjp.0705840