α 1-Adrenoceptor antagonist properties of CGP 12177A and other β-adrenoceptor ligands: Evidence against β 3- Or atypical β-adrenoceptors in rat aorta

Abstract

1. 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. 2. 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 pK B value of 5.26. In contrast, CGP 12177A (≤ 300 μM) had no effect on contraction induced by the thromboxane-mimetic, U46619. 3. In binding studies, CGP 12177A competed monophasically with [ 3H]prazosin binding (Hill slope, 0.95, 95% CL: 0.76-1.13), giving a pK i value of 5.48, in good agreement with the pK B from functional studies. 4. Competition experiments with various other β-adrenoceptor ligands showed that they all displaced [ 3H]prazosin in a manner consistent with one-site competition. pK 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 pK 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). 5. 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.