ALpha1-adrenoceptor antagonist properties of CGP 12177A and other beta-adrenoceptor ligands: evidence against beta(3)- or atypical beta-adrenoceptors in rat aorta.

1. The alpha(1)-adrenoceptor antagonist properties of the beta-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 beta-adrenoceptor ligands were measured to investigate any correlation between alpha(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 (<or=300 microm) had no effect on contraction induced by the thromboxane-mimetic, U46619. 3. In binding studies, CGP 12177A competed monophasically with [(3)H]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 beta-adrenoceptor ligands showed that they all displaced [(3)H]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 beta-adrenoceptor ligands in phenylephrine-constricted rat aorta can be attributed to alpha(1)-adrenoceptor blockade and are unrelated to effects at beta(3)-adrenoceptors or atypical beta-adrenoceptors.