The effects of SB 216469, an antagonist which discriminates between the alpha(1A)-adrenoceptor and the human prostatic alpha(1)-adrenoceptor

1 The affinity of the alpha-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha(1)-adrenoceptor subtypes by radioligand binding and at functional alpha(1)-adrenoceptor subtypes in isolated tissues. 2 In radioligand binding studies with [H-3]-prazosin, SE 216469 had a high affinity at the alpha(1A)-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha(1B)-adrenoceptors of the rat spleen and liver (7.7-8.2). 3 At cloned rat alpha(1)-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha(1)-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha(1a)-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha(1b)-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha(1d)-adrenoceptor (8.7-9.2). 4 At functional alpha(1)-adrenoceptors, SE 216469 had a similar pharmacological profile, with a high affinity at the alpha(1A)-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA(2) = 9.5 - 10.0), a low affinity at the alpha(1B)-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha(1D)-adrenoceptors of the rat aorta (8.8). 5 Several recent studies have concluded that the alpha(1)-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha(1A)-adrenoceptor subtype. However, the affinity of SE 216469 at human prostatic alpha(1)-adrenoceptors (pA(2) = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha(1a)-adrenoceptors (human, rat, bovine) or the native alpha(1A)-adrenoceptors in radioligand binding and functional studies in the rat. 6 Our results with SE 216469, therefore, suggest that the alpha(1)-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha(1a)-adrenoceptor or native alpha(1A)-adrenoceptor. Since it has previously been shown that the receptor is not the alpha(1B)- or alpha(1D)-adrenoceptor, the functional alpha(1)-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the alpha(1)-adrenoceptors currently defined by pharmacological means.