Different subtypes of α(1A)-adrenoceptor mediating contraction of rat epididymal vas deferens, rat hepatic portal vein and human prostate distinguished by the antagonist RS 17053

Abstract

1. The α1-adrenoceptor subtype mediating contraction of the rat hepatic portal vein to phenylephrine was characterized by use of competitive antagonists previously shown to have selectivity between the expressed α1-subtype clones. Prazosin competitively antagonized the phenylephrine contractions with a pA2 value of 9.2, as did WB 4101 (pA 9.4), 5-methyl urapidil (pA2 8.6), indoramin (pA2 8.4) and BMY 7378 (pA2 6.5). 2. The pA2 values on the rat portal vein correlated highly with their previously published pA2 values for the α(1A)-adrenoceptors mediating contraction of the rat epididymal vas deferens and human prostate and poorly with those for the α(1B)- and α(1D)-adrenoceptors mediating contraction of the rat spleen and aorta, respectively. The antagonist pA2 values on the rat portal vein correlated highly with their previously published pK1 values for the expressed α(1a)-clone and poorly with those for the expressed α(1b)- and α(1d)-clones. Therefore the results show that contraction of the rat portal vein to phenylephrine is mediated by α(1A)-adrenoceptors. 3. The novel α1-adrenoceptor antagonist RS 17053 had a relatively high affinity for the α(1A)-adrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the α(1B)-adrenoceptors in the rat spleen (pA2 7.2) or the α(1D)-adrenoceptors in the rat aorta (pK(B) 7.1), in agreement with its selectivity for the expressed α(1a)-clone. However, RS 17053 had over 100 fold lower affinity for the α(1A)-adrenoceptors mediating contraction of the rat portal vein (pK(B) 7.1) and human prostate (pK(B) 7.1) compared with its affinity for the α(1A)-adrenoceptors in the rat epididymal vas deferens or the expressed α(1a)-clone. 4. The difference in affinity of RS 17053 between the rat epididymal vas deferens and rat portal vein cannot be explained by a species difference in the receptor. Therefore RS 17053 may distinguish between subtypes of the α(1A)-adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed α(1a)-clone.