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

3 The novel ax-adrenoceptor antagonist RS 17053 had a relatively high affinity for the aAadrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the alB-adrenoceptors in the rat spleen (pA2 7.2) or the aID-adrenoceptors in the rat aorta (pKB 7.1), in agreement with its selectivity for the expressed a,.-clone. However, RS 17053 had over 100 fold lower affinity for the aIA-adrenoceptors mediating contraction of the rat portal vein (pKB 7.1) and human prostate (pKB 7.1) compared with its affinity for the alA-adrenoceptors in the rat epididymal vas deferens or the expressed aa-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 aIA-adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed ala-clone.

Signal Transduction Pathways Associated with α₁-Adrenoceptor Subtypes in Cells and Tissues Including Human Prostate

“…A low affinity was also found at the α 1A -adrenoceptor in rat portal vein but not in the epididymal vas deferens [5]. This difference may reflect different subtypes or states of α 1A -adrenoceptors and the low RS 17053 affinity receptor may be similar to that provisionally called the α 1L -subtype.…”

“…The probability of receptor identity was suggested by a high correlation between the functionally defined tissue affinities (pA 2 values) and the pK i values from binding experiments using membranes from cells transfected with a given subtype. Subsequently a similar approach has characterised the contraction of the rat portal vein and human prostate as mediated via the α 1A -subtype [5, 6]. In all these tissues the affinity of prazosin was 9 or above with the exception of the prostate (8.5).…”

“…However the compound RS 17053 had a high affinity at α 1a -sites but was 100-fold weaker at human prostatic α 1A -adrenoceptors [5, 7]. A low affinity was also found at the α 1A -adrenoceptor in rat portal vein but not in the epididymal vas deferens [5].…”

Pharmacological characterization of α-adrenoceptors that mediate contraction in splenic artery strips from the pig

“…Several α 1 -adrenoceptor antagonists with various degrees of subtype selectivity are currently available, such as WB-4101 (α 1A ≥α 1D >α 1B ), benoxathian (α 1A =α 1D >α 1B ), 5-methylurapidil (α 1A >α 1D >α 1B ), RS-17053 (α 1A >α 1D =α 1B ) and BMY (α 1D >>α 1B =α 1A ) (Goetz et al 1995;Eltze, 1996;Ford et al 1996;Marshall et al 1996). No competitive antagonists with high selectivity for α 1B -adrenoceptors have been reported to date, but the sensitivity to irreversible alkylation by chloroethylclonidine can be used to differentiate α 1B -and α 1D -adrenoceptors from α 1A -adrenoceptors (Hieble et al 1995).…”

Properties of Alpha-1-Adrenergic Receptors in the Rat Prostate: Effect of Experimental Diabetes

“…The recent International Union of Pharmacolo-gy Nomenclature and Adrenoceptors classified · 1 -adrenoceptors into three subtypes, i.e., · 1A , · 1B , and · 1D [12]. The results of · 1 -adrenoceptor subtyping in the human prostate have been variable with reports of the presence of · 1A [6], · 1B [13], · 1C [14], · 1A + · 1B [15] and · 1A [16,17] subtypes in this tissue. Canine prostate has been reported to contain the · 1C subtype [7], whereas the rat prostate has been reported to contain the · 1A subtype [11].…”