Effects of ρ‐Da1a a peptidic α1A‐adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats

• Published in: British journal of pharmacology 2013-02, Vol.168 (3), p.618-631
• Main Authors: Palea, S, Maiga, A, Guilloteau, V, Rekik, M, Guérard, M, Rouget, C, Rischmann, P, Botto, H, Camparo, P, Lluel, P, Gilles, N
• Format: Article
• Language: English
• Subjects: anaesthetized rats; arterial pressure; benign prostatic hyperplasia; human prostatic adenoma; intraurethral pressure; Research Papers; snake toxin; α1A‐adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02231.x

Background and Purpose ρ‐Da1a, a 65 amino‐acid peptide, has subnanomolar affinity and high selectivity for the human α1A‐adrenoceptor subtype. The purpose of this study was to characterize the pharmacological effects of ρ‐Da1a on prostatic function, both in vivo and in vitro. Experimental Approach ρ‐Da1a was tested as an antagonist of adrenaline‐induced effects on COS cells transfected with the human α1A‐adrenoceptor as well as on human isolated prostatic adenoma obtained from patients suffering from benign prostatic hyperplasia. Moreover, we compared the effects of ρ‐Da1a and tamsulosin on phenylephrine (PHE)‐induced increases in intra‐urethral (IUP) and arterial pressures (AP) in anaesthetized rats, following i.v. or p.o. administration. Key Results On COS cells expressing human α1A‐adrenoceptors and on human prostatic strips, ρ‐Da1a inhibited adrenaline‐ and noradrenaline‐induced effects. In anaesthetized rats, ρ‐Da1a and tamsulosin administered i.v. 30 min before PHE significantly antagonized the effects of PHE on IUP. The pKB values for tamsulosin and ρ‐Da1a for this effect were similar. With regards to AP, ρ‐Da1a only reduced the effect of PHE on AP at the lowest dose tested (10 μg·kg−1), whereas tamsulosin significantly reduced PHE effects at doses between 10 and 150 μg·kg−1. Conclusions and Implications ρ‐Da1a exhibited a relevant effect on IUP and a small effect on AP. In contrast, tamsulosin antagonized the effects of PHE on both IUP and AP. We conclude that ρ‐Da1a is more uroselective than tamsulosin. ρ‐Da1a is the most selective peptidic antagonist for α1A‐adenoceptors identified to date and could be a new treatment for various urological diseases.