title: Effects of ρ-Da1a a peptidic α(1)             (A) -adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats.
abstract: OBJECTIVE
  ρ-Da1a, a 65 amino-acid peptide, has subnanomolar affinity and high selectivity for the human α(1)             (A) -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.
  
  
  METHODS
  ρ-Da1a was tested as an antagonist of adrenaline-induced effects on COS cells transfected with the human α(1)             (A) -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.
  
  
  RESULTS
  On COS cells expressing human α(1)             (A) -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 pK(B)  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
  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 α(1A) -adenoceptors identified to date and could be a new treatment for various urological diseases.
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, Toulouse, France. stefano.palea@urosphere.com
authors.forename: S
authors.initials: S
authors.lastname: Palea
authors.forename: A
authors.initials: A
authors.lastname: Maiga
authors.forename: V
authors.initials: V
authors.lastname: Guilloteau
authors.forename: M
authors.initials: M
authors.lastname: Rekik
authors.forename: M
authors.initials: M
authors.lastname: Guérard
authors.forename: C
authors.initials: C
authors.lastname: Rouget
authors.forename: P
authors.initials: P
authors.lastname: Rischmann
authors.forename: H
authors.initials: H
authors.lastname: Botto
authors.forename: P
authors.initials: P
authors.lastname: Camparo
authors.forename: P
authors.initials: P
authors.lastname: Lluel
authors.forename: N
authors.initials: N
authors.lastname: Gilles
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000368:Aged; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D004546:Elapid Venoms / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D014521:Urethra / Q000187:drug effects / Q000502:physiology
chemical_list: C549220:AdTx1 peptide, Dendroaspis angusticep; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D004546:Elapid Venoms; D010455:Peptides; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D010656:Phenylephrine; D000077409:Tamsulosin; D009638:Norepinephrine; D004837:Epinephrine