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Publications (7)13.18 Total impact

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    ABSTRACT: Background and Purposeρ-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 Approachρ-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 ResultsOn 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 Implicationsρ-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.
    British Journal of Pharmacology 02/2013; 168(3). · 5.07 Impact Factor
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    ABSTRACT: Background and Purposeρ‐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 Approachρ‐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 ResultsOn 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 Implicationsρ‐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.
    British Journal of Pharmacology 01/2013; 168(3). · 5.07 Impact Factor
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    ABSTRACT: Experimental urethral obstruction in rats alters micturition patterns with non-voiding activity (NVA) during filling cystometry, showing similarity to that observed in human detrusor overactivity. Several drug classes with therapeutic potential in overactive bladder in humans have been tested in this model in rats, rabbits or guinea pigs, but no detailed analysis of drug effects on cystometric patterns has been published. The present study uses a rat model of overactivity with partial bladder outflow obstruction (BOO) in combination with the procedures to analyse NVA to study the effects of the anticholinergic drug tolterodine and the novel β(3)-adrenoceptor agonist mirabegron. The current data for the first time show that NVA in rats with BOO is sensitive to both the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron, but with clear differences between the two drugs: during progression of bladder filling, tolterodine affected both the amplitude and frequency of NVA whereas mirabegron affected primarily the frequency. In addition, tolterodine dose-dependently reduced voiding contractions, while mirabegron did not. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism which is sensitive to cholinergic excitatory and beta-adrenergic inhibitory inputs. Such concepts could provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs. To investigate the hypothesis that tolterodine and the β(3)-adrenoceptor agonist mirabegron exert their actions on the motor component of the motor/sensory system in the bladder wall: non-voiding activity (NVA). The present study used standard cystometric techniques and a conscious rat model of partial bladder outflow obstruction (BOO). A single dose of either tolterodine (0.01, 0.1 0.3 or 1.0 mg/kg) or mirabegron (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg) was given i.v. to each animal. In the dose ranges used, tolterodine reduced the voiding contraction amplitude, whereas mirabegron did not. Non-voiding activity consisted of small (<0.6 mmHg) and large (>0.6 mmHg) transients. As a fill progressed, both tolterodine and mirabegron reduced the cumulative activity of the large non-voiding contractions, but had little effect on the small transients. Tolterodine affected both the amplitude and frequency of NVA, whereas mirabegron affected primarily the frequency. Non-voiding activity is sensitive to muscarinergic antagonists and β(3)-adrenoceptor agonists, but there are clear differences between the two drugs. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism with cholinergic excitatory and adrenergic inhibitory inputs. Such concepts may provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs.
    BJU International 07/2012; 110(2 Pt 2):E132-42. · 3.05 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Journal of Urology - J UROL. 01/2009; 181(4):506-507.
  • European Urology Supplements - EUR UROL SUPPL. 01/2009; 8(4):210-210.
  • Journal of Urology - J UROL. 01/2009; 181(4):569-569.