Spinal effects of the fesoterodine metabolite 5-hydroxymethyl tolterodine and/or doxazosin in rats with or without partial urethral obstruction.
OBJECTIVE
The combination of muscarinic receptor and alpha(1)-adrenoceptor antagonists is increasingly used for benign prostatic hyperplasia related lower urinary tract symptoms. In addition to the well established peripheral site of action, little is known about the central effects of muscarinic receptor antagonists and muscarinic receptor/alpha(1)-adrenoceptor antagonist combinations on bladder function, partly due to poor brain penetration after systemic administration. We assessed the effects of intrathecal 5-hydroxymethyl tolterodine, an active metabolite of fesoterodine, in obstructed and nonobstructed rats, and of combined intrathecal 5-hydroxymethyl tolterodine/doxazosin in a rat model of partial urethral obstruction.


METHODS
We used 80 male Sprague-Dawley rats to test various doses of intrathecal 5-hydroxymethyl tolterodine and/or intrathecal doxazosin on urodynamic parameters. Urodynamic evaluation without anesthesia was done 3 days after bladder and intrathecal catheterization. Two weeks before urodynamics 40 rats underwent partial urethral obstruction.


RESULTS
Intrathecal 5-hydroxymethyl tolterodine had no urodynamic effects in nonobstructed rats. Compared to controls obstructed rats had increased bladder pressure and weight, and voiding frequency. In obstructed rats 5-hydroxymethyl tolterodine restored urodynamic parameters to those seen in nonobstructed animals. Doxazosin had effects similar to those of intrathecal 5-hydroxymethyl tolterodine. When the 2 drugs were combined, at the doses used only small additional effects were observed.


CONCLUSIONS
Urodynamic changes in obstructed rats can be normalized by intrathecal 5-hydroxymethyl tolterodine and by intrathecal doxazosin. The central pathways on which the 2 drugs act seem to be up-regulated with partial urethral obstruction and less relevant under normal conditions.
Füllhase
Claudius
C
Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA. claudius.fuellhase@med.uni-muenchen.de
Soler
Roberto
R
Gratzke
Christian
C
Brodsky
Marina
M
Christ
George J
GJ
Andersson
Karl-Erik
KE
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D003408:Cresols / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D017292:Doxazosin / Q000494:pharmacology* / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects*; D014524:Urethral Obstruction / Q000188:drug therapy*
C109909:5-hydroxymethyl tolterodine; D000317:Adrenergic alpha-Antagonists; D001559:Benzhydryl Compounds; D003408:Cresols; C526675:fesoterodine; D017292:Doxazosin