Effects of tolterodine on afferent neurotransmission in normal and resiniferatoxin treated conscious rats.
OBJECTIVE
The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters.


METHODS
The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine.


RESULTS
In resiniferatoxin treated animals (0.3 mg kg-1 subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 microg kg-1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 microg kg-1 tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 microg kg-1 apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment.


CONCLUSIONS
Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding.
Hedlund
Petter
P
Department of Clinical and Experimental Pharmacology, Lund University Hospital, Lund, Sweden.
Streng
Tomi
T
Lee
Tack
T
Andersson
Karl-Erik
KE
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D005260:Female; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D010665:Phenylpropanolamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects; D014563:Urodynamics
D001559:Benzhydryl Compounds; D003408:Cresols; D004224:Diterpenes; D018727:Muscarinic Antagonists; D009498:Neurotoxins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C024353:resiniferatoxin