Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions.
BACKGROUND
Antimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity.


RESULTS
Intravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 microM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed. In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC. In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant. In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment. Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume.


CONCLUSIONS
Despite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.
Angelico
Patrizia
P
Pharmaceutical R & D Division, Recordati S.p.A., Via Civitali 1, 20148 Milan, Italy. Angelico.P@Recordati.it
Velasco
Cristina
C
Guarneri
Luciano
L
Sironi
Giorgio
G
Leonardi
Amedeo
A
Testa
Rodolfo
R
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology*; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000494:pharmacology*; D051381:Rats; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects*; D014546:Urinary Catheterization; D014549:Urinary Incontinence / Q000188:drug therapy; D014554:Urination / Q000187:drug effects*
D001559:Benzhydryl Compounds; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C005419:oxybutynin