Pharmacological effects of tolterodine on human isolated urinary bladder

Abstract

Tolterodine, ( R)- N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, is an antimuscarinic drug developed for the treatment of overactive bladder with symptoms of frequency, urgency and urge incontinence. We investigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), ( R)- N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine, on the contractions induced by carbachol, KCl, CaCl 2 and electrical field stimulation in human isolated urinary bladder smooth muscles, using the muscle bath technique. Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome region of the bladder. Carbachol (10 −9–10 −2 M) caused concentration-dependent contraction of human detrusor smooth muscles. Tolterodine (10 −9–10 −6 M), DD 01 (10 −9–10 −6 M), oxybutynin (10 −8–10 −6 M), propiverine (10 −8–10 −6 M), atropine (10 −9–10 −6 M), pirenzepine (10 −8–10 −5 M), methoctramine (10 −8–10 −5 M) and 4-diphenylacetoxy- N-methylpiperidine (4-DAMP) (10 −9–10 −6 M) caused typical shifts to the right of the concentration–response curves for carbachol, except for higher concentrations (10 −5 M) of oxybutynin and propiverine, which caused a decrease of about 30% of the maximum contractile responses to carbachol. All the slopes of the regression lines of Schild plots were close to unity, and the rank order of p A 2 values was: atropine=DD 01=tolterodine=4-DAMP=oxybutynin>propiverine=pirenzepine>methoctramine. Tolterodine (10 −9–10 −6 M) and DD 01 (10 −9–10 −6 M) did not inhibit the KCl-induced (80 mM) and CaCl 2-induced (5 mM) contractions, while oxybutynin (10 −8–10 −5 M) and propiverine (10 −8–10 −5 M) significantly inhibited the contractions. Electrical field stimulation (2–60 Hz) caused frequency-dependent contraction of human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 10 −6 M atropine, tolterodine and DD 01 did not inhibit the residual contractions induced by electrical field stimulation at any of the frequencies, while oxybutynin (10 −5 M) and propiverine (10 −5 M) significantly inhibited the atropine-resistant part of the contractions. The results suggest that the inhibitory effects of tolterodine and DD 01 are mediated only by their antimuscarinic action, which is equal to that of oxybutynin and significantly greater than that of propiverine, and that tolterodine and DD 01 have neither Ca 2+ channel antagonist action nor inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tolterodine as a therapeutic drug for overactive bladder with symptoms of frequency, urgency and urge incontinence.