Pharmacological effects of tolterodine on human isolated urinary bladder

Tolterodine, (R)-N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylprop anamine, is an antimuscarinic drug developed for the treatment of overactiv e bladder with symptoms of frequency, urgency and urge incontinence. We inv estigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-ph enylpropanamine, on the contractions induced by carbachol, KCl, CaCl2 and e lectrical field stimulation in human isolated urinary bladder smooth muscle s, 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 concent ration-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), pr opiverine (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-methyl piperidine (4-DAMP) (10(-9)-10(-6) M) caused typical shifts to the right of the concentration-response curves for carbachol, except for higher concent rations (10(-5) M) of oxybutynin and propiverine, which caused a decrease o f about 30% of the maximum contractile responses to carbachol. All the slop es of the regression lines of Schild plots were close to unity, and the ran k order of pA(2) values was: atropine = DD 01 = tolterodine = 4-DAMP = oxyb utynin > 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 CaCl2-induced (5 mM) contractions, while oxybutynin (10(-8)-10(-5) M) a nd propiverine (10(-8)-10(-5) M) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contracti on 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 stimu lation at any of the frequencies, while oxybutynin (10(-5) M) and propiveri ne (10(-5) M) significantly inhibited the atropine-resistant part of the co ntractions. 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, a nd that tolterodine and DD 01 have neither Ca2+ channel antagonist action n or inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tol terodine as a therapeutic drug for overactive bladder with symptoms of freq uency, urgency and urge incontinence. (C) 1999 Elsevier Science B.V. All ri ghts reserved.