Dependency of detrusor contractions on calcium sensitization and calcium entry through LOE-908-sensitive channels.

1. The subcellular mechanisms regulating stimulus-contraction coupling in detrusor remain to be determined. We used Ca(2+)-free solutions, Ca(2+) channel blockers, cyclopiazonic acid (CPA), and RhoA kinase (ROK) inhibitors to test the hypothesis that Ca(2+) influx and Ca(2+) sensitization play primary roles. 2. In rabbit detrusor, peak bethanechol (BE)-induced force was inhibited 90% by incubation for 3 min in a Ca(2+)-free solution. By comparison, a 20 min incubation of rabbit femoral artery in a Ca(2+)-free solution reduced receptor-induced force by only 5%. 3. In detrusor, inhibition of sarcoplasmic reticular (SR) Ca(2+) release by 2APB, or depletion of SR Ca(2+) by CPA, inhibited BE-induced force by only 27%. The CPA-insensitive force was abolished by LaCl3. By comparison, 2APB inhibited receptor-induced force in rabbit femoral artery by 71%. 4. In the presence of the non-selective cation channel (NSCC) inhibitor, LOE-908, BE did not produce an increase in [Ca(2+)]i but did produce weak increases in myosin phosphorylation and force. 5. Inhibitors of ROK-induced Ca(2+) sensitization, HA-1077 and Y-27632, inhibited BE-induced force by approximately 50%, and in combination with LOE-908, nearly abolished force. 6. These data suggest that two principal muscarinic receptor-stimulated detrusor contractile mechanisms include NSCC activation, that elevates [Ca(2+)]i and ROK activation, that sensitizes cross bridges to Ca(2+).

Rapid effects of estrogen and progesterone on tone and spontaneous rhythmic contractions of the rabbit bladder.

Previous studies indicate that bladder instability in man may be associated with increased spontaneous rhythmic contractile activity. Ca(2+) influx plays a central role in smooth muscle contractions, and recent evidence suggests that steroid hormones rapidly affect Ca(2+) influx. Therefore we tested the hypothesis that estrogen and progesterone modulates spontaneous rhythmic detrusor contractions. Tissues were secured to isometric force (F) transducers in tissue baths and length-adjusted until K(+)-depolarization produced maximum contractions (F(o)). Spontaneous rhythmic contractions (SRC) were sampled before and immediately after addition of estradiol or progesterone (10(-5) M) to tissue baths. The average frequency and amplitude of SRC were, respectively, 0.156 Hz and 0.053 F/F(o) (n = 24). Estradiol caused an immediate reduction in SRC, such that by 10 min, tone, frequency and amplitude were each reduced by, respectively, 36%, 46% and 47% (n = 7, P < 0.05). However, progesterone caused an immediate weak contraction, and at steady state (10 min), progesterone increased frequency of SRC by 152% but decreased SRC amplitude by 50% (n = 10, P < 0.05). Novel therapies using unique steroids that do not interact with genomic receptors may potentially reduce bladder smooth muscle activity, thereby reducing detrusor instability.

Differential effects of sex hormones and phytoestrogens on peak and steady state contractions in isolated rabbit detrusor.

PURPOSE: Recent evidence suggests that sex steroids may produce rapid inhibition of voltage operated Ca2+ channels (VOCCs). Detrusor smooth muscle is highly dependent upon Ca2+ influx for receptor-activated contractions. Thus, we examined the relative effectiveness of a select group of sex steroids and dietary phytoestrogens to relax detrusor contracted with the muscarinic receptor agonist, bethanechol (BE) and the purinergic P2X receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP). MATERIALS AND METHODS: Isolated strips of rabbit detrusor were secured to isometric force transducers in a tissue bath and length-adjusted until maximum contractions were achieved. Peak (P) contractile responses were recorded for alpha,beta-MeATP (P(ATP)) and BE (P(BE)) and steady-state (SS) responses were recorded for BE (SS(BE)) in the presence and absence of selected sex steroids and phytoestrogens (10 microM, unless indicated). RESULTS: The L-type VOCC inhibitor, nifedipine (1 to 10 microM), completely inhibited P(ATP) but reduced SS(BE) by approximately 50%, whereas the VOCC and non-VOCC inhibitor, SKF 96365, inhibited SS(BE) by approximately 95%, suggesting that P(ATP) was entirely dependent on L-type VOCCs, but (BE)-induced contractions depended also on activation of non-VOCCs. 17Beta-estradiol (estradiol) and progesterone inhibited P(ATP) by approximately 60% and 20%, respectively, and 32 microM estradiol and ethinyl estradiol inhibited SS(BE) by approximately 80 and 95%, respectively. Inhibition by estradiol was potentiated, rather than blocked, by the nuclear estrogen receptor antagonist, tamoxifen. Moreover, tamoxifen alone nearly completely relaxed SS(BE). The inactive metabolite of estradiol, 17alpha-estradiol, inhibited both P(ATP) and P(BE) by approximately 40%. Testosterone had no effect on P(ATP) and P(BE). The phytoestrogen and tyrosine kinase inhibitor, genistein, inhibited SS(BE) by 44%, whereas daidzein, a phytoestrogen without tyrosine kinase inhibitory activity, produced only a 7% inhibition. None of the phytoestrogens examined inhibited P(BE), whereas all inhibited P(ATP) by approximately 20 to 35%. A comparison of inhibition of (BE) and alpha,beta-MeATP-induced contractions by selected estrogen isomers showed some distinct differences. For example, estrone did not inhibit P(BE) or SS(BE), but inhibited P(ATP) by approximately 20%, whereas DES inhibited SS(BE) by nearly 90%, but P(ATP) by a lesser degree (approximately 70%). CONCLUSIONS: Our data support the hypothesis that 17beta-estradiol, ethinyl estradiol, DES, tamoxifen and genistein may relax detrusor contractions by inhibition of both VOCCs and non-VOCCs. Moreover, our data show that genistein, a dietary phytoestrogen with tyrosine kinase inhibitory activity, selectively reduced alpha,beta-MeATP-induced peak and BE-induced steady-state contractions, sparing the maximum response to BE. Lastly, the inactive isomer, 17alpha-estradiol, inhibited both BE- and alpha,beta-MeATP-induced contractions. These data suggest that certain dietary phytoestrogens (for example, genistein) or sex steroids, especially those with weak activity at the nuclear steroid site (for example, 17alpha-estradiol), or tamoxifen may prove therapeutically useful in treating overactive bladder caused by elevated muscarinic and purinergic receptor activation.

Comparative quality-of-life analysis after radical prostatectomy or external beam radiation for localized prostate cancer.

OBJECTIVES: To determine and compare quality-of-life (QOL) evaluations from patients who received external beam radiation therapy or radical prostatectomy for the treatment of localized prostate cancer, and to compare differences in QOL assessments for urinary and sexual function after radical prostatectomy as reported by patient and physician. METHODS: Two hundred three patients treated by radical prostatectomy and 257 patients treated by external beam irradiation, all beyond 12-month follow-up after therapy, responded to a QOL questionnaire. The difference in responses with regard to bladder, bowel, and sexual function, overall satisfaction with treatment, and choice of the same treatment were assessed. Satisfaction with and choice of the same treatment were also specifically assessed according to bowel and bladder function and current disease status. The medical records of patients treated by radical prostatectomy were reviewed by an independent data manager to record the physician's assessment of continence and sexual function for comparison with that patient's assessment as noted in the questionnaire. RESULTS: Problems with urinary continence were more frequent among patients treated by radical prostatectomy; problems with gastrointestinal function were more frequent after irradiation. Sexual dysfunction was similar in both groups, although surgical patients experienced a greater impact on sexual relationships. The physician estimates of urinary continence were more favorable than the patient-reported outcomes. However, the physician estimate of sexual function closely approximated that of the patient. Preservation of sexual function among patients who underwent nerve-sparing surgery was disappointingly low. Only for the response to the question dealing with difficulty in achieving an erection was there a statistically significant benefit for patients receiving nerve-sparing versus non-nerve-sparing procedures. Patient satisfaction with and choice of the same treatment varied according to function and current disease status. Patients who had incontinence or bowel dysfunction or had evidence of recurrent disease were statistically less likely to choose the same treatment again when compared with functional and disease-free counterparts. Because irradiated patients were on average 6 years older than surgical patients, responses were adjusted for age; adjustment for age did not alter results. CONCLUSIONS: QOL is determined by the treatment received, by the assessment source, and by the patient's function and disease status at the time of assessment. Prospective and longitudinal studies will more accurately quantify immediate and chronic alterations in QOL. Uniformity of evaluation through consolidation of QOL instruments will permit more accurate cross-series and cross-treatment comparisons.

Intravesical dimethyl sulfoxide for primary amyloidosis of the bladder.

Primary bladder amyloidosis is a rare disease. Treatment recommendations are necessarily anecdotal. We report a case of a 52-year-old woman treated successfully with intravesical dimethyl sulfoxide instillation.

Laparoscopic pyelolithotomy.

Laparoscopic surgery has been applied to virtually every aspect of urinary tract disease. Presented is a case of laparoscopic-extended pyelolithotomy accomplished in a 16-month-old child with a large cystine stone that occupied the child's entire renal pelvis. Although not the first pyelolithotomy accomplished laparoscopically, we believe this to be the first extended laparoscopic pyelolithotomy and also believe this is the youngest patient in whom laparoscopic pyelolithotomy has been done. Extracorporeal shock wave lithotripsy and percutaneous and endoscopic stone techniques have drastically modified the management of urolithiasis. However, select cases in which these techniques may not be applicable (such as this toddler with bulky cystine lithiasis) may require open surgery. The laparoscopic approach represents an excellent, yet less-invasive option.