Hiroaki Kikukawa

Pharmacological effects of tolterodine on human isolated urinary bladder

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-phenylpropa namine, on the contractions induced by carbachol, KCl, CaCl2 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 pA2 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 CaCl2-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 Ca2+ 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.

Measurement of acetylcholine released from rabbit detrusor smooth muscle using HPLC with electro-chemical detection coupled with microdialysis procedure.

We measured the amount of acetylcholine (ACh) released from rabbit detrusor smooth muscles induced by electrical field stimulation (EFS) using microdialysis procedure. The dialysis probe was inserted through the detrusor muscle strip and was continuously perfused with a Ringer solution containing physostigmine sulfate, at a rate of 2 microl/min. The strip was suspended in an organ bath filled with the modified Krebs-Henseleit solution and then EFS was delivered. The isometric force was recorded and monitored in each muscle preparation. The dialysates were collected every 10 min. ACh was determined by a high performance liquid chromatography with electro-chemical detection. The contraction of the muscle strip and ACh release induced by EFS were increased in a frequency and duration dependent manner. There were some differences between frequency response curves of contraction and frequency dependent ACh release. In the contractile response, the maximum contractions were observed at lower frequencies, while ACh releases reached the maximum at higher frequencies. There was a significant, but not simple correlation between EFS-induced contraction and ACh release. The results suggest that this new method is useful to investigate the ACh release from rabbit detrusor smooth muscles, and that other neurotransmitters than ACh possibly contribute to EFS-induced contraction.

Primitive neuroectodermal tumour of the kidney with spontaneous regression of pulmonary metastases after nephrectomy

A 23-year-old women was admitted complaining of a 7-month history of general fatigue, slight fever, right flank pain and gross haematuria. CT showed a a 13 ¥ 10 cm right renal mass (Fig. la) and several nodules in both lungs, suggesting multiple pulmonary metastases. CT and cavography revealed a filling defect in the right renal vein and the inferior vena cava (IVC), suggesting a tumour thrombus in both (Fig. la). Aortography showed the mass to be hypervascular (Fig. lb). She underwent radical nephrectomy with cavotomy under a diagnosis of metastatic RCC with IVC tumour thrombus. The pulmonary metastatic lesions decreased in size and number 14 days after surgery (Fig. 1c) and subsequently increasingly regressed with time. At 2 months after surgery they had completely regressed (Fig. 1d) . Before surgery her urinary excretion of homovanillic acid (HVA) and vanillylmandelic acid (VMA) were 3.3 and 3.3 mg/day (within the normal ranges; HVA 1.5–6.6 mg/day; VMA 1.3–5.1 mg/day). The histological findings of the resected tumour showed the typical small round to ovoid tumour cells and several neuroblastic Homer Wright rosettes, suggesting the tumour to be a primitive neuroectodermal tumour (PNET) or neuroblastoma (Fig. 2a). Positive reactions were obtained with the antibodies against synaptophysin, neurone-specific enolase, S100 protein and CD99 (MIC2) [1] (Fig. 2b) but not to chromogranin and neurofilament. Taken together, the histological findings and laboratory results suggested a diagnosis of PNET of the kidney. The resection of the primary lesion was probably responsible for the complete regression of the pulmonary metastases. The patient remains well 1 year after surgery.

Pharmacologic Actions of Temiverine (p-INN) and its Active Metabolite, RCC-36, on Isolated Human Urinary Bladder Muscle

Background: Temiverine (p‐INN) is a newly synthesized drug that is expected to have anticholinergic action. We investigated the pharmacologic actions of temiverine and its active metabolite, RCC‐36, on isolated human bladder.

Lower urinary tract dysfunction in type 1 familial amyloidotic polyneuropathy in Kumamoto, Japan.

Objective: To evaluate lower urinary tract dysfunction of type 1 familial amyloidotic polyneuropathy (FAP) patients in Kumamoto, Japan.

Neurologic toxicity associated with interferon α therapy for renal cell carcinoma

Abstract  A 67‐year‐old man received interferon α (IFN α) therapy for lung metastases of renal cell carcinoma (RCC). Multiple pulmonary metastases disappeared completely. However, neurological toxicity was detected by magnetic resonance imaging (MRI) as abnormal brain lesions. After discontinuation of IFN α therapy, his neurological symptoms and abnormal lesions on MRI disappeared completely. Complete remission of RCC has continued, and results of neurological study have remained normal for 5 years after discontinuation of IFN α therapy.

Isolated Renal Tuberculosis following Intravesical Bacillus Calmette-Guérin Therapy for Bladder Cancer

We present a case of isolated renal tuberculosis following bacillus Calmette-Guérin (BCG) therapy for bladder cancer. In the presurgical radiographic examination, we suspected an atypical renal cell carcinoma. According to the diagnosis of renal cell carcinoma, we performed a radical nephrectomy. The histological findings were tuberculosis-specific inflammatory changes and the patient received an antituberculous multiple drug therapy for a year. It is concluded that we should pay attention to the possibility of a renal tuberculosis granuloma in any patient who presented with subacute formed renal masses following BCG treatment before deciding on the strategy of the treatment of the renal masses, especially in patients who had received such a treatment which induced an immunocompromised state.

Effects of castration on nitric oxide-mediated relaxations in male rat corpus cavernosum smooth muscle.

Background: The effects of castration on nitric oxide- mediated relaxations and nitric oxide synthase activity in male rat corpus cavernosum smooth muscles. Methods: Eight-week-old male rats were assigned to two groups: control (sham operated) and castrated animals. After 8 weeks, corpus cavernosum smooth muscle strips were mounted in an organ bath for isometric tension recordings. Electrical field stimulation (EFS) was applied to the strips precontracted with 30 µM phenylephrine. The microdialysis probe was inserted into the strip, and Krebs-Henseleit solution was perfused into the probe. The dialysate during EFS and cholinergic stimulation was collected, and the amount of NO–2/NO–3 (NOx) released in the dialysate was measured by the Greiss method. Sodium nitroprusside and carbachol were cumulatively added to the strips precontracted with 30 µM phenylephrine. Results: EFS caused frequency-dependent relaxations and NOx releases in the strips. Pretreatment with Nω-nitro-L-arginine (100 µM) and tetrodotoxin (1 µM) completely inhibited relaxations and NOx releases. The maximum relaxation in the castration group was significantly greater than that in the control group. The release of NOx was significantly greater in the castration group than in the control group. Sodium nitroprusside relaxed the tissues in both groups similarly. Carbachol failed either to relax the tissue or to increase the amount of NOx production in the tissue. Conclusion: The present data suggest that castration enhances nitric oxide synthase activity and nitric oxide-mediated relaxations in the male rat corpus cavernosum.

Low serum PSA levels of diabetes mellitus-caused end-stage renal disease patients

of healthy volunteers, and that the PSA levels of CGN are representativesfortheESRDpopulation.Theprevalenceof prostate cancer was not significantly different between the two groups, yet there is a tendency for a decreased number of patients with PSA values >4 ng/ml in the DM group, in comparison with the CGN group (Table 1). The levels of testosterone associated with increased prostate cancer risk, and those of insulin that promotes prostate cancer cell growth, are lower in DM patients [5]; these factors remain at lower levels after the patients advance to ESRD, which may explain low PSA levels in the DM group. Our results suggest that DM is associated with decreased PSAlevels,andlikelyofprostatecancerrisk,irrespectiveof the complication of ESRD. These results support an inverse relationship between DM and prostate cancer.