Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rats.

In unanaesthetized, normal rats, continuous cystometry revealed that pituitary adenylate cyclase activating peptide (PACAP-27), administered intrathecally or intra-arterially near the bladder, stimulated micturition. The localization of PACAP-27 in the rat lower urinary tract was studied by immunohistochemistry, and the direct effects on the smooth muscles of the rat detrusor and urethra were investigated in vitro. In the intact rat, 1.0 nmol of PACAP-27 administered intrathecally as well as intra-arterially close to the bladder, but not intravenously, increased micturition pressure, decreased micturition volume and bladder capacity, and facilitated spontaneous bladder contractions. PACAP-27 immunoreactive structures were extremely scarce in the lower urinary tract, and the peptide had negligible effects on isolated detrusor muscle contracted by carbachol or stimulated electrically, or on urethral preparations contracted by noradrenaline. These results suggest that PACAP-27 has facilitatory actions on micturition both at the spinal cord and peripheral ganglionic levels.

Role of intrathecal tachykinins for micturition in unanaesthetized rats with and without bladder outlet obstruction.

1. The effects on micturition of RP 67,580, a selective NK1 receptor antagonist, and SR 48,968, a highly, potent antagonist at NK2 receptor sites, given intrathecally (i.t.) or intra-arterially (i.a.) near the bladder, were investigated in unanaesthetized rats with and without bladder outlet obstruction. 2. In normal rats, RP 67,580, given i.t. in doses of 2 and 20 nmol per rat, decreased micturition pressure, but did not change other cystometric parameters. After 20 nmol of RP 67,580, dribbling incontinence due to retention was observed in 1 out of 7 animals. This effect was reversible. I.t. RP 67,580 in a dose of 2 nmol, had no effect on hyperactivity induced by intravesically instilled capsaicin. 3. In animals with bladder hypertrophy secondary to outflow obstruction, RP 67,580, given i.t. in a dose of 2 nmol per rat, decreased the micturition pressure, but had no effect on other cystometric parameters. After 20 nmol, dribbling incontinence due to retention was observed in 5 out of 7 animals. 4. RP 67,580, given i.a. in a dose of 4 nmol, had little effect on the cystometric parameters investigated, both in normal animals and rats with bladder hypertrophy. 5. SR 48,968, given i.t. in doses of 2 and 20 nmol per rat, had no clear-cut effects on the micturition pattern in normal rats, or rats with bladder hypertrophy. However, the drug reduced capsaicin-induced bladder hyperactivity. When given i.a. in a dose of 4 nmol, SR 48,968 had no effect on cystometric parameters in normal rats or rats with bladder hypertrophy. 6. The effects of both RP 67,580 and SR 48,968 were stereoselective, their enantiomers (RP 68,651 and SR 48,965) being inactive.7. These results thus suggest that at the spinal level there is a tachykinin involvement (via NK,receptors) in the micturition reflex induced by bladder filling, both in normal rats, and, more clearly, in animals with bladder hypertrophy secondary to outflow obstruction. The bladder response to filling was not influenced by blockade of vesical NKI and NK2 receptors. On the other hand, the bladder hyperactivity evoked by intravesical capsaicin seems to involve NK2 receptors both at the bladder and spinal levels.

Micturition in conscious rats with and without bladder outlet obstruction: role of spinal alpha 1-adrenoceptors.

1. In normal rats and rats with bladder hypertrophy secondary to outflow obstruction, undergoing continuous cytometry, we examined the responses to the selective alpha 1-adrenoceptor antagonist doxazosin given intrathecally (i.t.) and intra-arterially (i.a.). In addition, we investigated the effects of the drug on L-dopa-induced bladder hyperactivity in normal, unobstructed rats. 2. Doxazosin 50 nmol (approximately 60 micrograms kg-1), given i.t., decreased micturition pressure in normal rats and in animals with post-obstruction bladder hypertrophy. The effect was much more pronounced in the animals with hypertrophied/overactive bladders. Doxazosin did not markedly affect the frequency or amplitude of the unstable contractions observed in obstructed rats. In contrast, however, doxazosin reduced L-dopa-induced bladder overactivity. When tested, the enantiomers of doxazosin produced qualitatively similar effects to doxazosin, but there was no evidence of stereoselectivity. 3. The results suggest that in addition to the well documented action on prostatic and lower urinary tract smooth muscle, and an effect on the sympathetic outflow to the bladder, bladder neck, prostate, and external urethral sphincter, doxazosin may have an action at the level of the spinal cord and ganglia, thereby reducing activity in the parasympathetic nerves to the bladder. This effect is more pronounced in rats with bladder hypertrophy than in normal rats.

Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats.

Apomorphine, given subcutaneously (s.c.), induces erection and bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system. In paraplegic patients, apomorphine was reported to cause bladder overactivity. This suggests that apomorphine may have a spinal site of action also for stimulation of erection. The present study was initiated to evaluate the effect of apomorphine on erectile function in spinalized rats. Apomorphine (100 microg/kg, s.c.) was given to awake, unrestrained male Sprague-Dawley rats (300 g) with or without spinal cord injury, made at the Th 8 level 2 weeks before the experiment. Intracavernous pressure changes from baseline were evaluated as time to first response to apomorphine (TFR; sec), number of phasic pressure changes in the first 30 min (PP30), duration (D; sec) of the phasic pressure changes, the amount of increase in tonic peak pressure (TPP; cmH2O), and burst peak pressure (BPP; cmH2O). Blood pressure (cmH2O) was recorded via an intra-arterial catheter. Apomorphine, 100 microg/kg, caused no significant differences in TFR (217.8 vs 271.2), PP30 (6.4 vs 6.5), D (38.9 vs 37.6.), TPP (51.0 vs 54.0) and BPP (128.9 vs 160.4) between normal (n=8) and spinalized rats (n=6). However, blood pressure decreased significantly more in spinalized than in normal animals (17.7 vs 43.3; P<0.05). The results suggest that both in normal rats, and in rats with spinal cord injury, apomorphine given s.c., can produce erection. This finding supports the use of apomorphine for treatment of erectile dysfunction in paraplegia patients. However, due consideration should be given to possible decreases in blood pressure.

Stimulation of bladder activity by volume, L-dopa and capsaicin in normal conscious rats--effects of spinal alpha 1-adrenoceptor blockade.

To study possible differences in alpha 1-adrenoceptor involvement in the spinal mechanisms mediating bladder activity induced by volume (bladder filling), central (L-dopa), and peripheral (capsaicin) stimulation, we investigated if these types of bladder activity were modified by intrathecal (i.t.) or intra-arterial (i.a.) administration of the alpha 1-adrenoceptor antagonist, indoramin. Indoramin is selective for the alpha 1A-adrenoceptor subtype, whereas most clinically used alpha 1-adrenoceptor antagonists, including doxazosin, have no subtype selectivity. The drug effects were studied by continuous cystometry in normal, conscious rats and rats with bladder activity evoked by intraperitoneal L-dopa (50 mg/kg after carbidopa pretreatment), or by intravesical capsaicin (30 microM). I.t. indoramin (50 nmol) significantly decreased micturition pressure, and increased bladder capacity and micturition volume. Dribbling incontinence due to urinary retention was observed in one of ten rats. L-dopa-stimulated bladder overactivity was significantly attenuated by i.t. or i.a. indoramin (50 nmol). Similar effects of i.t. and i.a. doxazosin (50 nmol) have been reported previously. Intravesical capsaicin (30 microM) caused bladder activity, which was attenuated by i.t. indoramin (50 nmol), but not by i.t. doxazosin (50 nmol). I.a. indoramin did not reduce capsaicin-induced bladder activity; doxazosin was moderately effective. The results suggest that the bulbospinal micturition reflex evoked by bladder filling and L-dopa involves a descending pathway where transmission is partly mediated by spinal alpha 1-adrenoceptors. Bladder overactivity evoked by intravesical capsaicin, which elicits a vesicospinal-vesical reflex, was not affected by i.t. doxazosin in a dose that attenuates activity mediated through the bulbo-spinal pathway. This suggests less involvement of spinal alpha 1-adrenoceptors in the vesico-spinal-vesical than in the bulbo-spinal voiding reflex.

Role of supraspinal tachykinins for micturition in conscious rats with and without bladder outlet obstruction.

In order to clarify the role of supraspinal tachykinins in volume-induced micturition and in bladder hyperactivity secondary to bladder outlet obstruction, conscious, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular administration of RP 67,580, a selective antagonist of neurokinin (NK)-1 receptors and/or SR 48,968, a selective antagonist of NK-2 receptors. In normal rats, RP 67,580 or SR 48,968, at a dose of 2 nmol, caused no marked changes in cystometric parameters. Higher doses (up to 20 nmol) caused dose-dependent decreases in micturition pressure and increased bladder capacity, micturition volume and residual urine. A combination of the two drugs, each at a dose of 2 nmol, significantly decreased micturition pressure and increased bladder capacity. In rats with bladder outlet obstruction, the antagonists suppressed micturition dose-dependently, producing urinary retention in two out of eight rats already at a dose of 2 nmol. At a dose of 20 nmol, dribbling incontinence, due to urinary retention, was seen in five out of ten rats. A combination of the two drugs (2 nmol of each drug) caused urinary retention in three out of nine animals and significantly increased bladder capacity, micturition volume and residual volume. The results suggest that outflow obstruction in rats increases the effects of tachykinins in supraspinal structures involved in micturition, and that antagonism of supraspinal NK-receptors may depress the micturition reflex. Whether or not this implies that supraspinal NK-receptors can be targets for drugs aimed for inhibiting bladder hyperactivity in humans should be explored.

[A study of postmortem infectious lesions of bacteremia and fungemia patients--relationship between fungemia and deep mycoses].

Postmortem infectious lesions were analyzed in 63 patients with bacteremia and fungemia. Bacterial infection was found in 36 patients, deep mycoses in 27 and cytomegalovirus infection in 7. Among deep mycoses patients, yeast was noticed in 17, Aspergillus in 13 and Mucor in one. Infectious lesions were not observed in 10 cases. Fifteen cases of 23 leukopenic patients were complicated with deep mycoses. Deep mycoses was noticed in 43% of bacteremia and fungemia patients, but not in candicemia patients. Fungemia due to Candida was related to blood access, however, not to deep mycoses. On the other hand, disseminated mycoses was found in 4 of 5 cases with Trichosporon beigelii fungemia. T. beigelii infection is noticeably life-threatening to the immunocompromised host.

[Effects of various methanol extracts of crude drugs on experimental subacute and chronic hepatic injury].

The effects of 5 crude drugs (Myricae Cortex, Polygoni Avicularis Herba, Hyperici Erecti Herba, Forsythiae Fructus, Desmodii Herba) on subacute and chronic hepatic injuries induced by carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT) were investigated in rats. All of these crude drugs suppressed significantly the increase of several biochemical parameters with CCl4-injection twice per week for 4 weeks. Polygoni Avicularis Herba and Desmodii Herba among 5 crude drugs also protected the subacute hepatic injury induced by ANIT-injection for 4 weeks. In addition, the therapeutic effect of Desmodii Herba on the chronic hepatic injury induced by CCl4-injection for 9 weeks was recognized. Desmodii Herba has protective effects on the acute and subacute hepatic injuries induced by CCl4 or ANIT and an improving effect on the chronic injury induced by CCl4. Though the increase of hydroxylproline content in the liver began 4 weeks after the CCl4 or ANIT treatment, every crude drug had no significant effect against the liver fibrosis in these study.

[Protective effects of various methanol extracts of crude drugs on experimental hepatic injury induced by carbon tetrachloride in rats].

The protective effects of 67 methanol extracts of crude drugs on rat hepatic injury by carbon tetrachloride (CC14) were examined. In terms of the release of intrahepatic enzymes and bilirubin into the blood, 11 methanol extracts decreased these factors significantly. Among them methanol extracts of Caryophylli Flos, Angelicae Dahuricae Radix, Polygoni Avicularis Herba, Myricae Cortex and Forsythiae Fructus were newly found to have protective effects against acute hepatic injury induced by CCl4. And then these 11 extracts which protected hepatic injury by CCl4 were investigated for their membrane stabilizing and inhibitory effects of lipid peroxidation. The extract of Bupleuri Radix only decreased the hemolysis induced by hypotonic pressure. Nine kinds of extracts without those of Desmodii Herba and Bupleuri Radix suppressed the lipid peroxidation induced by CCl4 in rat hepatic microsomes. In addition, Scutellariae Radix, Caryophylli Flos and Myricae Cortex were shown to have inhibitory effects of non-enzymatic lipid peroxidation in rat hepatic mitochondria. This study reports that the methanol extracts of Caryophylli Flos, Angelicae Dahuricae Radix, Polygoni Avicularis Herba, Myricae Cortex and Forsythiae Fructus protect the hepatic injury by CC14 and these protective effects are connected with the inhibitory effects of the lipid peroxidation in hepatic microsomes.

[Spontaneous rupture of the urinary bladder in a woman with radiation cystitis: a case report].

A 79-year-old woman was admitted to our hospital with gross hematuria and abdominal pain. She had had a uterine cancer 11 years previously and received 56 Gy 60Co external irradiation combined with 129 Gy 137Cs internal irradiation. She had a sign of pan-peritonitis. An emergency operation revealed an intraperitoneal rupture of the dome of the urinary bladder 8 cm in length. Because a primary suturing of the bladder wall was unsuccessful, bilateral cutaneous ureterostomy was performed. Histologically, the ruptured bladder wall showed a mucosal erosion and fibrosis of the muscle layer.

[Mass screening for prostate cancer in Nagano].

In three villages in Nagano, we performed mass screening for prostate cancer by digital rectal examination, transabdominal ultrasonography and serum prostate specific antigen. The cancer detection rate was 5.1% (9/178). Serum prostate specific antigen was especially useful for cancer detection.

[Significance of PSA-density: analysis in PSA gray zone cases].

We studied the sensitivity and specificity of digital examination and prostate specific antigen (PSA) density to detect prostatic cancer in those patients whose PSA values are in a range of 4 to 10 ng/ml or in a gray zone. Sextant prostate biopsy revealed 14 cases (17.2%) of prostatic cancer out of 81 PSA gray zone cases. The sensitivity of digital examination was 38.5%, and the specificity was 73.0%. If we use 0.29 as a PSA density cut-off value, the sensitivity was 70.0%, and the specificity was 70.0%. At a PSA density cut off value of 0.22, we could obtain 90% sensitivity, which was considered applicable for detection of cancer in PSA gray zone cases.

[Posttraumatic priapism in a 6-year-old boy: a case report].

A 6-year-old boy showed priapism after blunt perineal trauma. We diagnosed him with venous priapism mainly based on clinical symptoms, although we could not deny an arterial type. In fear of possible erectile dysfunction as a late complication of the venous type, we performed a shunt operation. The shunt was created between glans penis and corporacavernosa, resulting in disappearance of priapism and preservation of erectile function. We also reviewed 14 cases reported previously.

[Chromophobe cell renal carcinoma: a case report].

A 61-year-old man was admitted to our hospital because of the left renal mass lesion. We performed left radical nephrectomy under the diagnosis of renal cell carcinoma. The tumor showed a dark red color. The pathological diagnosis was chromophobe cell renal carcinoma. We could not make the diagnosis before the operation by echography, computed tomography or magnetic resonance imaging. It is still controversial whether this diagnosis can be made preoperatively.

[Laparoscopic adrenalectomy at Shinshu University School of Medicine].

We report our experience with transperitoneal laparoscopic adrenalectomy in 26 cases (mean age 45 years). We experienced primary aldosteronism in 19 cases, Cushing syndrome in 6 cases and non-functioning tumor in one case. There was no significant difference in the operation time between right and left, men and women, primary aldosteronism and Cushing syndrome. The blood loss decreased with training. There were no severe complications during and after the operation. The weight of the resected adrenal glands increased. The blood loss decreased significantly compared with the open surgery. Transperitoneal laparoscopic adrenalectomy is becoming the safe and standard surgery for the adrenal gland tumor, and the number of suitable cases for this procedure is expected to increase in the future.

[Partial nephrectomy using a microwave tissue coagulator for bilateral renal cell carcinomas: a case report].

We report a case of bilateral renal cell carcinomas in a 56-year-old male treated by partial nephrectomy at the same time using a microwave tissue coagulator technique. The patient did not need dialysis after the operation because we did not need to sacrifice the artery feeding to normal renal tissue during the operation. This technique has advantages of nephron sparing without occlusion of the renal artery, and decreased operation time and blood loss.

[A case of transitional cell carcinoma presenting as rupture of a renal arteriovenous malformation].

A 76-year-old man was seen at this hospital for the treatment of asymptomatic gross hematuria. Retrograde pyelography revealed a filling defect in the left lower calyx. The diagnosis was left renal pelvic carcinoma by urinary cytology. The patient underwent left nephrouretectomy with partial cystectomy. Hemosiderin accumulation on histological examination demonstrated an arteriovenous malformation in the left lower calyx. Transitional cell carcinoma was confirmed apart from the arteriovenous malformation, and no relation between the two was seen. These findings suggest the coexistence of a renal arteriovenous malformation with a renal pelvic and ureteral carcinoma. Hematuria was due probably to rupture of the renal arteriovenous malformation.

[Metastatic renal tumor of malignant salignant salivary-gland-like tumor of the lung: A case report].

A 17-year-old woman was admitted to our hospital for the investigation of asymptomatic gross hematuria. Twenty nine months ago, she had received the right lower lobectomy because of the malignant salivary gland type mixed tumor of the bronchus. The intravenous pyelography and the right retrograde pyelography showed the irregular wall of the right renal pelvis. The computerized tomography showed a hypodense tumor which occupied the lower half of the right kidney. Cystoscopy showed bleeding from the right ureteral orifice. Chest X-ray revealed multiple lung metastases at the first examination, but right nephrectomy was performed because gross hematuria continued. The tumor thrombus, which spreaded into vena cava, was removed. The pathological diagnosis was the metastatic renal tumor of malignant salivary gland type mixed tumor. The patient died 102 days postoperatively.

[Results of myocutaneous flap for extensive skin defect in the external genitalia].

We reviewed 12 patients who underwent myocutaneous flap plasties to reconstruct the genital skin. The patients included 9 who underwent a radical excision of malignant tumor involving the genital, inguinal or sacral skin, 1 with an extensive radiation ulcer of the genitalia and 2 with an ulcerating cancer of the scrotum or groin. In the latter 2 patients the plasty was intended to cover an unresectable ulcerating cancer. A gracilis myocutaneous flap was used in 10 patients, and a tensor fascia lata myocutaneous flap in 2 patients. Postoperatively, partial or total necrosis of the skin of the flap developed in 8 patients. In 4 of these, infection complicated the necrosis. Although debridement, resuture or free skin transplantation was needed in these patients, wound healing was ultimately achieved in 10 patients who underwent radical excision of malignant tumor or radiation ulcer. In contrast, the intended coverage of an unresectable ulcerating cancer was unsuccessful in two other patients. No patients had motor disturbance after wound healing. However, one patient developed stricture of the urethra and vagina which had been opened through the flap, and another patient complained of gait disturbance and difficult defecation because of an swelling of the flap around the anus. Incision or excision was required to relieve the complaints in these 2 patients. These results indicate that a myocutaneous flap is useful to cover an extensive skin defect of the genitalia, but may be accompanied by postoperative complications particularly before wound healing. Appropriate management is necessary to achieve the intended reconstruction.

[Results of the conservative treatment of urinary incontinence in women].

We reviewed 115 incontinent women undergoing conservative treatment. Urinary incontinence was caused by pelvic floor weakness (genuine stress incontinence) in 54 patients, by involuntary detrusor contraction (detrusor instability) in 38 and by both (mixed type) in 23. Tricyclic antidepressants or alpha-adrenergic stimulators were given to 30 patients with pelvic floor weakness; Incontinence disappeared in 4 patients (13%) and was improved in other 3 patients (10%). Twenty-two patients with pelvic floor weakness underwent pelvic floor exercise with or without medication; Incontinence disappeared in 8 patients (36%) and was improved in other 11 patients (50%). The presence or absence of medication did not affect the results. Twenty-eight patients with involuntary detrusor contraction underwent bladder training combined with medication of detrusor relaxants. Incontinence disappeared in 4 patients (14%) and was improved in other 13 patients (46%); There was no significant difference in the results between smooth muscle relaxants and tricyclic antidepressants. Of the 23 patients with mixed type, 11 underwent bladder training with medication; Incontinence disappeared in 2 patients (18%) and was improved in 3 patients (27%). The remaining 11 patients received medication, pelvic floor exercise or urethral dilatation, and only 2 patients were cured or improved of incontinence. Follow-up of the patients with involuntary detrusor contraction or mixed type showed that urinary incontinence tended to recur after discontinuation of medication. These results indicate that incontinent women with pelvic floor weakness should be treated first with pelvic floor exercise, and then with bladder training with medication. Although it has only a limited effect, it is an acceptable treatment of urinary incontinence caused by involuntary detrusor contraction.