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Biomedical subjects

T Shinkawa

Publications and source records attributed to T Shinkawa.

At least 37 records · Page 2Linked to original sources
PubMed1996

Molecular effects of M17055, furosemide and thiazide on cardiac hypertrophy of spontaneously hypertensive rats.

Although diuretics have been clinically shown to reduce cardiovascular morbidity and mortality, the effects of diuretics on cardiac hypertrophy are poorly understood. In this study, we examined the molecular effects of diuretics on hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHR) were given p.o. M17055 (a novel "high ceiling" diuretic) 1.25, 2.5 or 5 mg/kg/day, furosemide 50 mg/kg/day or trichlormethiazide 30 mg/kg/day for 5 weeks. After the treatment, cardiac myosin isoforms were analyzed by gel electrophoresis, and cardiac hypertrophy-related gene expressions were examined by Northern blot analysis. These three diuretics significantly reduced cardiac hypertrophy of SHR. M17055 and furosemide, but not trichlormethiazide, significantly increased the proportion of cardiac V3 myosin of SHR by enhancing the gene expression of beta-myosin heavy chain. On the other hand, trichlormethiazide, but not M17055 or furosemide, suppressed the increased cardiac gene expression of skeletal alpha-actin in SHR. Cardiac collagen type III expression of SHR was decreased only by treatment with M17055. Plasma thyroid hormone levels of SHR were slightly decreased by M17055 and by furosemide and were negatively correlated with cardiac V3 myosin contents. Thus the effects on the gene expression of cardiac contractile proteins and collagen are significantly different among these three types of diuretics, which suggests that these diuretics may have different cardiac actions independent of their diuretic and antihypertensive actions. The increased cardiac V3 myosin induced by M17055 and by furosemide may be partially due to the decreased plasma thyroid hormone.

Animals↗
PubMed1996

Protective effect of human ulinastatin against gentamicin-induced acute renal failure in rats.

We investigated the protective effect of human ulinastatin against gentamicin-induced acute renal failure in rats. Gentamicin sulfate was subcutaneously injected at a dose of 200 mg/kg for 5 consecutive days. After 3 days administration of gentamicin, a slight decrease in renal function was observed, as well as granulovascular degeneration in the proximal tubular cells as a change in the renal histology. After 5 days administration of gentamicin, a remarkable increase in plasma concentration of creatinine (from 0.27 +/- 0.02 to 1.17 +/- 0.18 mg/dL) and urea nitrogen (from 17.8 +/- 0.6 to 48.8 +/- 5.1 mg/dL) and a significant decrease in creatinine clearance (from 0.64 +/- 0.08 to 0.20 +/- 0.03 mL.100 g-1.min-1) were observed. In addition, an apparent increase in urinary excretion of N-acetyl-beta-D-glucosaminidase and albumin was detected. In the renal histology, proximal tubular necrosis and desquamation of the epithelial cells in the cortex were observed. Furthermore, hyaline cast formation was frequently observed in the outer stripe of the outer medulla. Ulinastatin at doses of 100,000 or 300,000 U/kg was coadministered intraperitoneally just after each gentamicin injection. Ulinastatin treatment showed a dose-dependent suppression of gentamicin-induced biochemical alterations and histological changes. After 5 days treatment with 300,000 U.kg-1.day-1 of ulinastatin, the magnitude of gentamicin-induced changes in renal function was significantly lessened, by 45-80%. The score for proximal tubular injuries and the rate of hyaline cast formation were also significantly lower in the same group of animals than those in the group treated with gentamicin alone. In the in vitro study, ulinastatin at 10-300 U/mL showed a concentration-dependent suppression on the fragility of the lysosomal membrane isolated from rat kidney cortex during hypotonic treatment. These results indicate that human ulinastatin has a prominent protective effect on gentamicin-induced acute renal failure in rats, and the lysosomal membrane stabilizing effect is possibly involved as a mechanism of this action.

Acute Kidney Injury↗
PubMed1995

Controlled release of poly-D,L-lactic acid containing bleomycin.

By use of four types of in vivo degradable polylactic acid (PLA), i.e. PLA with an average molecular weight of 1500 (1500DL), 2200 (2200DL), 2800 (2800DL) and 3500 (3500DL), preparations of bleomycin (BLM)-containing solid forms (polymers) were tested. The in vitro release of BLM from the polymers was also examined in an immersion system. By the melt-pressing technique, five types of BLM (2.5 mg) containing solid forms, i.e. 1500DL polymer, 2200DL polymer, 2800DL polymer, 3500DL polymer and 1500DL + 3500DL (a mixture of 1500DL and 3500DL) polymer were prepared. In all five types of polymers, cumulative BLM release was controlled to less than 5% by the third day and no initial burst of the release was observed. BLM release from the polymer continued for 3 weeks at the shortest and 6 weeks at the longest. Various polymers containing BLM could be useful for the site of drug administration or anti-cancer release pattern.

Bleomycin↗
PubMed1994

[Drug distribution and antitumor effect of bleomycin incorporated in poly DL-lactic acid in rats].

Two bleomycin (BLM)-containing agents (BLM-PLA, BLM-SOL) were prepared, and the drug distribution and antitumor effect were studied. BLM-PLA is an agent in which BLM is incorporated into biodegradable low-molecular-weight polylactic acid, and BLM-SOL is an aqueous solution of BLM. BLM-PLA or BLM-SOL was subcutaneously administered in the back of rats. When BLM-PLA was implanted, high BLM activity of the connective tissues near the implants was maintained for 2 weeks. On the other hand, BLM activity was very low when BLM-SOL was administered. The effects of BLM-PLA, BLM-SOL and nontreatment on tumor growth and survival time were compared using subcutaneous tumor of Yoshida sarcoma in 21 rats each. The survivors and mean survival time in BLM-PLA group, BLM-SOL group and nontreatment group was 14 and 44.6 days, 5 and 23.7 days, and 0 and 11.3 days, respectively. BLM-PLA was superior to BLM-SOL in both drug distribution and antitumor effect, and consequently BLM-PLA could be a useful tool in loco-regional chemotherapy.

Animals↗
PubMed1993

Loop and distal actions of a novel diuretic, M17055.

We investigated the mechanism of action of a novel 'high ceiling' diuretic, M17055, in in vivo clearance studies with anesthetized dogs during water diuresis and in vitro microperfusion studies of isolated rabbit renal tubules. In the clearance study, intravenous infusion of M17055 (1 mg/kg per h) decreased free water clearance and increased urinary excretion of Na+ and Cl- to a greater extent than did a maximum dose of furosemide (30 mg/kg per h). With the maximum dose of furosemide, an additional dose of M17055 or hydrochlorothiazide resulted in additional suppression of free water clearance. These results indicate that M17055 has some additional mechanisms of action in the distal nephron. In isolated rabbit cortical thick ascending limb of Henle's loop, M17055 applied to the lumen decreased the lumen positive transepithelial voltage at concentrations over 10(-6) M and suppressed the lumen-to-bath 36Cl- flux at 10(-5) M. In the connecting tubule, M17055 added to the lumen suppressed lumen negative transepithelial voltage in a concentration-dependent manner in a range from 10(-4) to 10(-3) M. The effect of M17055 on transepithelial voltage was also observed in the distal convoluted tubule and cortical collecting duct. Moreover, 10(-3) M of M17055 in the lumen significantly decreased the lumen-to-bath 22Na+ flux in the cortical collecting duct. From these observations, it appears that M17055 acts not only on the thick ascending limb of Henle's loop but also on the distal segments via inhibition of electrogenic Na+ transport.

Animals↗
PubMed1993

Treatment of infertility associated with endometriosis by selective tubal catheterization under hysteroscopy and laparoscopy.

OBJECTIVE: To evaluate the efficacy of treatment for infertility associated with endometriosis by selective tubal catheterization under hysteroscopy and laparoscopy. STUDY DESIGN: Eighty-eight infertile women who underwent selective tubal catheterization with insufflation of oil-soluble radiopaque dye were reviewed. The efficacy of treatment was analyzed with regard to conception rate. RESULTS: The conception rate after selective tubal catheterization was higher in women with endometriosis (60%) than in women without endometriosis (36.5%) (p < 0.05). Most women conceived within the first 4 months after treatment. No statistical difference in conception rate was observed among patients with stage I, II, or III disease. CONCLUSIONS: Selective tubal catheterization with insufflation of oil-soluble radiopaque dye was an effective treatment for infertility associated with endometriosis.

Catheterization↗
PubMed1993

Beneficial effect of a novel diuretic, M17055, on blood pressure and cardiovascular hypertrophy in spontaneously hypertensive rats.

We investigated the effects of a novel diuretic, M17055, on blood pressure and cardiovascular hypertrophy in spontaneously hypertensive rats (SHR). M17055 was orally administered once a day for 24 consecutive days to 14-week-old male SHR. M17055 at doses of 1.25, 2.5 and 5 mg/kg/day exerted a dose-related diuretic and antihypertensive effect during the treatment. The weight of the left ventricle normalized by body weight on the following day of the last dosage was significantly (P < 0.01) reduced by M17055 at doses of 2.5 and 5 mg/kg/day in a dose-dependent manner. The effect of M17055 on cardiac hypertrophy was more potent (P < 0.01) than that of captopril, when the comparison was performed at the doses of M17055 and captopril inducing the same extent of blood-pressure decrement. Vascular hypertrophy was evaluated by the media/lumen ratio (M/L) in the thoracic aorta and the first branch of the superior mesenteric artery. In the aorta, M/L was slightly, but not significantly, decreased by M17055 at doses of 2.5 and 5 mg/kg/day, whereas it was decreased significantly (P < 0.01) by captopril. In the mesenteric artery, the ratio was significantly (P < 0.05) reduced by M17055 at a dose of 5 mg/kg/day. These results suggest that M17055 possesses beneficial properties for the clinical treatment of hypertension.

Animals↗
PubMed1993

[A basic study on usefulness of bleomycin incorporated in poly DL-lactic acid].

Poly DL-lactic acid (PLA) is one of the biodegradable polymers. Bleomycin (BLM) incorporated into small cylinders of PLA blends was prepared as a new dosage (BLM-PLA). When BLM-PLA was preserved in saline, the dissolution rate of BLM from BLM-PLA was 49.2% after 7 days, 85.2% after 14 days and 99.7% after 21 days, respectively. BLM-PLA was implanted subcutaneously into the back of 36 rats. On days 3, 7, 14, 21, 28 and 35, the connective tissues near the implants, lymph node, lung, liver and kidney were removed and BLM activity was measured. The BLM concentration was maintained at a high level in the connective tissues until 14 days, and in the lymph node between 21 and 28 days. On the other hand, the BLM level was low in the lung, liver and kidney. Consequently, it was suggested that PLA is useful as a carrier for drug delivery system and that administration of BLM-PLA is an effective anti-cancer modality, especially in local chemotherapy.

Animals↗
PubMed1993

Effect of a novel diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-o- sulfonic acid, potassium salt (M17055) on Na+ and K+ transport in the distal nephron segments.

By using an in vitro microperfusion technique, we examined whether a novel loop diuretic, 7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-o-sul fonic acid, potassium salt (M17055), a derivative of quinolinone oxime sulfonic acids, affects Na+ and K+ transport in the distal nephron segments, including the cortical collecting duct and connecting tubule (CNT) isolated from rabbit kidneys. M17055 added to the lumen at 1 mM caused a positive deflection of transepithelial voltage (VT) by 2.2 +/- 0.4 mV. The response was less than that evoked by 10 microM amiloride (8.9 +/- 0.1 mV). In the collecting duct cell of the cortical collecting duct from normal rabbits, M17055 depolarized the basolateral membrane by 9.2 +/- 1.3 mV, whereas amiloride hyperpolarized it by 7.6 +/- 2.4 mV. In the cortical collecting duct from deoxycorticosterone acetate-treated rabbits, despite the fact that both agents depolarized the basolateral membrane of the collecting duct cell, amiloride consistently hyperpolarized the apical membrane, whereas M17055 did not cause any significant changes in apical membrane voltage. In the presence of 2mM Ba++ in the lumen, the apical membrane voltage deflection by M17055 was abolished. In addition, the magnitude of the apical membrane voltage deflection caused by an abrupt increase in luminal K+ concentration from 5 to 50 mM was significantly reduced. In the CNT, both amiloride and M17055 caused a positive deflection of VT. However, M17055 depolarized the basolateral membrane by 6.6 +/- 1.6 mV, whereas amiloride hyperpolarized it by 4.4 +/- 1.1 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1993

Effects of amiloride and a novel diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-o-su lfonic acid, potassium salt (M17055), on calcium transport in the rabbit connecting tubule.

To elucidate the mechanisms of relative anticalciuric effect of a diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-o-sul fonic acid, potassium salt (M17055), having sites of action on the Henle's loop plus the distal nephron segments, we measured intracellular calcium concentration ([Ca++]i) of the rabbit connecting tubule perfused in vitro by using the microscopic fluorometry with fura 2. First, we confirmed that parathyroid hormone increases [Ca++]i by a mechanism mediated by cyclic AMP. We also confirmed that the Na+/Ca++ exchanger in the basolateral membrane is essential for the extrusion of Ca++ across this membrane. In the presence of 10 nM parathyroid hormone in the bath, the elimination of Na+ from the lumen decreased [Ca++]i, supporting the view that a decrease in Na+ supply from the apical membrane enhances the Na+/Ca++ exchanger in the basolateral membrane. Under a similar condition, the addition of 10 microM amiloride in the lumen also decreased [Ca++]i, further supporting the view that the inhibition of Na+ entry across the apical membrane causes similar effect as does Na+ elimination. Under a similar condition, the addition of 1 mM M17055 in the lumen exerted a similar effect on [Ca++]i as did amiloride. Because M17055 did not further decrease [Ca++]i when Na+ was eliminated from the lumen, the effect of M17055 is mediated by an inhibition of Na+ entry across the apical membrane. From these observations we conclude that either inhibition or diminution of Na+ entry across the apical membrane of the connecting tubule increases the Ca++ extrusion across the basolateral membrane via the Na+/Ca++ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1992

A novel quinolinone diuretic, M12285, and its activation mechanism through sulfate conjugation.

The diuretic activity of a quinolinone oxime diuretic, M12285, was examined after renal arterial, i.v. and portal injection in rats. M12285 injected into the renal artery at a dose of 1 mg/kg caused no diuretic effect, whereas i.v. and portal injections induced marked diuresis dose dependently. The minimum effective dose with portal injection was lower (1 mg/kg) than that with i.v. injection (3 mg/kg) and the start of the effect was faster with portal injection. These results indicated that some metabolic modification in the liver is necessary for the diuretic activity to appear. Accordingly, we performed in situ rat liver perfusion with M12285 and obtained several metabolites. Renal arterial injection of each fractionated metabolite of M12285 revealed that all the diuretic activity derived from one of these metabolites. From IR and 1H-nuclear magnetic resonance (1HNMR) measurements, the chemical structure of this active metabolite was assumed to be a sulfate-conjugated form of M12285 at the oxime moiety. Based on this tentative chemical structure, we synthesized the oxime sulfate of M12285 (potassium salt, M17000) and confirmed the identity of IR and 1HNMR spectra. Administration of M17000 into the renal artery induced apparent diuresis in a dose-dependent manner in both rats and dogs. These results indicate that the oxime sulfate of M12285 is responsible for the diuretic activity of M12285. Therefore, we synthesized several derivatives of M17000 and confirmed their possible therapeutic value as a novel family of diuretics, namely quinolinone oxime sulfonic acids.

Animals↗
PubMed1992

Hysteroscopic assessment of midsecretory-phase endometrium, with special reference to the luteal-phase defect.

To investigate the functional aspects of secretory-phase endometrium, hysteroscopy was performed in 61 patients for in vitro fertilization-embryo transfer (IVF-ET), and 50 women for infertility evaluation. All women had normal ovulatory cycles. The hysteroscopic assessment of secretory-phase endometrium was made by characterizing the glandular openings (GO) and vasculature. The assessments were classified as 'good': characterized by ring-type GO and well-developed vessels; and 'poor': characterized by dot and/or punctate-type GO and fine vasculature. In the 30 patients classified 'good' prior to the IVF cycle, there was a higher pregnancy rate (40%) than in 'poor' ones (13%). Thirty of 50 infertile women were classified 'good', and their average age was lower than that of the remaining 20 in the 'poor' group. Preovulatory estradiol was significantly higher in the 'good' than in the 'poor' group. From an analysis of 20 patients with a 'poor' assessment, it was demonstrated that the maturation of secretory-phase endometrium was affected by a failure of folliculogenesis, progesterone secretion, endometrial growth and menstrual shedding.

Adult↗
PubMed1992

Pharmacological properties of the novel highly potent diuretic 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt.

7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt (M17055, CAS 114417-20-8) showed potent diuretic and saluretic effects dose-dependently, in rats (p.o.), mice (p.o.) and dogs (i.v.), at doses of 0.1-100 mg/kg, 0.3-100 mg/kg and 0.01-30 mg/kg, respectively. The efficacy of M17055 for diuresis, natriuresis and chloruresis was much higher than that of hydrochlorothiazide and almost the same as that of furosemide. These results indicate that this compound may be classified as a "high ceiling diuretic". The potencies of M17055 for natriuresis in rats (p.o.), mice (p.o.) and dogs (i.v.) calculated with ED50 values were 38, 34 and 24 times, respectively, more potent than those of furosemide. Urinary excretions of sodium, chloride and potassium increased in parallel with urinary volume with the administration of M17055 or furosemide, whereas an apparent dissociation with urinary calcium and sodium excretion was observed with M17055 alone. In rats, the increase of urinary calcium excretion with M17055 was significantly lower than that with furosemide under comparable conditions of natriuresis. Moreover, in mice, M17055 decreased urinary calcium excretion at doses with low effectiveness. In clearance studies using anesthetized dogs, M17055 suppressed negative free water clearance (CH2O) under saline loaded conditions, and it decreased positive CH2O under water diuretic conditions. These changes in the effects on CH2O induced by M17055 resemble those of loop diuretics. However, M17055 could not shift negative CH2O to positive, while furosemide was able to do so. Moreover, positive CH2O decreased to nearly zero with M17055, while urine remained dilute with furosemide even at 30 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗