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The aim of this study was to assess the cardiovascular effects of silodosin (CAS 160970-54-7, (-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyllamino)propyll-2,3-dihy-dro-1H-indole-7-carboxamide, KMD-3213), a potent selective alpha1A-adrenoceptor (AR) antagonist used for the treatment of dysuria. In conscious dogs, orally administered silodosin, at doses (0.2, 2 and 20 mg/kg) considerably higher than the pharmacologically effective dose, decreased blood pressure. These doses, however, had no effects on heart rate or on the electrocardiogram (PR interval, QRS interval, QT interval or QTc). In addition, the cardiac effects of silodosin were evaluated in an in vitro electrophysiological study. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current, leaving a residual tail current of 45 % control at 10 micromol/L. However, the concentration that inhibited the HERG tail current was considerably higher than its affinity for alphal-ARs. These results suggest that while the alpha1B-AR subtype is mainly involved in the regulation of blood pressure, the alphalA-AR subtype is not. There seems to exist no evidence of a correlation between the function of alphal-AR and ECG changes reflecting inhibition of the HERG current. The cardiovascular profile of silodosin suggests therefore that it is a safe and well-tolerated drug.

The present study was performed to investigate the modifying effects of arctiin, a plant lignan isolated from Arctium lappa (burdock) seeds, on uterine carcinogenesis induced by N-ethyl-N-nitrosourea (ENU) initiation in mice. Female ICR mice aged 5 weeks were administered a single intra-uterine injection of ENU at a dose of 50 mg/kg via the vagina. After 1 week, the animals were fed a soybean-free diet containing 0 (control), 0.004, 0.02 and 0.1% of arctiin for 26 weeks. Histopathological examinations revealed the development of uterine proliferative lesions such as adenocarcinoma, atypical hyperplasia, adenomyosis, and endometrial hyperplasia. However, there were no significant differences in the incidences and severities of these lesions among the groups. These results indicate that arctiin showed no definite modifying effects on uterine carcinogenesis under the present experimental conditions.

Aims Our main aim was to compare the prostatic selectivity of silodosin with that of other α1-adrenoceptor (AR) antagonists. Methods We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. Results In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED15/ID50) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). Conclusions Our results clearly demonstrate that silodosin is a potent and highly selective α1A-AR antagonist. A selective α1A-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients. Neurourol. Urodynam. 25:792–799, 2006. © 2006 Wiley-Liss, Inc.

The duration of action of Silodosin (KMD-3213) against the phenylephrine-induced increase in intraurethral pressure in urethane-anesthetized rats was compared with that of tamsulosin hydrochloride. Silodosin, tamsulosin, or vehicle was orally administered to fasted male rats. Then, under urethane anesthesia, a cannula was inserted into the prostatic urethra. Phenylephrine, at a dose of 30 microg/kg, was infused (infusion rate: 36 ml/h; infusion time: 100 s/kg) via the femoral vein at 12 h, 18 h, or 24 h after administration of the study drug, and the intraurethral pressure in the prostate region was measured. Although the plasma silodosin concentration would have resolved within a few hours, silodosin significantly inhibited the phenylephrine-induced increase in intraurethral pressure (versus the vehicle-treated group) at 12 h, 18 h, and 24 h after its oral administration (at doses of 100 microg/kg and above, 1000 microg/kg and above, and 3000 microg/kg, respectively). On the other hand, tamsulosin hydrochloride showed no inhibitory action at 24 h after its oral administration at doses up to 3000 microg/kg. Thus, silodosin inhibits the phenylephrine-induced increase in intraurethral pressure for a longer time than tamsulosin hydrochloride.

We compared the urethral and cardiovascular eSects of silodosin (selective a1A-adrenoceptor antagonist) ,an ovel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective a1A/a1D-adrenoceptor antagonist) and naftopidil (selective a1D-adrenoceptor antagonist) .W e evaluated the eSects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin＞silodosin＞naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED15 value for hypotensive eSect/ID50 value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients. Key words―silodosin (KMD-3213); a1A-adrenoceptor; benign prostatic hyperplasia; intraurethral pressure

Background —Activation of vascular chymase plays a major role in myointimal hypertrophy after vascular injury by augmenting the production of angiotensin (ANG) II. Because chymase is synthesized mainly in mast cells, we assumed that the chymase-dependent ANG II formation could be downregulated by tranilast, a mast cell–stabilizing antiallergic agent. We have assessed inhibitory effects of tranilast on neointima formation after balloon injury in the carotid artery of dogs, which share a similar ANG II–forming chymase with humans, and further explored the pathophysiological significance of vascular chymase. Methods and Results —Either tranilast (50 mg/kg BID) or vehicle was orally administered to beagles for 2 weeks before and 4 weeks after balloon injury. Four weeks after the injury, remarkable neointima was formed in the carotid arteries of vehicle-treated dogs. Chymase mRNA levels and chymaselike activity of vehicle-treated injured arteries were increased 10.2- and 4.8-fold, respectively, those of uninjured arteries. Angiotensin-converting enzyme (ACE) activity was slightly increased in the injured arteries, whereas ACE mRNA levels were not. Tranilast treatment completely prevented the increase in chymaselike activity, reduced the chymase mRNA levels by 43%, and decreased the carotid intima/media ratio by 63%. In vehicle-treated injured arteries, mast cell count in the adventitia showed a great increase, which was completely prevented by the tranilast treatment. Vascular ACE activity and mRNA levels were unaffected by tranilast. Conclusions —Tranilast suppressed chymase gene expression, which was specifically activated in the injured arteries, and prevented neointima formation. Suppression of the chymase-dependent ANG II–forming pathway may contribute to the beneficial effects of tranilast.

Summary To improve the automation or artificial intelligence of welding operations, it is necessary to develop high-performance sensors. Laser visual sensors are designed to recognise the configuration or detect the position of a weld by irradiating a slit light on to the welded joint, receiving the light with a CCD camera, and converting the two-dimensional information into three-dimensional information by image processing. The visual sensors for welding robots must be free from the influences of welding process disturbances, such as arc light, heat, spatter and fume. This paper describes optical component arrangements and image processing algorithms. The optical component of a sensor head helps avoid optical window contamination caused by spatter or fume. The image processor used can process image data quickly and accurately even if welding arc light illuminates the workpiece surface. The accuracy of weld position detection is within ±0.2 mm.

It is necessary to develop excellent sensors in order to improve the automation or the artificial intelligence of the welding operation.Laser visual sensors are designed to recognize the configuration or debect the position of a weld by irradiating a slit light on to the weld joint, receiving the light with a CCD camera, and then converting the two dimensional information into three dimensional information by using image processing.The visual sensors for the welding robot must be free from the influence of welding process disturbances, such as light, heat, spatter and fumes.This paper deals with optical component arrangements and image processing algorithms. The optical component of a sensor head helps to avoid optical window contamination caused by spatters or fumes. The image processor can process image data very quickly and accurately, even if the welding arc light illuminates the surface of the workpiece. The accuracy of detecting the position is within ±0.2 mm.

Changes in the visual organ with aging were investigated non-surgically in male WBN/Kob rats, in which spontaneous diabetic mellitus commonly occurs. Male Wistar/ST rats at the ages of 5, 9, 13, 17, 23, 27, 36, 45, 54, 67 and 80 weeks were examined for changes in the peri-orbital region, eyelid, lens, corpus vitreum and ocular fundus by macroscopic inspection and fundoscopy. The area around the eyelid was stained with reddish-brown excretions from the Harderian gland. This stain was frequently observed in rats of both strains aged 54 weeks or over, showing no difference in frequency between WBN/Kob rats and Wistar/ST rats. Lens opacity was observed in male WBN/Kob rats aged 67 weeks or over, and narrowing of the retinal artery and vein in those aged 36 weeks or over. The occurrence of lens opacity was consistent with that of visual dysfunction as determined by a test of the ability to differentiate light from dark using a Y-shaped apparatus (Kiyosawa et al., 1993).

This study explores the effects of the anti-allergic and anti-fibrotic agent tranilast on adjuvant- and streptococcal cell wall-induced arthritis in rats, animal models of rheumatoid arthritis in humans. Tranilast (150 or 300 mg/kg, twice daily) or vehicle only was administered orally to the two arthritis models, from 17 days before sensitization. As a comparative control, methotrexate (0.1 mg/kg, once daily) was given to another group. Tranilast suppressed the increase in foot volumes, paw thicknesses, clinical scores, and histopathological scores of the ankle joints in both models dose-dependently. In addition, the fibrosis indices of the ankles were dramatically decreased by tranilast in both of the models. Compared to the effects of methotrexate, tranilast seemed to work more effectively in the streptococcal cell wall-induced arthritis model than in the adjuvant-induced arthritis model. From these observations, it can be concluded that tranilast suppresses the development of arthritis in multiple models and is potentially a novel therapeutic agent for human rheumatoid arthritis. Keywords:: tranilast, rheumatoid arthritis, adjuvant-induced arthritis, streptococcal cell wall-induced arthritis, methotrexate

The toxicity profile of silodosin, a selective alpha(1A)-adrenoceptor antagonist, was evaluated. The lethal doses were 800 mg/kg in rats and 1500 mg/kg in dogs. Repeated-dose studies revealed fatty degeneration of hepatocytes and an induction of drug-metabolizing enzymes at 15 mg/kg/day or more in male rats, mammary gland hyperplasia at 60 mg/kg/day or more in female rats, and degeneration of the seminiferous tubular epithelium at 25 mg/kg/day or more only in young dogs. Silodosin was negative in all mutagenicity studies, except for a weak positive in a chromosomal aberration assay conducted without metabolic activation. In carcinogenicity studies, mammary gland tumors and pituitary adenomas were increased in female mice given 150 mg/kg/day or more and 400 mg/kg/day respectively, while thyroid follicular cell carcinoma was increased in male rats given 150 mg/kg/day. Reproductive studies in rats revealed a decreased male fertility at 20 mg/kg/day or more and a prolonged estrous cycle at 60 mg/kg/day or more. Silodosin did not exhibit any teratogenic potential in either rats or rabbits, and had no effects on the postnatal development of rat offspring. In safety pharmacology studies, silodosin produced no severe effects on the central nervous, cardiovascular, or respiratory systems. In conclusion, silodosin exhibited adequate safety margins between the clinically recommended dose and those at which toxic effects or safety pharmacological changes were detected. As a new therapeutic drug for the micturition difficulties caused by benign prostatic hyperplasia, silodosin should have few serious side effects in clinical use.

The effects of silodosin, an alpha(1A)-adrenoceptor (AR) antagonist, and of other alpha(1)-AR antagonists on the phenylephrine (PE)-induced increase in intraurethral pressure (IUP) and on blood pressure (BP) were studied in anesthetized rats. The drugs were administered intravenously (i.v. study) or intraduodenally (i.d. study). IUP and BP were measured via catheters inserted into the prostatic urethra and common carotid artery, respectively. In the i.v. study, drugs were administered every 30 min for effects on BP, and 5 min before each PE-injection (30 microg/kg, every 60 min) with stepwise increases in dose for effects on IUP. In the i.d. study, one dose of drug was administered per rat, then IUP and BP were observed for 4 h [IUP being measured time-dependently following PE-injection (30 microg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID(50) for IUP and ED(15) for BP were calculated, and uroselectivity was determined as ED(15)/ID(50) for each drug. All drugs both inhibited the IUP increase and lowered BP, each effect being dose-dependent. The order of uroselectivities was silodosin (11.7)tamuslosin (2.24)naftopidil (0.133) in the i.v. study, and silodosin (26.0)tamuslosin (3.82)naftopidil (1.39) in the i.d. study. Selectivity for the lower urinary tract (LUT) was higher for silodosin than for tamsulosin (alpha(1A)/alpha(1D)-AR), naftopidil (alpha(1D)-AR), or prazosin (non-selective alpha(1)-AR). These results suggested that an alpha(1A)-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.

Our aim was to compare the cardiovascular effects of mitiglinide ((+)-monocalcium bis[(2S,3a,7a-cis)-α-benzylhexahydro-γ-oxo-2-isoindolinebutyrate] dehydrate), a novel hypoglycemic drug, with those of glibenclamide and glimepiride, two sulfonylurea drugs. In isolated canine coronary arteries (organ-bath method), mitiglinide, glibenclamide, and glimepiride competitively antagonized the cromakalim-induced relaxation (pA2 values, 5.29, 7.36, and 7.49, respectively). In isolated perfused rat hearts (Langendorff method) subjected to a 12-min global ischemia followed by a 30-min reperfusion, mitiglinide (3 × 10− 6 mol/l) altered neither the change in coronary perfusion flow nor the alterations in cardiac functions associated with reperfusion. In contrast, both glibenclamide (3 × 10− 8 mol/l) and glimepiride (1 × 10− 7 mol/l) significantly reduced coronary perfusion flow after reperfusion. Moreover, at 30 min of reperfusion: (1) glibenclamide induced a significant increase in left ventricular end-diastolic pressure and significant decreases in left ventricular systolic pressure, left ventricular developed pressure, and the maximum first derivative of left ventricular pressure, while (2) glimepiride induced significant decreases in left ventricular developed pressure and the maximum first derivative of left ventricular pressure. Thus, the cardiovascular effects of mitiglinide (at least, in these rat and dog preparations) may be weaker than those of glibenclamide and glimepiride.

Purpose: We evaluated the effects of the nonselective muscarinic receptor agonist carbachol (CCh) and its antagonist atropine on ureteral function in anesthetized dogs.Materials and Methods: Drug effects were evaluated on elevated pressure in a completely obstructed ureter and peristalsis in its partially obstructed fellow ureters as well as on intravesical isovolumetric pressure.Results: CCh (0.1 to 1.0 μg/kg intravenously) dose dependently decreased elevated pressure and peristalsis in completely and partially obstructed ureters, respectively, and increased intravesical isovolumetric pressure. On the other hand, atropine (0.1 to 1.0 mg/kg intravenously) had no significant effects on these 3 variables. Prior administration of atropine (1.0 mg/kg intravenously) completely inhibited the described CCh induced effects.Conclusions: Our results demonstrate that in anesthetized dogs cholinergic receptor stimulation has a suppressive effect on ureteral pressure and peristalsis in obstructed ureters, in c...

In our preliminary experiment, we found that a constant infusion of a high dose of parathyroid hormone-related protein induced both hyperphosphataemia and hypocalcaemia, secondary to renal dysfunction. Therefore, in this study, we developed two types of parathyroid hormone-related protein-induced hypercalcaemia models. One is the hypercalcaemia model, which did not show renal-dysfunction-induced hypocalcaemia. This model might be suitable for estimating hypocalcaemic activities of drugs, especially of those that act on bone resorption. The other is the model for estimating histological changes, which is associated with renal dysfunction. We then used these models to investigate the effects of three different bisphosphonates. Since the hypercalcaemic effect of parathyroid hormone-related protein infusion plateaued at 20 pmol/h, and higher doses of parathyroid hormone-related protein caused an elevation of blood urea nitrogen, the parathyroid hormone-related protein infusion rate was fixed at 20 pmol/h to avoid renal dysfunction and at 40 pmol/h to elicit renal dysfunction. The hypocalcaemic efficiencies of clodronate and etidronate were almost the same but pamidronate was 17.9 times more potent than clodronate. Additionally, both clodronate and pamidronate decreased the plasma concentrations of blood urea nitrogen and the Ca2+ times inorganic P product, whereas etidronate lacked these effects. Clodronate suppressed renal calcification and tubular dilatation in the renal-dysfunction model. These data indicated that clodronate and pamidronate not only decrease the plasma Ca2+ concentration but also improve the renal dysfunction induced by hypercalcaemia.

Purpose: We pharmacologically characterized the functional β-adrenoceptor subtypes mediating porcine ureteral smooth muscle relaxation. Materials and Methods: The effects of various β-adrenoceptor agonists and antagonists on KCl induced tonic contractions in isolated porcine ureteral preparations were evaluated using a functional experimental technique. Results: The rank order of potency for the catecholamines tested was isoprenaline > adrenaline > noradrenaline. All β 2 -adrenoceptor agonists tested (salbutamol, procaterol and terbutaline) attenuated the KCl induced contraction. The 2 β 3 -adrenoceptor agonists CL-316243 (( R , R )-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-benzodioxole-2,2-dicarboxylate], Kissei, Nagano, Japan) and CGP-12177A ((±)[4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2 H -benzimidazol-2-one hydrochloride], Funakoshi, Tokyo, Japan) also relaxed the ureter. The β 1 -adrenoceptor agonist dobutamine had a relaxing effect on the ureter only at high concentrations (over 1 × 10 −5 M). Isoprenaline induced relaxation was antagonized by the β 2 -adrenoceptor antagonist ICI-118,551 ((±)-1-[(2,3-dihydro-7-methyl-1 H -inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride, Sigma, St. Louis, Missouri) but not by the β 1 -adrenoceptor antagonist CGP 20712A ((±)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulphonate, Funakoshi). In the presence of 1× 10 −7 M CGP 20712A plus 1 × 10 −7 M ICI-118,551 the β 3 -adrenoceptor antagonist SR 58894A (3-(2-allylphenoxy)-1-[(1 S )-1,2,3,4-tetrahydronaphth-1-ylamino]-(2 S )-2-propanol hydrochloride, Kissei) antagonized isoprenaline induced relaxation. Conclusions: Our results suggest that porcine ureteral smooth muscle is relaxed by β 2 and β 3 -adrenergic stimulation, as in humans.

Intimal hyperplasia is a serious problem after percutaneous transluminal coronary angioplasty. In this study, we assessed the effect of tranilast on vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet. In this animal model, intimal hyperplasia more severe than that in rabbits fed on a normal diet was observed. In addition, medial thickening and lipid deposits in both media and intima were also noted. These findings indicate that balloon injury caused intimal and medial hyperplasia and that this hyperplasia was accelerated by the high cholesterol load. Tranilast (300 mg/kg) significantly decreased the intimal area, medial area, and stenosis ratio, and increased the luminal/total area ratio, in the cholesterol-fed rabbits. These results suggest that tranilast may be useful for prevention of restenosis after percutaneous transluminal coronary angioplasty of patients, including those with a clinical risk of hypercholesterolemia.

We investigated therapeutic effects of a rapid- and short-acting non-sulfonylurea hypoglycemic agent, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229), on streptozotocin (STZ)-induced non-insulin-dependent diabetes mellitus (NIDDM) rats. The effects exerted by KAD-1229 on the post-prandial plasma glucose rise in STZ-induced mild NIDDM (mNIDDM) rats were different from those of sulfonylureas. When KAD-1229 with liquid meal (10 kcal/kg) was given to the mNIDDM rats, the plasma glucose migration was similar to that of normal healthy rats. On the contrary, glibenclamide had little or no effect on the plasma glucose rise 0.5-1 hr after oral administration, and its effect was only evident 2-5 hr after dosing. Tolbutamide showed similar hypoglycemia to that induced by glibenclamide at 2-5 hr with insufficient efficacy at 0.5 hr. Gliclazide sufficiently suppressed the level of post-prandial plasma glucose. However, its complete inhibition of post-prandial plasma glucose was associated with the extra-hypoglycemia 1-5 hr after oral administration. We also tested the efficacy of KAD-1229 in more severe STZ-induced NIDDM (sNIDDM) rats to elucidate the effects of the drug on the long-term glycemic controls and diabetic complications. When the sNIDDM rats were treated with 10 mg/kg KAD-1229 twice a day for about 17 weeks, increases in fasting plasma glucose and hemoglobin A1c were inhibited. Furthermore, treatment with KAD-1229 suppressed the development of microalbuminuria and cortical cataract. We conclude that the rapid- and short-acting insulinotropic agent KAD-1229 is able to improve the deterioration in the glycemic controls and inhibit the development of diabetic complications in STZ-induced NIDDM rats.

Intimal hyperplasia is a serious problem after percutaneous transluminal coronary angioplasty (PTCA). In this study, we investigated the effects of tranilast on intimal hyperplasia in both in vivo and in vitro experiments. For the in vivo experiments, we used the balloon injury model and the cuff treatment model of rabbits fed regular chow. In the balloon injury model, tranilast decreased intimal area, intima/media ratio, stenosis ratio and vascular DNA content after endothelial injury. Also in the cuff treatment model, tranilast suppressed the intimal hyperplasia. In the in vitro experiments, we assessed the effects of tranilast on platelet-derived growth factor-induced rabbit vascular smooth muscle cell (VSMC) migration and proliferation and on collagen synthesis by VSMCs. Tranilast inhibited VSMC migration, proliferation and collagen synthesis. These results suggest that tranilast has a suppressive effect on intimal hyperplasia after a vascular injury such as PTCA.

To evaluate the role of macrophages in glomerulonephritis, the relationship between the existence of macrophages and proteinuria in the long course of glomerulonephritis was studied in accelerated Masugi nephritis in the rat. Non-specific esterase staining was used as a marker of macrophages and the kinetics of glomerular macrophages was analysed by an image processor. Macrophages became detectable 48 hours after nephrotoxic serum injection and their accumulation reached a maximum level at 5 days. At 1 month, they had clearly decreased. At 3 months, however, many macrophages were found within the capsular drop-like lesions and crescents. Urinary protein excretion took roughly the same time course as the number of macrophages for 2 weeks. However, at 1 month, whereas macrophages had decreased, the proteinuria kept a persistently high level. At 3 months it showed a tendency to decrease. The correlation between the rate of appearance of macrophages and the urinary protein excretion assessed in 20 cases exhibited no significance. In addition, descrepancy in their time course was evident at 1 month. Although macrophages may happen to contribute to the tissue injury resulting in proteinuria in the early phase of nephrotoxic serum nephritis, factors other than macrophages should be considered in the subsequent duration of proteinuria in this model.