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Titanium (Ti) is the most widely used implant material in dentistry and orthopedics but the release of metal ions from Ti implants results in increased bone resorption by enhancing the production of inflammatory cytokines from the macrophages and facilitating osteoclast differentiation. Thymosin β4 (Tβ4) has several biological activities, such as promoting wound healing, angiogenesis, cell proliferation and migration in mammalian cells. This study examined the role of Tβ4 in osteoblasts via focal adhesions (FAs) and ERK1/2 signaling related to cell adhesion and proliferation for cell survival on the Ti surface. As a result, cell adhesion and proliferation increased in the Tβ4 treated cells (Tβ4/MC3T3-E1) but was significantly lower in the Tβ4 knock-down cells by Tβ4-siRNA (si-Tβ4/MC3T3-E1) than that of the untreated cells. The levels of FAK phosphorylation, paxillin expression, and paxillin localization were higher in the Tβ4/IMC3T3-E1 cells than that of the untreated cells but lower in the si-Tβ4/MC3T3-E1 cells. In addition, the levels of cell proliferation, Grb2 and Ras protein expression and phosphorylation of ERK1/2 were higher in the Tβ4/MC3T3-E1 cells than in the untreated cells but lower in the si-Tβ4/IMC3T3-E1 cells. These results suggest that Tβ4 might be a good nanomolecule that promotes osteoblast survival by facilitating adhesion and proliferation on the Ti surface.

Elastic network model (ENM) based normal mode analysis has become popular as its capability and suitability for the study of protein dynamics. However, the existing ENMs often fail to reproduce the experimentally observed B-factor (i.e., atomic fluctuation) because of oversimplification of their force-fields. In this work, we have proposed a robust ENM (RENM) in which, for reflecting inter-connections accused from surrounding molecules in a unit cell, symmetric constraints based on crystal space group are applied to the representative single molecule as well as its intra-connections are also represented by using lumped masses and specific spring constants depending on the types of amino acids and chemical bonds, respectively. More than 500 protein structures are tested by RENM. Their results show better agreement with experimental B-factor without additional computation burden compared to those of traditional ENM. Moreover, the global spring constant is quantitatively determined as a function of temperature at 100K and 290K, which enables us to compute directly atomic fluctuations and vibrational density of state without any fitting process. Thus, RENM is expected to play an important role in understanding protein dynamics based on its crystal structure information.

A variational principle is applied to the diffusion equation to numerically obtain the fission gas release from a spherical grain. The two-zone method, originally proposed by Matthews and Wood, is modified to overcome its insufficient accuracy for a low release. The results of the variational approaches are examined by observing the gas concentration along the grain radius. At the early stage, the concentration near the grain boundary is higher than that at the inner points of the grain in the cases of the two-zone method as well as the finite element analysis with the number of the elements at as many as 10. The accuracy of the two-zone method is considerably enhanced by relocating the nodal points of the two zones. The trial functions are derived as a function of the released fraction. During the calculations, the number of degrees of freedom needs to be reduced to guarantee physically admissible concentration profiles. Numerical verifications are performed extensively. By taking a computational time comparable to the algorithm by Forsberg and Massih, the present method provides a solution with reasonable accuracy in the whole range of the released fraction.

The vascular relaxant effect of the rootbark extract of Paeonia moutan was evaluated in isolated rat thoracic aorta. The methanolic extract of the rootbark showed a vasorelaxant activity in rat aortic preparations precontracted with 0.3 microM phenylephrine (IC50 value: 16.8 microg/mL). The activity-guided fractionation of the extract led to the isolation of five active principles such as paeoniflorin (1), paeonidanin (2), methylpaeoniflorin (4), tetragalloylglucose (5) and pentagalloylglucose (6), and these active ingredients potently relaxed phenylephrine-induced contraction of rat aortic preparations in a concentration-dependent manner (IC50 values: 19.4, 7.9, 10.1, 5.1 and 3.6 microM, respectively). These results suggest that pinane glycosides and galloylglucoses might be the components responsible for the vasorelaxant properties of the rootbark extract of P. moutan, and their vasorelaxant effects may be mediated through increases in the release of nitric oxide from endothelial cells.

Introduction Melanin concentrating hormone is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight mediated by the melanin concentrating hormone receptor subtype 1 (MCH1). Compelling pharmacological evidence implicating MCH1 signaling in the regulation of food intake and energy expenditure has generated a great deal of interest by pharmaceutical companies as MCH1 antagonists may have potential therapeutic benefit in the treatment of obesity and metabolic syndrome. Methods Although radioligand receptor binding assay has been one of the most powerful tools for receptor research and drug discovery, the limitations of radioisotopes and the problems related to safety and waste disposal limits their application in high throughput screening and has led to a growing interest in alternative, nonradioactive technologies. To develop a sensitive and reproducible assay system for MCH1, the time-resolved fluorescence (TRF) receptor binding assay with AcroWell filter plates was tested and validated. Results Comparing to the radioligand receptor binding assay for MCH1, the TRF assay presented higher Z / Z ′ factors with the lower signal-to-noise ratio. The known high-affinity MCH1 receptor antagonist, SNAP-7941, exhibited an IC 50 value of 1.66 ± 0.10 nM that is very similar to the IC 50 value of MCH in a radioligand binding assay with an excellent correlation coefficient (0.9884). Discussion These results suggest that our TRF receptor binding assay for MCH1 can achieve the desired sensitivity and reproducibility to replace the radioligand receptor assay in a fluorometric system that can be developed for high throughput screening.

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) in rat and dog models of coronary artery occlusion and reperfusion. In addition, we sought to clarify the efficacy of KR-32570 on reperfusion-induced fatal ventricular arrhythmia. In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-32570 (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 50.7%, 35.3%, 33.5% and 27.0% for 0.03, 0.1, 0.3 and 1.0 mg/kg, respectively (P0.05). In anesthetized beagle dogs that underwent 1.2-h occlusion followed by 3.0-h reperfusion, KR-32570 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 28.9% in vehicle-treated group to 8.0% (P0.05), and reduced the reperfusion-induced release in creatine kinase isoenzyme MB, lactate dehydrogenase, Troponin-I and glutamic-oxaloacetic transaminase. KR-32570 dose-dependently decreased the incidence of premature ventricular contraction, ventricular tachycardia or ventricular fibrillation induced by ischemia and reperfusion in rats. Similar results were obtained in dogs with reperfusion-induced arrhythmia. In separate experiments to assess the effects of timing of treatment, KR-32570 given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (40.9% and 46.1%, respectively) compared with vehicle-treated group. In all studies, KR-32570 caused no significant changes in any hemodynamic profiles. Taken together, these results indicate that KR-32570 significantly reduced the myocardial infarction and incidence of arrhythmias induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles. Thus, it could be potentially useful in the prevention and treatment of myocardial injuries and lethal ventricular arrhythmias.

A series of 4-substituted (benzo[b]thiophene-2-carbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardioprotective efficacy both in vitro and in vivo. Several analogs exhibited a strong inhibition on NHE-1, and which was generally well correlated with their cardioprotective efficacy. Especially the 4-nitro 20 and cyano 50 compounds excellently improved the cardiac function and reduced infarct size against ischemia/reperfusion injury.

A series of (5-arylfuran-2-ylcarbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardiprotective efficacy against ischemia-reperfusion injury. Starting with (5-phenylfuran-2-ylcarbonyl)guanidine 47 with a moderate inhibitory effect on NHE-1, the compounds with various substituents at the phenyl ring were investigated with the aim to optimize the potency. In this study, the 2,5-disubstituted compounds appeared to have better activities than the other analogues, and the 2-methoxy-5-chlorophenyl compound 85 was found as a potent inhibitor of NHE-1 (IC(50) = 0.081 microM). Furthermore, 85 showed a marked reduction of infarct size in the rat myocardial infarction model in vivo and significant improvement of cardiac contractile function in the isolated rat heart ischemia model in vitro.

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) on ischemia/reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts. In addition, the effects of KR-32570 on the Na(+)/H(+)-exchanger (NHE) and lipid peroxidation were also evaluated. KR-32570 strongly inhibited the recovery from acidosis induced by an NH(4)Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC(50): 0.05 and 1.16 microM for KR-32570 and cariporide, respectively). In isolated perfused rat hearts subjected to 30-min ischemia/30-min reperfusion, KR-32570 (1-10 microM) significantly and concentration dependently improved cardiac contractile function and severe contracture in conjunction with causing a marked reduction in lactate dehydrogenase release. Additionally, it (1-10 microM) significantly increased the content of ATP, creatine phosphate and glycogen as well as decreased the tissue lactate content in heart homogenates following ischemia and reperfusion. KR-32570 (1-10 microM) significantly decreased the concentration of 8-iso-prostaglandin F(2 alpha), a reliable marker for oxidant stress, in perfusates from rat hearts subjected to ischemia and reperfusion. In separate experiments, KR-32570 significantly lowered the concentration of malondialdehyde in rat liver homogenate and inhibited Cu(2+)-induced peroxidation of low-density lipoprotein. Taken together, these results suggest that KR-32570 possesses potent cardioprotective effects in perfused rat hearts, and its effects may be mediated by inhibition of NHE-1, preservation of high-energy phosphates, and inhibition of lipid peroxidation.

Essential oils extracted fromEucalyptus blakelyi (1,8-cineole, 77.5%),Melaleuca fulgens (1,8-cineole, 56.9%) and 1,8-cineole were shown to have fumigant toxicity against different development stages ofSitophilus oryzae. The eggs ofS. oryzae were the most tolerant, followed by pupae, larvae and adults in that order.M. fulgens oil,E. blakelyi oil and 1,8-cineole at 100 µl per liter of air gave, respectively, LT50 values of 16.2, 17.4 and 9.1 h for adults, 31.1, 19.3 and 17.5 h for larvae, 55.6, 75.2 and 39.7 h for pupae, and required >7 days for eggs. Only 1,8-cineole (200 µl −1 air) gave a significant egg kill by 7 days and the LT95 was 134.5 h. 1,8-Cineole could be a useful new fumigant.

A novel class of alkoxybenzylcyanoguanidine analogs as the inhibitors of restenosis was discovered, which showed the inhibitory effects on angiotensin II-induced cell proliferation, determined by [ 3 H]thymidine incorporation method. The compound, N'-(4-nitrophenyl)guanidine analog 19, showed 62% inhibition of [ 3 H]thymidine incorporation at 1 μM concentration. In addition, the compound 19 inhibited intimal thickening dose-dependently after balloon injury, which suggests the therapeutic potential for restenosis.

MOX fuel rod behavior due to PCMI during power transients was evaluated using a finite element code, ABAQUS. Clad elongation is calculated through a coupled temperature–displacement analysis where a half-pellet is axisymmetrically modeled. Parametric study for the PCMI model is preliminary performed to identify the dominant factors and examine the applicable range of the model. The comparison of the predicted results with recent MOX in-pile data shows that the centerline temperature and clad elongation are evaluated within an acceptable range.

The cardioprotective effects of (2S,3R,4S)-N′-benzyl- N′′-cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydro- xy-2-methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) were evaluated against ischemic/reperfusion injury in isolated rat hearts in vitro and in anesthetized rats and dogs in vivo. In isolated perfused rat hearts subjected to a 30-min global ischemia/30-min reperfusion, KR-31372 (1–10 µM) significantly improved severe contracture (end-diastolic pressure and time to contracture), markedly reduced reperfusion lactate dehydrogenase release, and enhanced the recovery of reperfusion contractile function (left ventricular developed pressure and double product) in a concentration-dependent manner compared with the vehicle-treated group. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, intravenous KR-31372 dose-dependently reduced infarct size from 58.6% to 48.5, 48.1 and 39.6% at 0.3, 1.0 and 3.0 mg/kg, respectively (p < 0.05). In anesthetized beagle dogs that underwent a 1.5-hour occlusion followed by a 5-hour reperfusion, KR-31372 (2 mg/kg, i.v.) markedly reduced infarct size from 57.0% in controls to 28.0% (p < 0.05). The cardioprotective effects of KR-31372 on contractile function in globally ischemic rat hearts and on reperfusion injury in anesthetized rats were significantly reversed by pretreatment with selective adenosine triphosphate-sensitive potassium (KATP) channel blockers, sodium 5-hydroxydecanoate and glibenclamide. Taken together, these results indicate that KR-31372 possesses potent cardioprotective effects in rats and dogs and its effects may be mediated by activation of mitochondrial KATP channels.

Six out of 42 essential oils extracted from species of the family Myrtaceae found in Australia were shown to have potent fumigant toxicity against three major stored-grain insects: Sitophilus oryzae, Tribolium castaneum and Rhyzopertha dominica. These were the essential oils from Eucalyptus nicholii, E. codonocarpa, E. blakelyi, Callistemon sieberi, Melaleuca fulgens and M. armillaris. The LD50 and LD95 of the selected essential oils against S. oryzae adults were between 19.0–30.6 and 43.6–56.0 μl/l air, respectively. Also, these oils were approximately twice as toxic to T. castaneum and R. dominica at the LD95. Fumigant effects of the essential oils rich in 1,8-cineole were considered to warrant further research into their potential for commercial use.

The present study was performed to investigate the effects of chronic administration of quercetin on lipid peroxidation and glutathione concentration in rat liver. Male Sprague–Dawley rats were divided into two groups, one of which was fed a normal diet and the other a vitamin E-free diet. Each of these groups was divided further into three subgroups and treated with quercetin administered orally at either 2 or 20 mg/day or with vehicle for 4 weeks. The concentrations of α-tocopherol in serum and liver increased following quercetin treatment, and these increases were significantly greater in rats maintained on a vitamin E-free diet. Quercetin significantly decreased the concentration of malondialdehyde (an indicator of lipid peroxidation) in the liver and this decrease was more pronounced in vitamin E-deprived rats than in those maintained on a normal diet (55–60% and 25–35% decrease in malondialdehyde concentrations, respectively). Quercetin treatment decreased the glutathione concentration and glutathione reductase activity (40 and 34%, respectively) in the liver significantly and to a similar extent in vitamin E-deprived and -undeprived rats. Collectively, these results suggest that quercetin may act not only as an antioxidant, but also as a prooxidant in rats.

The present study was performed to examine mitogen-activated protein kinase associated pathways in mediation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cell apoptosis in cultured Jurkat T cells. TCDD significantly decreased cell viability in a concentration-dependent manner (P

The threshold porosity above which fission gas release channels would be formed extensively in the rim region of high burnup UO2 fuel was estimated by the Monte Carlo method and Hoshen–Kopelman algorithm. With the assumption that both rim pore and rim grain can be represented by cubes, the pore distribution in the rim was simulated three-dimensionally by the Monte Carlo method according to rim porosity and pore size distribution. Using the Hoshen–Kopelman algorithm, the fraction of open rim pores interlinked to the outer surface of a fuel pellet was derived as a function of the rim porosity. The simulation revealed that it is the rim porosity rather than the pore size distribution or rim thickness that determines the fraction of open pores connected to the pellet surface. The analysis also indicated that the threshold porosity is around 24%, above which the number of rim pores forming release channels increases very rapidly.

The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 microM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 microM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 microM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity.

Pu-Er-Zr oxide as an inert matrix fuel (IMF) could be an attractive option for a once-through LWR strategy aimed at reducing the currently growing plutonium stockpiles. A basic question related to the practical introduction of such an IMF into a current-day LWR, without affecting any significant change in fuel element design and core performance, is the irradiation behaviour of the proposed IMF. The present paper reports first results from a corresponding validation experiment which has been launched recently, viz. the comparative in-pile testing of specialty fabricated IMF and PuO2/UO2 mixed-oxide (MOX) fuel rodlets in the Halden reactor. The maximum linear power rating was limited to about 25 kW/m during the currently reported initial testing phase, as compared to the design value of 35 kW/m to be aimed at during subsequent cycles at Halden. While fuel centre-line temperatures were found to be within the expected range for both fuel types, the variation of pressure in the rodlets has clearly indicated significant densification in the IMF specimens, with fission gas release being non-detectable at the low burnups achieved to date. A possible sintering model for the IMF is proposed to explain the experimental results obtained during this moderate-power testing phase, viz. the apparent "geometrical stability" of the IMF in spite of its strong initial densification

LWR MOX fuel, fabricated either by direct mechanical blending of UO2 and PuO2 powders or by two stage mixing, inevitably has Pu-rich particles dispersed in the matrix of fuel pellet, whose Pu concentrations are higher than pellet average one and whose size distribution depends on specific fabrication method. This paper describes a mechanistic thermal conductivity model of MOX fuel by considering this inhomogeneous microstructure and explains the wide scattering of measured MOX's thermal conductivity. The developed model has been incorporated into a KAERI's fuel performance code, COSMOS, and then evaluated using measured data for irradiated MOX fuel. The measured temperatures were obtained from both homogeneous MOX at beginning of life and inhomogeneous MOX at high burnup. The COSMOS predicts the thermal behavior of MOX fuel well except for irradiation test accompanying substantial fission gas release. This over-prediction of fuel temperature, that is, the under-prediction of thermal conductivity, in the M...

Toxicity of various essential oils and their volatile components against the red flour beetle, Tribolium castaneum (Herbst) was determined. The most potent fumigant toxicity was found in essential oil from rosemary (LD 50 = 7.8 μl/l air) followed by the oils of lemon (LD 50 = 16.2 μl/l air), basil (LD 50 = 17.8 μl/l air), lime (LD 50 = 17.9 μl/l air), and peppermint (LD 50 = 25.8 μl/l air). 1,8-Cineole was the most toxic fumigant compound found in rosemary essential oil (LD 50 = 7.4 μl/l air) followed by menthone (LD 50 = 8.5 μl/l air) and p -cymene (LD 50 = 11.4 μl/l air). 1,8-Cineole exhibited similar fumigant toxicity against a PH3-resistant T. castaneum relative to the susceptible insects. Therefore, 1,8-cineole and rosemary essential oil could be a safer fumigant to control stored-product insect pests than those currently used.

To analyze the effect of an inhomogeneous mixture of an PuO 2 powder on fission gas release in MOX fuel, a model has been developed using the assumption that gas release mechanism in Pu-rich particles is identical with that in UO 2 fuel. A parametric study was performed to see the respective effect of the number density, size and fraction of Pu retained in the Pu-rich particles on gas release in MOX fuel. The model shows that, for the condition of all the other remaining parameters being fixed, more gas is released in a MOX fuel for lower number density of, smaller size of, and larger fraction of Pu retained in, the Pu-rich particles. However, there exists some condition or combination of parameters for which the effect of inhomogeneity on gas release is negligible depending on the characteristics of MOX fuel. Comparison with measured data for OCOM MOX fuel shows that the present model can predict the level of gas release in MOX fuel once the release mechanism in the Pu-rich particles is known.

The creep model for Zircaloy-4 has been improved by including the metallurgical effect of Zircaloy cladding. Based on the experimental results in which the creep strain rate is highest for stress relief annealed cladding (SRA) and lowest for recrystallized cladding (RXA), the annealing factor was introduced and derived by iterative calculations until the best predictions for all the rods were obtained. The creep model has been incorporated into the KAERIs fuel performance code COSMOS and then verified with 4 cladding creep data, of which 3 cases exhibit creepdown and the other one creepout. The model predicts well the creep behavior of UO2 fuel rods in PWRs. The prediction does not show any discernable difference between the high- and low-Sn claddings. With satisfactory agreement between predicted and measured values, the comparison indicates no difference in creep behavior between MOX and UO2 fuel rods as expected. Although there are controversies over the experimental method and the analysis procedures for clad creepout, COSMOS generally well predicts the creep behavior, even in the case of creepout, if the creepout factor is applied. # 2001 Elsevier Science Ltd. All rights reserved.

In an organometallic CH3NH3PbI3 (MAPbI3) perovskite solar cell, we have demonstrated a vastly compact TiO2 layer synthesized by double-step deposition, through a combination of sputter and solution deposition to minimize the electron-hole recombination and boost the power conversion efficiency. As a result, the double-step strategy allowed outstanding transmittance of blocking layer. Additionally, crystallinity and morphology of the perovskite film were significantly modified, provoking enhanced photon absorption and solar cell performance with the reduced recombination rate. Thereby, this straightforward double-step strategy for the blocking layer exhibited 12.31% conversion efficiency through morphological improvements of each layer.

Purpose Nonsteroidal anti-inflammatory drugs are a mainstay for medical treatment of chronic lower back pain (CLBP). Increased dose intervals for medication have been associated with increased patient adherence to prescriptions. The purpose of this clinical trial was to compare the efficacy and safety of a once daily dose of aceclofenac controlled release (CR) and a twice daily dose of aceclofenac for CLBP management. Materials and methods A prospective, randomized, single center, open-label clinical trial was performed to compare the efficacy and safety of aceclofenac CR (200 mg once daily) to aceclofenac dose (100 mg twice daily). Fifty patients in each group were enrolled for the study. The primary end point was Visual Analogue Scale (VAS) change at baseline to that at 2 weeks after medication and safety profiles. Also, change in quality of life measured by EuroQoL 5D (EQ-5D) and Oswestry Disability Index (ODI) functional score for the lumbar spine were also assessed. Results Within groups at pre- and post-treatment, there were significant VAS reductions for aceclofenac CR and aceclofenac (p=0.028). EQ-5D increased significantly in both groups (p=0.037). ODI scores decreased significantly in both groups (p=0.012). However, there were no significant differences between aceclofenac CR and aceclofenac at pre- and post-treatment. Patients with aceclofenac CR showed significant increases in heartburn and indigestion and adverse gastrointestinal effects, compared to aceclofenac. Conclusion In patients with CLBP, aceclofenac CR and aceclofenac demonstrated significant symptomatic pain relief, improvement in quality of life and functional scores. Aceclofenac CR slightly increased gastrointestinal adverse effects, such as heartburn and indigestion.

Background context Traumatic spinopelvic dissociation, sometimes referred to as U-shaped sacral fracture, is a very rare high-energy trauma. The surgical management of spinopelvic dissociation includes decompression, reduction, and fixation. Purpose We report a novel surgical technique for the treatment of spinopelvic dissociation that uses growing rods and a pedicle screw system, which is often used to treat patients with early onset scoliosis. Study design This case report used a technical report of spinopelvic dissociation surgery using spinopelvic fixation and the growing rod technique. Patient sample One case was used as the patient sample. Outcome measure Radiographic outcomes, including plain X-ray, three-dimensional computed tomography, and magnetic resonance imaging scan were the outcome measures. Methods The radiographic outcomes were compared preoperatively, postoperatively, and at the 1-year follow-up with bony union. Results Growing techniques improved traumatic sacral angulation, displacement, and canal encroachment, and provided sufficient structural support. Conclusion The growing rod technique for spinopelvic dissociation under intraoperative neurophysiological monitoring could be a useful alternative surgical option, especially in patients without neurologic deficit.

PURPOSE Teriparatide markedly increases bone formation and strength, while reducing the incidence of new-onset osteoporotic vertebral compression fractures (OVCFs). In some countries, expenses for teriparatide use are covered by medical insurance for up to 6 months; however, the national medical insurance of the authors' country does not cover these expenses. This retrospective cohort study compared the therapeutic effects of teriparatide on the initial onset of a new OVCF after treatment of osteoporosis and/or related OVCFs with regard to therapeutic durations of longer than 3 months (LT3M) or shorter than 3 months (ST3M). MATERIALS AND METHODS From May 2007 to February 2012, 404 patients who were prescribed and administered teriparatide and who could be followed-up for longer than 12 months were enrolled. They were divided into two groups depending on teriparatide duration: LT3M (n=132) and ST3M (n=272). RESULTS The group with the teriparatide duration of LT3M showed significantly less development of an initial OVCF within 1 year (p=0.004, chi-square). Duration of teriparatide use, body mass index, pre-teriparatide lowest spinal bone mineral density, and severity of osteoporosis significantly affected multiple regression analysis results (p

The arising critical implications of G-protein-coupled receptor kinase 2 and 5 (GRK2 and 5) in heart failure have been attracting attention and inhibitors of GRK2 and 5 were considered as a novel therapeutic strategy to prevent and treat heart failure disease. Despite this large therapeutic potential, to date few GRK2 inhibitors have been identified and GRK5 inhibitors in public have been unknown. In our efforts to discover a novel scaffold with potent GRK2 and GRK5 inhibitory activities, we found that a series of 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amines have been identified as a new class of GRK2 and 5 kinase inhibitor. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK2 and 5. This research highlight discusses the processing and findings of the recent study.

Erythropoietin-producing hepatocellular receptor tyrosine kinase subtype A2 (EphA2) is an attractive therapeutic target for suppressing tumor progression. In our efforts to discover novel small molecules to inhibit EphA2, a class of compound based on 4-substituted quinazoline containing 7-(morpholin-2-ylmethoxy) group was identified as a novel hit by high throughput screening campaign. Structural modification of parent quinazoline scaffolds by introducing substituents on aniline displayed potent inhibitory activities toward EphA2.

Human Urotensin-II (U-II) is the most potent mammalian vasoconstrictor known.1 Thus, a U-II antagonist would be of therapeutic value in a number of cardiovascular disorders.2 Here, we describe our work on the prediction of the structure of the human U-II receptor (hUT2 R) using GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) complete sampling Monte Carlo method. With the validation of our predicted structures, we designed a series of new potential antagonists predicted to bind more strongly than known ligands. Next, we carried out R-group screening to suggest a new ligand predicted to bind with 7 kcal mol(-1) better energy than 1-{2-[4-(2-bromobenzyl)-4-hydroxypiperidin-1-yl]ethyl}-3-(thieno[3,2-b]pyridin-7-yl)urea, the designed antagonist predicted to have the highest affinity for the receptor. Some of these predictions were tested experimentally, validating the computational results. Using the pharmacophore generated from the predicted structure for hUT2 R bound to ACT-058362, we carried out virtual screening based on this binding site. The most potent hit compounds identified contained 2-(phenoxymethyl)-1,3,4-thiadiazole core, with the best derivative exhibiting an IC50 value of 0.581 μM against hUT2 R when tested in vitro. Our efforts identified a new scaffold as a potential new lead structure for the development of novel hUT2 R antagonists, and the computational methods used could find more general applicability to other GPCRs.

The functional level of children with progressive neuromuscular disease is a major factor that affects the quality of life (QOL) of parents. However, only a few publications have reported changes in the QOL of parents after correctional spinal surgery.The purpose was to compare changes in QOL for both patients and parents after spinal correctional surgery for better sitting balance and to analyze correlation among radiographic parameters, functional outcome, and QOL questionnaires. Finally, the QOL of patients and parents was compared with the population norm.This study is a retrospective analysis of prospectively gathered data.From 2008 to 2011, 58 patients who underwent correctional surgery for progressive neuromuscular scoliosis and their parents were enrolled.A Muscular Dystrophy Spine Questionnaire (MDSQ) and short-form questionnaire 36 (SF-36) were used.The gathered functional outcome and QOL data using MDSQ and SF-36 for both enrolled patients and parents were compared preoperatively, postoperatively at 3 months, and at 1-year follow-up.Mean age was 15.0±4.1 years. Forty male and 18 female patients were enrolled. Mean follow-up was 38.4±13.7 months. Cobb angle was 61.5°±23.5° preoperatively, 39.0°±20.1° immediately postoperative, and 40.0°±20.2° at the final follow-up. Cobb angle, pelvic obliquity, and lumbar lordosis were significantly improved after surgery (p.001). Among sitting-related questions, answers to questions 15 (sitting comfortably), 16 (change weight in wheelchair), 22 (sit all day), 24 (sit at table for meal), 26 (keep balance while sitting in wheelchair), and 27 (look good while sitting in wheelchair) were significantly improved after correctional surgery (p.001). Regarding the SF-36 scales for patients, bodily pain and social functioning significantly improved postoperatively (p.001).Muscular Dystrophy Spine Questionnaire results indicated that patients had significantly improved sitting balance-related outcomes, whereas the SF-36 indicated improvements only in bodily pain and social functioning scales. For parents, no SF-36 scales improved significantly postoperatively. Accordingly, improved sitting balance and QOL for neuromuscular scoliosis patients after surgery do not necessarily increase parent QOL.

The cardioprotective and hemodynamic effects of KR-31378, a highly cardioselective ATP-sensitive potassium channel activator with minimal hypotensive effect, were evaluated in rats and dogs, and compared with those of BMS-191095 and lemakalim. KR-31378 did not show any significant effect on methoxamine-induced aortic constriction up to doses of 300 μM, whereas BMS 191095 produced a moderately potent relaxant effect (IC50: 9.0 μM). In conscious rats, KR-31378 slightly increased blood pressure only at high dose (100 mg/kg, iv), unlike BMS-191095 that dose-dependently decreased blood pressure (ED20: 2.03 mg/kg). In anesthetized beagle dogs, KR-31378 was approximately 100-fold less potent than BMS-191095 for most hemodynamic parameters (iv ED20 for blood pressure lowering: 33.7 and 0.37 mg/kg, respectively). In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-31378 (iv) dose-dependently reduced the infarct zone from 58.6% to 42.1%, 36.6%, and 34.3% for 0.1, 0.3, and 1.0 mg/kg, respectively (P < 0.05), the effects being comparable to those of BMS 191095. In anesthetized beagle dogs that underwent 2-h occlusion followed by 4.5-h reperfusion, KR-31378 (2 mg/kg, iv infusion) markedly reduced the infarct zone from 48.7% in controls to 19.1% at a dose of 2 mg/kg (P < 0.05). The reduction in infarct zone afforded by KR-31378 in rats was inhibited by pretreatment with selective ATP-sensitive potassium channel blockers, sodium 5-hydroxydecanoate and glibenclamide. These results indicate that KR-31378 is a potent cardioprotective agent with potentially minimal hypotensive effects. Thus, it could be potentially useful in the prevention and treatment of acute myocardial infarction. Drug Dev. Res. 54:182–190, 2001. © 2002 Wiley-Liss, Inc.

This paper describes the design, synthesis, and biological evaluation of a novel anti-ischemic compound, (2S,3S,4R)-N-(6-amino-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-benzopyranyl)-N'-benzyl-N"-cyanoguanidine (33), and the structure-activity relationships leading to the discovery of this compound. Compound 33 significantly reduced the myocardial infarct zone to area at risk (IZ/AAR) in the ischemic myocardium rat model with high cardioselectivity. Since the cardioprotective effect of compound 33 is reversed by ATP-sensitive potassium channel (K(ATP)) blockers, its anti-ischemic effect appears to be at least mediated by K(ATP) opening. In addition, compound 33 shows good protective activity on neuronal cells against oxidative stress, and therefore it is suggested that compound 33 may have therapeutic potential both in cardio- and in neuroprotection.

Based on measured rim characteristics of LWR high burnup UO2 fuel, the pressure of rim pores and the additional pellet swelling due to rim formation have been modeled. Using the assumption that the number of Xe atoms retained in the rim pores is the same as that which is depleted from the rim matrix, excessive pore pressure is derived as a function of temperature, pellet average burnup and pore radius. The rim pores with small radii are calculated to be highly overpressurized at high burnup. Comparison with experimental data shows that, while the pellet swelling obtained with best-estimate rim width is underpredicted, the one calculated with conservative rim width agrees well with the measured data for rim burnups between 50 and 65 GWd/tU. On the other hand, the measured swelling at 85 GWd/tU is about in-between the two calculations.

Toxicity of various essential oils and their volatile constituents towards the rice weevil, Sitophilus oryzae (L.) (Coleoptera: Curculionidae), was determined. The most potent toxicity was found in essential oil from eucalyptus (LD 50 =28.9 μl/l air). GC-MS analysis of essential oil from eucalyptus showed it to be rich in 1,8-cineole (81.1%), limonene (7.6%) and α -pinene (4.0%). Treatment of S. oryzae with each of these terpenes showed 1,8-cineole to be most active (LD 50 =23.5 μl/l air). In addition to 1,8-cineole, benzaldehyde (LD 50 =8.65 μl/l air) occurring in peach and almond kernels had a potent fumigant toxicity towards the rice weevils. Therefore, benzaldehyde and other natural volatiles could be a safer fumigant to control stored-grain insect pests than those currently used.

This study tested whether hypocapnic constriction of the rabbit basilar artery in vitro can be triggered by serotonin, and whether the resulting constriction is (1) due to the alkaline pH associated with hypocapnia, and (2) endothelin-1 mediated. Hypocapnic alkaline solution (25 mM NaHCO(3); pH 7.76; pCO(2) 14.2) or isocapnic alkaline solution (50 mM NaHCO(3); pH 7.73; pCO(2) 35.0) rarely altered basal tension. Serotonin (3 microM) challenge in hypocapnic or isocapnic alkaline solution resulted in near maximal tension. Washout of the serotonin did not decrease tension in 54% of the tissues, as plateau tension was maintained for 2-2.5 h. The plateau tension of washed tissues was relaxed by 1-3 microM PD145065 (Ac-D-Bhg-L-Leu-Asp-L-Ile-L-Ile-L-Trp), BQ610 (homopiperidinyl-CO-Leu-D-Trp(CHO)-D-Trp), and BQ788 (N-cis-2, 6-dimethyl-piperidinocarbonyl-L-gamma-MeLeu-D-Trp (COOCH(3))-Nle), endothelin ET(A)/ET(B), endothelin ET(A), and endothelin ET(B) receptor antagonists, respectively. In contrast, serotonin-induced tension in normal solution (25 mM NaHCO(3); pH 7.42; pCO(2) 36.9) was maintained for only 40 min (mean). These results demonstrate that (1) constriction due to hypocapnia in vitro can be triggered by serotonin and is endothelin-1 mediated and (2) alkaline pH in the absence of decreased pCO(2) is sufficient to elicit the constriction triggered by serotonin.

This study tested whether hypocapnic constriction of the rabbit basilar artery in vitro can be triggered by a nitric oxide (NO) synthase inhibitor, and whether the resulting constriction is (1) due to the alkaline pH associated with hypocapnia, and (2) endothelin-1 mediated. Hypocapnic (25 mM NaHCO(3); pH 7.76; pCO(2) 14.2) or isocapnic alkaline solution (50 mM NaHCO(3); pH 7.73; pCO(2) 35.0) rarely altered basal tension. N(G)-monomethyl-L-arginine monoacetate (L-NMMA; 0.1 mM) challenge in hypocapnic or isocapnic alkaline solution resulted in near maximal tension that was maintained for 2-2.5 h even following L-NMMA washout. L-NMMA challenge in normal solution (25 mM NaHCO(3); pH 7. 42; pCO(2) 36.9) also induced near maximal tension, although the tension was maintained for only 25 min (mean). Ac-D-Bhg-L-Leu-Asp-L-Ile-L-Ile-L-Trp (PD145065), homopiperidinyl-CO-Leu-D-Trp(CHO)-D-Trp (BQ610), and N-cis-2, 6-dimethyl-piperidinocarbonyl L-gamma-MeLeu-D-Trp (COOCH(3))-Nle (BQ788; 1-3 microM), endothelin ET(A)/ET(B), endothelin ET(A), and endothelin ET(B) receptor antagonists, respectively, completely relaxed the tension that resulted from L-NMMA challenge in hypocapnic or isocapnic alkaline solution. These results demonstrate that constriction due to hypocapnia in vitro can be triggered by an NO synthase inhibitor and is endothelin-1 mediated. Additionally, alkaline pH in the absence of decreased pCO(2) is sufficient to elicit the constriction.

This study tested whether (1) L-type Ca 2+ channel blockade and extracellular Ca 2+ removal prior to endothelin-1, as compared to during the endothelin-1 constriction, resulted in lesser inhibition, and (2) the reduced inhibition due to prior L-type Ca 2+ channel blockade resulted from enhanced non L-type Ca 2+ -channel-dependent constriction. Pretreatment of rabbit basilar artery in vitro with 1 μM verapamil, an L-type Ca 2+ channel blocker, inhibited 3, 10, 30, and 100 nM endothelin-1 constrictions to a lesser extent than verapamil addition during the plateau endothelin-1 constriction. Ni 2+ (0.03 and 0.1 mM), a nonselective cation channel blocker, relaxed the plateau endothelin-1 constrictions in vessels pretreated with verapamil to greater magnitudes than vessels unexposed to verapamil. Extracellular Ca 2+ removal prior to 10, 30, and 100 nM endothelin-1 also inhibited the endothelin-1 constrictions to smaller magnitudes than Ca 2+ removal during the plateau endothelin-1 constrictions. These results suggest that the reduced inhibition of the endothelin-1 constriction following pretreatment with L-type Ca 2+ channel blocker or Ca 2+ -free solution, as compared to addition of these agents during the endothelin-1 constriction, is the result of non L-type Ca 2+ channel opening and enhanced Ca 2+ -independent constriction, respectively.

To analyze fission gas release and gaseous swelling in UO 2 fuel, a model has been developed that can be used under both steady-state and transient operating conditions up to high burnup. With emphasis on the effect of external restraint stress on the behavior of gas bubbles at grain boundaries, the gaseous swelling due to grain edge bubbles, which affects gas release rate through the formation of release tunnels at grain edge, is described. Gas release rate at the grain edge is assumed to be proportional to both the fraction of grain edge bubbles interlinked to open space of fuel and the rate of gas atoms arriving at the grain edge bubbles. The model was compared with the data obtained from commercial reactors, Risφ-III Project, isothermal irradiation and post-irradiation annealing experiments. It is shown that the model predicts well the fractional fission gas release as well as the radial distribution of Xe gas across fuel pellet under various operating conditions. This suggests that the present model can be used for the analysis of fission gas release at high burnup fuel where strong external restraint stress may develop due to pellet cladding interaction.

The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.

The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo. KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 γ 10 μM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 non-competitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20–85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg−1) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1.74 mg kg−1). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg−1, respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mmHg, 1.04 and 7.96 mg kg−1, respectively). These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.

A model for rim porosity that takes into account the effect of overpressurization on rim pores is proposed for high-burnup UO 2 fuel. It is based on the assumption that all the fission gases produced are retained in rim pores, and the threshold pellet average burnup required for the formation of the rim region is 40 MWd/kg U. In addition, a thermal conductivity correlation is proposed that uses the rim porosity model developed. This correlation for the rim region considers both degradation of thermal conductivity with burnup across the fuel pellet and additional degradation at the pellet rim due to very high porosity. To calculate the temperature profile across the fuel pellet where the rim region is formed, the present correlation for the rim region is combined with the HALDEN, MATPRO, and SIMFUEL correlations for thermal conductivity for the fuel interior region where the rim feature does not exist. Application of the present correlation to the measured HALDEN fuel centerline temperature (Nuclear Energy Agency public database IFA562) shows that good agreement between the calculated and measured fuel centerline temperature is obtained when the present correlation is combined with HALDEN thermal conductivity. On the other hand, when it is combined with SIMFUEL thermal conductivity, which does not consider the effect on thermal conductivity of fission gases and other volatile fission products, lower centerline temperature is obtained due to the characteristics of the SIMFUEL.

The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.

A computer code called cosmos has been developed for the analysis of UO 2 and MOX fuel during steady-state and transient operating conditions. The main purpose of the cosmos is to calculate temperature distribution in the fuel and cladding, and fission gas release from the fuel. Experimental findings regarding such areas as rim effect and thermal conductivity degradation with burnup are taken into account to analyze high burnup fuel. In addition, a mechanistic fission gas release model developed based on physical processes is incorporated into the code to calculate gas release during steady-state conditions. An empirical model developed based on the amount of fission gas stored at the grain boundary is used for transient operations. Another important feature of the cosmos is that it can analyze fuel segments refabricated from base-irradiated fuel rods. This feature makes it possible to utilize database obtained from international projects such as halden and riso , many of which were collected from refabricated fuel segments. Based on models for UO 2 fuel, MOX features such as change in themo-mechanical properties and the effect of microscopic heterogeneity on fission gas release have been taken into account. The capacity of the cosmos has been tested with a number of experimental results from some international fuel irradiation programs. This paper provides a general description of the models contained in the cosmos and some of the comparison results between the calculations and measurements.

Hemodynamic profiles of SKP-450, a newly synthesized potassium-channel activator, were evaluated in conscious hypertensive rats of several types, and in anesthetized and conscious beagle dogs. In freely moving conscious rats, orally administered SKP-450 (0.03-0.3 mg/kg) dose-dependently decreased arterial pressure in spontaneously hypertensive rats (SHRs), renally hypertensive rats (RHRs), DOCA/salt-induced hypertensive rats (DHRs), and normotensive rats (NRs) with a greater potency than lemakalim except in DHRs (ED20 values: SKP-450, 0.021, 0.013, 0.024, and 0.034 mg/kg; lemakalim, 0.107, 0.018, 0.016, and 0.063 mg/kg, respectively). The blood pressure-reducing effects of SKP-450 reached their maximum within 30 min and lasted for approximately 4 h in all rats, and >6 h, particularly, in SHRs. In NRs, pretreatment with glibenclamide (20 mg/kg, i.v.) antagonized the hypotensive effect of SKP-450, whereas propranolol (2 mg/kg, i.v.) antagonized the tachycardiac response of SKP-450 (0.03 mg/kg, i.v.) without affecting its hypotensive response in NRs. In anesthetized beagle dogs, intraduodenally administered SKP-450 (0.003-0.03 mg/kg) dose-relatedly decreased arterial pressure (ED20 value, 0.007 mg/kg) for > or =3 h with its peak effects reached within 15 min and without significant changes in heart rate (HR). Antihypertensive effects of SKP-450 were accompanied by concurrent reduction in total peripheral resistance and dose-dependent increase in cardiac output. Indirect measures of myocardial oxygen demand such as rate-pressure product, tension-time index, and systolic time interval were dose-dependently decreased by SKP-450 without significant change in left ventricular dP/dt(max). SKP-450 significantly increased coronary blood flow and decreased coronary vascular resistance dose-dependently with a rapid onset of action and long duration of >4 h (maximal changes, 276 and 83.7% at 0.03 mg/kg, respectively). In conscious dogs, orally administered SKP-450 (0.03-0.3 mg/kg) produced a dose-related decrease in arterial pressure for > or =3 h, with its peak effects reached within 20 min (ED20 value, 0.030 mg/kg) accompanied by tachycardia. These results suggest that SKP-450 is a potent, orally active peripheral vasodilator activating ATP-sensitive potassium channels.

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450>SKP-818>lemakalim>SKP-310 (EC50: 0.12, 0.55, 0.71 and 5.89 µmol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3–100 µg/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED20: 9.8, 11.7 and 22.4 µg/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3–1,000 µg/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED20: 2.6, 4.2 and 588.8 µg/kg, respectively). They slightly increased left ventricular positive dP/dtmax with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (Emax: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.