The multiple realization of human color vision revisited.

Over the last 25 years, there has been a concerted effort to settle questions about multiple realization by bringing detailed scientific evidence to bear. Ken Aizawa and Carl Gillett have pursued this scientific approach to multiple realization with a precise theory and applications. This paper reviews the application of the Dimensioned approach to human color vision, addressing objections that have appeared in the literature.

Prolonged Duration of Erythropoiesis-Stimulating Agents' Action Delays Disease Progression in Anti-Thy 1 Antibody-Induced Chronic Glomerulonephritis Rats.

BACKGROUND: Although erythropoiesis-stimulating agents (ESAs) exert renoprotective effects in renal disease models, it has not been revealed whether the prolonged duration of action of ESAs contributes to their renoprotective effects. OBJECTIVE: We examined whether the prolonged duration of ESAs' action contributes to their renoprotective effects by comparing a divided administration of a short-acting ESA, epoetin beta (EPO), or a single administration of a long-acting ESA, epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), to a single administration of EPO in chronic glomerulonephritis (GN) rats. MATERIALS AND METHODS: Chronic GN was induced by intravenous injection of anti-Thy 1.1 antibody (0.6 mg/kg) into uninephrectomized rats (day 0). Chronic GN rats were intravenously injected once with vehicle (disease control; DC), EPO 5,000 IU/kg (single EPO), or C.E.R.A. 25 µg/kg (single C.E.R.A.) on day 1; or 3 times during the first week with EPO 1,667 IU/kg from day 1 (divided EPO; total 5,000 IU/kg). Hemoglobin (Hb) level and urinary total protein (U-TP) level which are the indexes of hematopoiesis and renoprotective effects, respectively, were measured several times over 8 weeks. RESULTS: Divided EPO and single C.E.R.A. increased Hb levels more greatly than did single EPO. In all chronic GN rats, elevated U-TP levels decreased transiently 2 weeks after chronic GN induction and then flared again. Single EPO significantly suppressed this exacerbation of U-TP levels compared to DC. Divided EPO and single C.E.R.A. each significantly suppressed the exacerbation of U-TP levels compared to single EPO. CONCLUSION: Prolonged duration of ESAs' action contributed significantly to their renoprotective effects.

JLP-centrosome is essential for the microtubule-mediated nucleocytoplasmic transport induced by extracellular stimuli.

JLP belongs to the JIP family whose members serve as scaffolding proteins that link motor proteins and their cargo for intracellular transport. Although JLP is mainly cytoplasmic, it accumulates as a focus in the perinuclear region when stimulated by extracellular stimuli. Focus formation, which changes the nucleus shape and concentrates the nuclear pores, depends on p38MAPK activation and the dynein retrograde motor protein complex. Extracellular stimuli trigger the tethering of PLK1 to the centrosome by JLP, leading to centrosome maturation and microtubule array formation. The centrosome localization domain of JLP is important for the binding of the centrosome and the formation of the JLP focus and the microtubule array. Furthermore, the formation of the JLP focus and the microtubule array is interdependent and important for the transport of NF-κB p65 to the nucleus and its unloading therein. In conclusion, JLP exhibits multiple functions in the nuclear translocation of NF-κB p65.

Epoetin beta pegol for treatment of anemia ameliorates deterioration of erythrocyte quality associated with chronic kidney disease.

BACKGROUND: Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) is currently widely used for the treatment of anemia associated with chronic kidney disease (CKD). Therapeutic control of anemia is assessed by monitoring haemoglobin (Hb) levels. However, certain qualitative aspects of erythrocytes are also impaired in CKD, including loss of deformability and shortened life-span. Therefore, monitoring Hb alone could potentially fail to reveal pathological changes in erythrocytes. Focusing on erythrocyte quality in CKD may lead to more effective anemia therapy with C.E.R.A. METHODS: A CKD rat model was induced by uninephrectomy followed by anti-Thy1.1 antibody injection. From 5 weeks after the operation, C.E.R.A. (0.6 µg/kg) or vehicle was administered every 2 weeks. Erythrocyte deformability was quantified with ektacytometry and erythrocyte turnover was estimated by biotin labeling. Intracellular calcium level was assessed by Fluo-3/AM. RESULTS: Erythrocyte deformability progressively declined in CKD rats. Furthermore, erythrocyte turnover in the circulation drastically accelerated in CKD rats. With administration of C.E.R.A. at a dose sufficient to adequately control Hb, deterioration of erythrocyte deformability and turnover in CKD rats were significantly improved. Intracellular calcium, which plays a pivotal role in the mediation of erythrocyte quality, was significantly increased in CKD and was normalized by C.E.R.A. CONCLUSION: C.E.R.A. treatment exerted a favorable effect not only on anemia but also on the improvement of erythrocyte quality. C.E.R.A. administered for the treatment of CKD-associated anemia may confer therapeutic benefits on erythrocytes.

Effects of telmisartan and olmesartan on insulin sensitivity and renal function in spontaneously hypertensive rats fed a high fat diet.

Although telmisartan, an angiotensin II receptor blocker (ARB), has an agonistic action for proliferator-activated receptor (PPAR)-γ in vitro, it remains to be determined whether telmisartan exerts such an action in vivo using a non-toxic dose (<5 mg/kg in rats). To address the issue, telmisartan (2 mg/kg) and olmesartan (2 mg/kg), another ARB without PPAR-γ agonistic action, were given to spontaneously hypertensive rats (SHR) fed a high fat diet (HFD). HFD decreased plasma adiponectin, and caused insulin resistance, hypertriglyceridemia and renal damage, which were improved by ARBs. Protective effects of telmisartan and olmesartan did not significantly differ. In addition, in vitro study showed that 1 µM of telmisartan did not elevate the mRNA expression of adipose protein 2, which is a PPAR-γ-stimulated adipogenic marker gene, in preadipocytes with 3% albumin. To obtain 1 µM of plasma concentration, oral dose of telmisartan was calculated to be 6 mg/kg, which indicates that PPAR-γ agonistic action is negligible with a non-toxic dose of telmisartan (<5 mg/kg) in rats. This study showed that 2 mg/kg of telmisartan and olmesartan ameliorated insulin resistance, hypertriglyceridemia and renal damage in SHR fed a HFD. As beneficial effects of telmisartan and olmesartan did not significantly differ, these were mediated through the PPAR-γ-independent actions.

Epoetin beta pegol, but not recombinant erythropoietin, retains its hematopoietic effect in vivo in the presence of the sialic acid-metabolizing enzyme sialidase.

Erythropoiesis-stimulating agents (ESAs) are widely used for treating chronic kidney disease (CKD)-associated anemia. The biological activity of ESAs is mainly regulated by the number of sialic acid-containing carbohydrates on the erythropoietin (EPO) peptide. Sialidase, a sialic acid-metabolizing enzyme that accumulates in CKD patients, is suspected of contributing to shortening the circulation half-life of ESAs. Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), is an EPO integrated with methoxypolyethylene glycol (PEG). It has been suggested that C.E.R.A. may exert a favorable therapeutic effect, even under conditions of elevated sialidase; however, no detailed investigation of the pharmacological profile of C.E.R.A. in the presence of sialidase has been reported. In the present study, we injected C.E.R.A. or EPO pre-incubated with sialidase into rats, and assessed the hematopoietic effect by reticulocyte count. The hematopoietic effect of C.E.R.A., but not EPO, was preserved after sialidase treatment, despite the removal of sialic acid. Proliferation of EPO-dependent leukemia cells (AS-E2) was significantly increased by desialylated C.E.R.A. and EPO compared to non-treated C.E.R.A. or EPO. In conclusion, we show that C.E.R.A. exerts a favorable hematopoietic effect even under conditions of elevated sialidase. Our findings may contribute to a better understanding of CKD and more effective therapeutic approaches based on a patient's profile of anemia.

Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats.

Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20  ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARγ) in femoral arteries and cultured endothelial cells. Although PPARγ is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARγ in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARγ/NF-κB signaling.

Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules.

Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats.

Chronic kidney disease (CKD) patients have a poor prognosis due to cardiovascular disease. Anemia and endothelial dysfunction are important risk factors for cardiovascular events in CKD patients, and treatment with erythropoiesis-stimulating agent (ESA) has been reported to improve the quality of life in CKD patients. In this study, we evaluated the effect of anemia correcting dose of epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) on endothelial function in 5/6 nephrectomized rats (Nx rats). C.E.R.A. was subcutaneously administered once a fortnight, 5 times in total, from 1 week after nephrectomy. Twenty-four hours after last administration, endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anesthetized Nx rats by ultrasound system. Femoral arteries were harvested for western blot analysis. C.E.R.A. significantly increased FMD of Nx rats. Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. Nox4 expression and nitrotyrosine accumulation were significantly decreased, and phosphorylation of eNOS was significantly enhanced in the femoral arteries of C.E.R.A.-treated rats. C.E.R.A. normalized hemoglobin levels but did not affect body weight, systolic blood pressure, heart rate, urinary protein excretion and plasma creatinine. These results indicate that C.E.R.A. prevented endothelial dysfunction in Nx rats, possibly through reduction of local oxidative stress and enhancement of eNOS phosphorylation in the arteries. This study provides the first evidence that C.E.R.A. prevented endothelial dysfunction in CKD model rats under conditions of amelioration of anemia.

Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus formation.

Sirolimus (SRL) is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS) play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC), an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs), SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL-induced up-regulation of NADPH oxidase subunit p22(phox) mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis.

Vitamin D receptor signaling enhances locomotive ability in mice.

Bone fractures markedly reduce quality of life and life expectancy in elderly people. Although osteoporosis increases bone fragility, fractures frequently occur in patients with normal bone mineral density. Because most fractures occur on falling, preventing falls is another focus for reducing bone fractures. In this study, we investigated the role of vitamin D receptor (VDR) signaling in locomotive ability. In the rotarod test, physical exercise enhanced locomotive ability of wild-type (WT) mice by 1.6-fold, whereas exercise did not enhance locomotive ability of VDR knockout (KO) mice. Compared with WT mice, VDR KO mice had smaller peripheral nerve axonal diameter and disordered AChR morphology on the extensor digitorum longus muscle. Eldecalcitol (ED-71, ELD), an analog of 1,25(OH)2 D3 , administered to rotarod-trained C57BL/6 mice enhanced locomotor performance compared with vehicle-treated nontrained mice. The area of AChR cluster on the extensor digitorum longus was greater in ELD-treated mice than in vehicle-treated mice. ELD and 1,25(OH)2 D3 enhanced expression of IGF-1, myelin basic protein, and VDR in rat primary Schwann cells. VDR signaling regulates neuromuscular maintenance and enhances locomotive ability after physical exercise. Further investigation is required, but Schwann cells and the neuromuscular junction are targets of vitamin D3 signaling in locomotive ability.

Renoprotective effect of epoetin beta pegol by the prevention of M2 macrophage recruitment in Thy-1 rats.

BACKGROUND: Glomerulonephritis (GN) develops via accumulation of extracellular matrix through macrophage recruitment in glomeruli. It is unclear whether epoetin beta pegol (continuous erythropoietin receptor activator, CERA), a long-acting erythropoiesis-stimulating agent, exerts a renoprotective effect by preventing glomerulosclerosis. We examined the renoprotective effect of CERA in rats with Thy-1 glomerulonephritis (Thy-1-GN), an animal model for mesangial proliferative glomerulonephritis. METHODS: Thy-1-GN was induced in F344 rats by injection of anti-Thy1.1 antibody. CERA (25 µg/kg) was intravenously administered 4 h before anti-Thy1.1 antibody injection. After 6 days, blood and urine was collected for biochemical analysis and kidneys harvested for analysis of histopathology and mRNA expression. RESULTS: In Thy-1-GN rats, CERA suppressed increased urinary total protein, urea nitrogen, and N-acetyl-ß-(D)-glucosaminidase. CERA significantly prevented glomerulosclerosis and expression of α-smooth muscle actin, collagen-1, and fibronectin. Increased macrophage infiltration and up-regulated monocyte chemotactic protein-1 were significantly suppressed by CERA. Furthermore, CERA also suppressed up-regulation of arginase-1, a marker of M2 macrophages. Arginase-1 expression levels strongly correlated with levels of collagen-1 and fibronectin mRNA. CONCLUSIONS: These results suggest that CERA has potential to protect kidney function through the prevention of glomerulosclerosis, accompanied by prevention of M2 macrophage recruitment.

GATA-4 transcription factor regulates cardiac COX-2 expression induced by nicorandil in left ventricle of rats.

BACKGROUND AND AIMS: Cardioprotective effects induced by delayed ischemic preconditioning and by nicorandil are mediated via expression of cardioprotective factors such as COX-2. The present study was undertaken to evaluate whether nicorandil could induce COX-2 in rats and to elucidate its mode of induction pharmacologically. METHODS AND RESULTS: Three hours after administration of nicorandil (10 mg/kg, p.o.), COX-2 mRNA and protein were significantly increased in the left ventricle, although other cardioprotective factors (Bcl-2, eNOS, hexokinase, HSP, and iNOS) were not increased. This COX-2 induction in the left ventricle was preceded by induction of GATA-4, which was significant from 1 h after administration. Ventricular levels of 6-keto-prostaglandin F1α were increased 6 h after administration. Although pinacidil or isosorbide dinitrate alone did not increase COX-2 mRNA, their combined application significantly increased COX-2 mRNA. Moreover, although glibenclamide or ODQ each partly inhibited the induction of COX-2 mRNA by nicorandil, their combined application significantly inhibited it. These results suggest that nicorandil induces COX-2 protein through both the activation of KATP channels and guanylate cyclase. CONCLUSION: The present study demonstrated that nicorandil induces COX-2 via GATA-4 induction in the heart through both KATP channel activation and its nitrate-like properties.

Nicorandil ameliorated hypertensive renal injury without lowering blood pressure in spontaneously hypertensive rats.

Proteinuria, a symptom of hypertensive renal injury, is a powerful predictor of mortality in chronic kidney disease patients with hypertension. The present study investigated whether a nonhypotensive dose of nicorandil could decrease hypertensive renal injury in male spontaneously hypertensive rats (SHR). Nicorandil (15 mg/kg/day, for 20 weeks) was administered in the drinking water to rats from 11 weeks old. Heart size, kidney size, and ß(2)-microglobulin occurring with tubular histopathological damage were each significantly greater in SHR than in Wistar-Kyoto (WKY) rats, as was 24-hour excretion of urinary protein (SHR: 33.1 ± 3.5 mg/day, WKY: 5.4 ± 0.3 mg/day). Nicorandil significantly decreased urinary protein (21.7 ± 2.8 mg/day), glomerular cell density, and histopathological score without affecting systolic blood pressure. Nicorandil increased expression of endothelial nitric oxide synthase (eNOS) protein in the renal cortex in SHR without affecting expressions of mRNA for endothelin or genes involved in tissue damage or fibrosis. eNOS expression was negatively correlated with glomerular cell density. In addition, nicorandil increased urinary excretion of NOx, but did not change the eNOS dimer-to-monomer ratio or the decreased level of renal heparan sulfate in SHR. In conclusion, in SHR, long-term administration of nicorandil can ameliorate hypertensive proteinuria, without lowering blood pressure, possibly through an increase in eNOS expression.

22-Oxacalcitriol prevents progression of endothelial dysfunction through antioxidative effects in rats with type 2 diabetes and early-stage nephropathy.

BACKGROUND: Vitamin D deficiency is associated with endothelial dysfunction in type 2 diabetes patients, but the effectiveness of vitamin D supplementation remains controversial. We assessed whether 22-oxacalcitriol (OCT) could prevent endothelial dysfunction in type 2 diabetes mellitus (DM) rats. METHODS: DM rats with early-stage nephropathy were treated for 10 weeks with OCT (0.2 µg/kg) three times per week or by an implanted insulin pellet. Endothelial dysfunction was assessed by femoral flow-mediated dilation (FMD). RESULTS: Insulin significantly improved FMD as blood glucose levels normalized. OCT also improved FMD without hypercalcemia or hyperphosphatemia and without affecting blood glucose or blood pressure. In femoral arteries, OCT significantly suppressed the elevated expression of p22(phox), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, and improved the endothelial nitric oxide synthase (eNOS) dimer-to-monomer ratio. In cultured endothelial cells, OCT significantly inhibited high-glucose (HG)-induced reactive oxygen species (ROS) production. Simultaneously, OCT significantly suppressed HG-induced p22(phox) expression and improved eNOS uncoupling as was observed in the in vivo study. CONCLUSION: In DM rats, OCT improved endothelial dysfunction, at least in part, by suppressing ROS generation through p22(phox) expression, which might contribute to improving eNOS uncoupling.

Renoprotection by continuous erythropoietin receptor activator in puromycin aminonucleoside-induced nephrotic syndrome.

BACKGROUND/AIMS: Recent studies have demonstrated that erythropoiesis-stimulating agents (ESAs) induce a tissue-protective effect in the kidney. In this study, we examined whether continuous erythropoietin receptor activator (CERA), a long-acting ESA, could prevent kidney injury, especially podocyte damage, in a rat model of nephrotic syndrome induced by puromycin aminonucleoside (PAN). METHODS: Rats were injected with CERA (30 µg/kg) or vehicle 4 h before the injection of PAN (50 mg/kg). Renal function, kidney injury, and podocyte damage were assessed at 7 days. RESULTS: The levels of proteinuria, BUN, and plasma creatinine significantly increased in rats with PAN-induced nephrosis. Treatment with CERA significantly prevented these deteriorations induced by PAN. Glomerular lesions, especially vacuolation of podocytes, and the increase of desmin expression in PAN-treated rats were significantly ameliorated by treatment with CERA. Treatment with CERA also significantly prevented the decrease in the protein productions of nephrin and podocin in the kidneys of PAN-treated rats. We found persistent activation of the Akt signaling pathway in the kidneys of CERA-treated rats. CONCLUSION: CERA could ameliorate renal dysfunction in PAN-induced nephrosis, which might be due to the amelioration of podocyte injury. CERA inhibited the depletion of nephrin and podocin, key components of the glomerular filtration barrier, and alleviated proteinuria. Activation of the Akt signaling pathway might be involved in the renoprotective effect of CERA.

Paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress.

Paclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats. After 7-day osmotic infusion of paclitaxel (5 mg/kg per day), FMD was measured by high-resolution ultrasound in the femoral artery of living rats. Paclitaxel significantly reduced FMD (21.6% ± 3.2% to 7.1% ± 1.7%); this reduction was prevented by co-treatment with nicorandil (15 mg/kg per day), while paclitaxel did not affect nitroglycerin-induced vasodilation. Diazoxide and tempol, but not isosorbide dinitrate, had an effect similar to nicorandil in preventing paclitaxel-induced decrease in FMD. Nicorandil significantly prevented paclitaxel-induced reduction in acetylcholine-induced vasodilation. On the underling mechanisms, paclitaxel increased reactive oxygen species (ROS) production (dihydrorhodamine 123, DCF fluorescence intensity) and NADPH oxidase (p47(phox), gp91(phox) mRNA) in arteries and human coronary artery endothelial cells (HCAECs), while paclitaxel reduced nitric oxide (NO) release (DAF-2 fluorescence intensity), but not endothelial NO synthase (eNOS) phosphorylation in HCAECs. Nicorandil prevented the increased ROS production in arteries and HCAECs, which was 5-hydroxydecanoate (5-HD)-sensitive but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)-resistant, without significant effect on the reduced NO release. In conclusion, nicorandil prevents paclitaxel-induced endothelial dysfunction, which may be brought by improved NO bioavailability due to the reduction of oxidative stress via K(ATP) channel activation.

Nicorandil prevents endothelial dysfunction due to antioxidative effects via normalisation of NADPH oxidase and nitric oxide synthase in streptozotocin diabetic rats.

BACKGROUND: Nicorandil, an anti-angina agent, reportedly improves outcomes even in angina patients with diabetes. However, the precise mechanism underlying the beneficial effect of nicorandil on diabetic patients has not been examined. We investigated the protective effect of nicorandil on endothelial function in diabetic rats because endothelial dysfunction is a major risk factor for cardiovascular disease in diabetes. METHODS: Male Sprague-Dawley rats (6 weeks old) were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg, once a day for 3 days) to induce diabetes. Nicorandil (15 mg/kg/day) and tempol (20 mg/kg/day, superoxide dismutase mimetic) were administered in drinking water for one week, starting 3 weeks after STZ injection. Endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anaesthetised rats. Cultured human coronary artery endothelial cells (HCAECs) were treated with high glucose (35.6 mM, 24 h) and reactive oxygen species (ROS) production with or without L-NAME (300 µM), apocynin (100 µM) or nicorandil (100 µM) was measured using fluorescent probes. RESULTS: Endothelial function as evaluated by FMD was significantly reduced in diabetic as compared with normal rats (diabetes, 9.7 ± 1.4%; normal, 19.5 ± 1.7%; n = 6-7). There was a 2.4-fold increase in p47phox expression, a subunit of NADPH oxidase, and a 1.8-fold increase in total eNOS expression in diabetic rat femoral arteries. Nicorandil and tempol significantly improved FMD in diabetic rats (nicorandil, 17.7 ± 2.6%; tempol, 13.3 ± 1.4%; n = 6). Nicorandil significantly inhibited the increased expressions of p47phox and total eNOS in diabetic rat femoral arteries. Furthermore, nicorandil significantly inhibited the decreased expression of GTP cyclohydrolase I and the decreased dimer/monomer ratio of eNOS. ROS production in HCAECs was increased by high-glucose treatment, which was prevented by L-NAME and nicorandil suggesting that eNOS itself might serve as a superoxide source under high-glucose conditions and that nicorandil might prevent ROS production from eNOS. CONCLUSIONS: These results suggest that nicorandil improved diabetes-induced endothelial dysfunction through antioxidative effects by inhibiting NADPH oxidase and eNOS uncoupling.

Left ventricular hypertrophy is associated with inflammation in sodium loaded subtotal nephrectomized rats.

The pathological influences of inflammation on left ventricular hypertrophy (LVH) were studied in subtotal nephrectomized (SNx) rats after 0.3% NaCl loading for 5 weeks. We found that mild hypertension, increased plasma levels of creatinine, inorganic phosphate, asymmetric dimethylarginine (ADMA), and parathyroid hormone (PTH) were observed in the present SNx rats without LVH. In the present study, the NaCl-loaded SNx (SNx + NaCl) rats were characterized by significant LVH and hypertension with aggravated values of all the parameters. We further confirmed that glomerular sclerosis, tubulointerstitial fibrosis, and inflammatory cell infiltration into the tubulointerstitial area, observed in the SNx rats, were more severely caused in the SNx + NaCl rats. In addition, plasma interleukin-6 (IL-6) levels in the SNx + NaCl rats were significantly increased compared to those in the SNx rats. These findings indicated that NaCl-loaded SNx rats developed LVH and hypertension, which were accompanied with increased plasma levels of PTH, creatinine, inorganic phosphorus, ADMA, and IL-6. Thus, these results suggest that inflammation as well as endothelial dysfunction would be correlated with LVH as non-traditional risk factors at the early stage in the present renal failure model.

Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus.

In the dentate gyrus of the hippocampus, new neurons are generated from neural stem/progenitor cells (NPCs) throughout life. As aging progresses, the rate of neurogenesis decreases exponentially, which might be responsible, in part, for age-dependent cognitive decline in animals and humans. However, few studies have analyzed the alterations in NPCs during aging, especially in primates. Here, we labeled NPCs by triple immunostaining for FABP7, Sox2, and GFAP and found that their numbers decreased in aged macaque monkeys (>20 years old), but not in aged mice. Importantly, we observed marked morphological alterations of the NPCs in only the aged monkeys. In the aged monkey hippocampus, the processes of the NPCs were short and ran horizontally rather than vertically. Despite these alterations, the proliferation rate of the NPCs in aged monkeys was similar to that in young monkeys. Thus, morphological alterations do not affect the proliferation rate of NPCs, but may be involved in the maintenance of NPCs in aged primates, including elderly humans.