Hyperlipidemias: Hayashi T

Hayashi T, Yokote K, Saito Y, Iguchi A. · Nagoya University Graduate School of Medicine, Department of Geriatrics, 65 Tsuruma-cho, Showa-ku, Nagoya City, 466-8550, Japan. · Expert Opin Pharmacother. · Pubmed #17927486 No free full text.

Abstract: Pitavastatin, (+)-monocalcium bis(3R,5S,6E)-7-(2-cyclopropyl-4-[4-fluorophenyl]-3-quinolyl-3,5-dihydroxy-6-heptenoate), is a totally synthetic statin developed in Japan with a molecular weight of 880.98. Pitavastatin achieves its potent pharmacologic action by strongly binding and inhibiting the active site of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and has potent low-density lipoprotein-cholesterol-lowering effects similar to atorvastatin and rosuvastatin. One other characteristic of the agent is that pitavastatin is minimally metabolized by the cytochrome P450 isozymes; it undergoes glucuronidation and is converted to the inactive lactone form, and, therefore, the incidence of any drug interactions is reduced. Due to the promising results observed in clinical trials, it has the potential to be an excellent addition to the worldwide lipid management market.

Hayashi T. · Department of Geriatrics, Nagoya University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #17824083 No free full text.

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Hayashi T. · Department of Geriatrics, Nagoya University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #15506437 No free full text.

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Tsunekawa T, Hayashi T, Kano H, Sumi D, Matsui-Hirai H, Thakur NK, Egashira K, Iguchi A. · Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Circulation. · Pubmed #11468195 links to  free full text

Abstract: BACKGROUND: The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known. METHODS AND RESULTS: We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3+/-3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9+/-3.4 to 22.0+/-3.7 micromol/L, P<0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin. CONCLUSIONS: Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.

Shimano H, Arai H, Harada-Shiba M, Ueshima H, Ohta T, Yamashita S, Gotoda T, Kiyohara Y, Hayashi T, Kobayashi J, Shimamoto K, Bujo H, Ishibashi S, Shirai K, Oikawa S, Saito Y, Yamada N. · The Research Committee for Primary Hyperlipidemia, Research on Measures for Intractable Diseases by the Ministry for Health, Labor, and Welfare in Japan. · J Atheroscler Thromb. · Pubmed #18603817 links to  free full text

Abstract: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases, proposing management for LDL cholesterol as the primary target, have successfully contributed to the prevention of cardiovascular events; however, recently, the impact of hypertriglyceridemia as an additional cardiovascular risk has become understood, especially in light of the rise in obesity, metabolic syndrome, and diabetes in the Japanese population. Rather than waiting to obtain conclusive domestic data confirming that hypertriglyceridemia is a cardiovascular risk factor and that its management is efficacious, we propose guidelines for hypertriglyceridemia using non-HDL cholesterol as a second target.

Tokuno A, Hirano T, Hayashi T, Mori Y, Yamamoto T, Nagashima M, Shiraishi Y, Ito Y, Adachi M. · First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan. · J Atheroscler Thromb. · Pubmed #17587764 links to  free full text

Abstract: AIM: Small dense (sd)-low-density lipoprotein (LDL) is a potent atherogenic lipoprotein. The overall atherogenicity of this lipoprotein can be precisely assessed by quantifying sd-LDL rather than by measuring the LDL size. We studied the effects of representative lipid-lowering agents (statin and fibrate) on sd-LDL-cholesterol (C) in patients with type 2 diabetes. METHODS: Sd-LDL-C was measured by the precipitation method established by Hirano and Ito. Large buoyant (lb)-LDL-C was calculated by subtracting sd-LDL-C from LDL-C. Type 2 diabetes patients (n=72) were administered lipid-lowering agents for three months: patients with hypercholesterolemia received 1 mg of pitavastatin and those with hypertriglyceridemia received 100 mg of micronized fenofibrate. RESULTS: Pitavastatin reduced LDL-C by 25% and reduced TG by 8%. The statin decreased sd-LDL-C by 26%, and lb-LDL-C by 22%. Fenofibrate reduced TG by 38% and increased HDL-C by 14%. The fibrate decreased sd-LDL-C by 23% without changing LDL-C. The pitavastatin-induced reduction of sd-LDL-C was significantly correlated with the reduction of LDL-C and apo B, whereas the fenofibrate-induced reduction of sd-LDL-C was correlated with the reduction of TG. CONCLUSION: Both statin and fibrate reduce the potency of atherogenic sd-LDL particles, but via different mechanisms: the former decreases total-LDL including sd-LDL, while the latter decreases sd-LDL specifically.

Kamishirado H, Inoue T, Sakuma M, Tsuda T, Hayashi T, Takayanagi K, Node K. · Kamishirado Heart Clinic, 1-7-13 Sugano, Ichikawa-city, Chiba 272-0824, Japan. · Angiology. · Pubmed #17351158 No free full text.

Abstract: Experimental data and preliminary clinical studies suggest that lipid-lowering drugs might have a beneficial effect on restenosis after coronary angioplasty. Recently, statins have been focused on prevention of restenosis after coronary stent implantation. However, their benefit has not yet been established. The authors studied the effects of statins on stent restenosis. We compared retrospectively the quantitative coronary angiographic (QCA) variables between 62 dyslipidemic patients treated with statins (pravastatin or fluvastatin) and 62 normolipidemic patients, as a control, treated without statins after undergoing successful coronary stent implantation with 6-month follow-up angiography from May 1999 to December 2002. Major cardiac events were about the same in both groups. Each of the QCA variables before and immediately after coronary stenting was similar in the 2 groups. At follow-up angiography, however, minimal lumen diameter (MLD) (2.12 -/+ 0.73 vs 1.78 -/+ 0.7; p < 0.01) was larger in the statin group than in the normolipidemia group. Both restenosis rate (15% vs 31%; p = 0.05) and target lesion revascularization rate (10% vs 24%; p = 0.05) were lower in the statin group than in the normolipidemia group. Statin reduced restenosis rate. The efficacy of statins appears to be dependent on their pleiotropic effects on vascular wall rather than on lipid-lowering effects.

Hayashi T, Esaki T, Sumi D, Mukherjee T, Iguchi A, Chaudhuri G. · Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. · Proc Natl Acad Sci U S A. · Pubmed #16801563 links to  free full text

Abstract: We evaluated the effects of a 0.5% cholesterol-enriched diet (HCD) on nitric-oxide synthase (NOS) and arginase expression and the modulating role of 17beta-estradiol (E(2)) on this phenomenon. Thirty oopherectomized rabbits were divided into three groups and treated for 15 weeks. Group I received normal chow; group II, HCD; and group III, HCD plus E(2) pellets. Animals in group II showed an increase in plasma lipids, and they demonstrated atheromatous lesions as well as expression of arginase I and II accompanied by a significant number of BrdU-positive cells in endothelial cells and intimal muscle cells, suggestive of an increase in cellular proliferation. There was significant expression of inducible NOS and increased staining of nitrotyrosine-positive areas. These were not observed in group I animals. In both groups, E(2) levels were low. In group III animals, E(2) supplementation led to a decrease in atheromatous lesions and BrdU-positive cells and reduced expression of both inducible NOS and arginase I and II accompanied by a decrease in nitrotyrosine staining. E(2) levels were increased. Our results suggest that E(2) was responsible for these effects, despite the animals being hyperlipidemic, similar to those in group II. Because arginase is responsible for cell proliferation by converting l-arginine to polyamines, our results indicate that expression of arginase may play an important role in cellular proliferation in atherosclerosis, and inhibition of arginase expression by E(2) may be another potential mechanism in attenuating atherogenesis.

Hayashi T, Nomura H, Esaki T, Hattori A, Kano-Hayashi H, Iguchi A. · Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. · J Diabetes Complications. · Pubmed #16112501 No free full text.

Abstract: BACKGROUND: Approximately 80% of cases of ischemic heart disease (IHD) occur in patients with nonstenotic coronary arteries, and few studies have systematically assessed exercise testing (TMT) as a predictor of risk in the elderly. METHODS: TMT was carried out using a protocol for the independent and active elderly (n=176). After 4.1+/-0.5 years follow-up, logistic regression analysis was performed for each coronary risk factor such as diabetes mellitus (DM) and hypercholesterolemia (HC). According to the results, patients were divided into Gp HC, hypercholesterolemic patients; Gp DM, diabetics; Gp HC+DM, hypercholesterolemic diabetics; and Gp C, nonhyperlipidemic and nondiabetics. Sensitivity and specificity of TMT for IHD (significant stenosis or acute coronary syndrome) were analyzed. RESULTS: Odds ratios for each risk factors are as follows: DM, 4.167; HC, 4.485; and DM+HC, 8.652. Notably, TMT was 17.59. Age was a significant risk, but hypertension was not. Positive ischemic signs in TMT were observed in 52.7%, 28.6%, 33.3%, and 16.3% in the Gp HC+DM, HC, DM, and C groups, respectively. Only three participants complained of chest pain during the TMT. Significant stenosis was observed in 75.0%, 71.4%, 69.2%, and 60.0% of coronary angiography (CAG)-receiving patients of Gp HC, DM, HC+DM, and C. During the observation term, acute coronary syndromes occurred in 4.7%, 3.3%, 5.5%, and 0% of patients in the Gp HC, DM, HC+DM, and C groups, respectively. The sensitivity of TMT for IHD was higher than 66.7% and specificity was higher than 94.1% in each group. CONCLUSION: An exercise tolerance test in the elderly, especially for diabetics and hypercholesterolemic patients, is useful for the diagnosis of IHD.

Tanaka T, Hidaka S, Masuzaki H, Yasue S, Minokoshi Y, Ebihara K, Chusho H, Ogawa Y, Toyoda T, Sato K, Miyanaga F, Fujimoto M, Tomita T, Kusakabe T, Kobayashi N, Tanioka H, Hayashi T, Hosoda K, Yoshimatsu H, Sakata T, Nakao K. · Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. · Diabetes. · Pubmed #16046303 links to  free full text

Abstract: Leptin augments glucose and lipid metabolism independent of its effect on satiety. Administration of leptin in rodents increases skeletal muscle beta-oxidation by activating AMP-activated protein kinase (AMPK). We previously reported that, as hyperleptinemic as obese human subjects, transgenic skinny mice overexpressing leptin in liver (LepTg) exhibit enhanced insulin sensitivity and lipid clearance. To assess skeletal muscle AMPK activity in leptin-sensitive and -insensitive states, we examined phosphorylation of AMPK and its target, acetyl CoA carboxylase (ACC), in muscles from LepTg under dietary modification. Here we show that phosphorylation of AMPK and ACC are chronically augmented in LepTg soleus muscle, with a concomitant increase in the AMP-to-ATP ratio and a significant decrease in tissue triglyceride content. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg develop obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK and ACC phosphorylation in regular diet-fed LepTg is attenuated, and tissue triglyceride content is increased in those given HFD. Of note, substitution of HFD with regular diet causes a robust recovery of soleus AMPK and ACC phosphorylation in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. In conclusion, soleus AMPK and ACC phosphorylation in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin.

Hayashi T, Taniguchi M, Kimura A, Miyataka M, Kurooka A, Taniwa T, Kiyoshima T, Matsuura M, Takeda N, Nakamura H, Kanamasa K, Ishikawa K. · Department of Cardiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan. · Angiology. · Pubmed #15378113 No free full text.

Abstract: The efficacy of combined thrombolysis and angioplasty for the purpose of coronary reperfusion after acute myocardial infarction has been controversial. The present study was conducted, therefore, to evaluate the effects of angioplasty following administration of conventional thrombolytic agents on the long-term prognosis of acute myocardial infarction patients. A total of 409 patients admitted to the hospital within 12 hours of the onset of infarction between January 1990 and May 2001 were studied retrospectively. These included 151 patients treated with thrombolysis alone (group T), 73 patients treated with angioplasty alone (group A), and 35 patients treated with angioplasty after thrombolysis (group T&A). Group T&A had shorter intervals from onset to initial treatment than group A (3.0 hours vs 6.3 hours, p < 0.01), a higher reperfusion success rate than group T (91.4% vs 74.8%, p < 0.01), and more improved left ventricular wall motion than group A. One-year cardiac mortality rates tended to be higher in group T, which had a higher rate of unsuccessful reperfusion than groups T&A or A (8.1% vs 3.4% vs 3.5%). The frequencies of hemorrhagic complications were similar among the 3 groups. From these findings, we conclude that thrombolytic therapy with subsequent angioplasty is an effective strategy for achieving cardiac reperfusion following acute myocardial infarction.

Taguchi A, Matsuyama T, Moriwaki H, Hayashi T, Hayashida K, Nagatsuka K, Todo K, Mori K, Stern DM, Soma T, Naritomi H. · Department of Cerebrovascular Disease, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565 Japan. · Circulation. · Pubmed #15184275 links to  free full text

Abstract: BACKGROUND: Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34- and CD133-positive cells present in peripheral blood, in maintenance of the vasculature and neovascularization. Immature populations, including CD34-positive cells, have been shown to contribute to vascular homeostasis, not only as a pool of endothelial progenitor cells but also as a source of growth/angiogenesis factors at ischemic loci. We hypothesized that diminished numbers of circulating immature cells might impair such physiological and reparative processes, potentially contributing to cerebrovascular dysfunction. METHODS AND RESULTS: The level of circulating immature cells, CD34-, CD133-, CD117-, and CD135-positive cells, in patients with a history of atherothrombotic cerebral ischemic events was analyzed to assess possible correlations with the degree of carotid atherosclerosis and number of cerebral infarctions. There was a strong inverse correlation between numbers of circulating CD34- and CD133-positive cells and cerebral infarction. In contrast, there was no correlation between the degree of atherosclerosis and populations of circulating immature cells. Analysis of patients with cerebral artery occlusion revealed a significant positive correlation between circulating CD34- and CD133-positive cells and regional blood flow in areas of chronic hypoperfusion. CONCLUSIONS: These results suggest a possible contribution of circulating CD34- and CD133-positive cells in maintenance of the cerebral circulation in settings of ischemic stress. Our data demonstrate the utility of a simple and precise method to quantify circulating CD34-positive cells, the latter providing a marker of cerebrovascular function.

Hoshida S, Hayashi T, Kanamasa K, Ishikawa K, Naka M, Kawarabayashi T, Yokoi Y, Matsuda M, Nagai Y, Yamada Y, Anonymous00004. · Osaka Rosai Hospital, Sakai, Japan. · Am J Cardiol. · Pubmed #14996589 No free full text.

Abstract: A prospective study was conducted of the differences in clinical characteristics between patients with acute myocardial infarction and those with unstable angina pectoris admitted to hospitals in the South-Osaka district of Japan. Gender and smoking were identified as discriminant risk factors for the incidence of acute myocardial infarction in patients < or =66 years with acute coronary syndromes; however, age alone affected the mode of presentation in older patients.

Takahashi-Yasuno A, Masuzaki H, Miyawaki T, Ogawa Y, Matsuoka N, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Nakao K. · Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. · Diabetes Res Clin Pract. · Pubmed #14625131 No free full text.

Abstract: OBJECTIVE: To investigate whether leptin receptor (Ob-R) Arg223Gln polymorphism influences serum lipid levels and whether this polymorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor, simvastatin [Clin. Cardiol. 16 (1993) 317]. DESIGN: Case-control association study. SUBJECTS: We studied 201 Japanese men without medical care, and 78 Japanese who took simvastatin. METHODS: Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid and leptin levels were determined. RESULTS: Subjects with the Arg/Arg homozygotes had significantly higher serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (TC: Arg/Arg: 213+/-3, Arg/Gln: 196+/-6, Gln/Gln: 184+/-5, P=0.004 for comparison among three genotypes, P=0.008 for difference between Arg/Arg and Arg/Gln, and P=0.025 for difference between Arg/Arg and Gln/Gln, LDL-C: Arg/Arg: 127+/-3, Arg/Gln: 112+/-6, Gln/Gln: 114+/-8, P=0.027) for comparison among three genotypes and P=0.011 for difference between Arg/Arg and Arg/Gln. Subjects with the Arg/Arg homozygotes had significantly lower serum high density lipoprotein cholesterol (HDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (Arg/Arg: 55+/-1, Arg/Gln: 62+/-3, Gln/Gln: 57+/-7, P=0.046) for comparison among three genotypes and P=0.013 for difference between Arg/Arg and Arg/Gln. In addition, in 78 patients with hypercholesterolemia who took 5 mg simvastatin, the TC lowering effect by simvastatin in subjects with the Arg/Arg homozygotes was significantly lower than in those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (the reduction in serum TC levels; 62+/-4 vs. 79+/-6, P=0.044). CONCLUSIONS: We demonstrate that Ob-R Arg223Gln polymorphism in Japanese men is associated with significant elevation of serum TC and LDL-C levels. Our data also show that the Arg/Arg homozygotes tend to show lowered level of serum HDL-C. Furthermore, this polymorphism tends to show an attenuated response to an HMG-CoA reductase inhibitor in terms of the cholesterol lowering effect. These results suggest that the Ob-R gene may serve as a novel modifier gene for hypercholesterolemia in Japanese men.

Inoue T, Takayanagi K, Hayashi T, Morooka S. · Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50 Minamikoshigaya, Saitama Koshigaya City 343-8555, Japan. · Int J Cardiol. · Pubmed #12957750 No free full text.

Abstract: BACKGROUND: Long-term administration of nitrates results in the development of tolerance. Nitrate tolerance is considered to occur in association with oxidative stress, although its underlying mechanisms are multi-factorial. Fluvastatin, a newly developed statin, is considered to have not only a cholesterol-lowering effect but also anti-oxidative properties. METHODS: In this study, the effect of fluvastatin on nitrate tolerance was investigated in 12 dyslipidemic patients (nine men and three women, aged 63.5+/-6.7 years), who were complicated with ischemic heart disease and had received organic nitrates for a long period. RESULTS: Four months after fluvastatin therapy, symptoms of angina were significantly reduced. Consumption of sublingual nitrates over 2 weeks significantly decreased (14.4+/-11.2 to 2.3+/-2.5 tablets, P<0.01). In exercise stress testing, exercise duration was significantly prolonged (275+/-73 to 360+/-86 s, P<0.01) and the blood pressure-heart rate products significantly increased (16368+/-2246 to 18381+/-1772, P<0.01). Both the percent change in forearm blood flow with reactive hyperemia (232+/-83 to 282+/-104%, P<0.05) and that after sublingual nitroglycerine (2.5+/-4.7 to 5.8+/-4.7%, P<0.05) were increased. Although the levels of total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol were unchanged, the serum anti-Ox-LDL titer (16.7+/-6.3 to 13.4+/-5.4 AcU/ml, P<0.05) and 8-OHdG level (1.11+/-0.34 to 0.73+/-0.34 ng/ml, P<0.05) decreased. CONCLUSIONS: Fluvastatin attenuated nitrate tolerance in dyslipidemic patients complicated with ischemic heart disease who had been receiving organic nitrates over long period. The anti-oxidative effect of fluvastatin may attenuate nitrate tolerance.

Hayashi T, Sumi D, Matsui-Hirai H, Fukatsu A, Arockia Rani P J, Kano H, Tsunekawa T, Iguchi A. · Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Japan. · Atherosclerosis. · Pubmed #12732383 No free full text.

Abstract: Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis, its effect on atherosclerosis is unknown. Accordingly, we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis. Male rabbits were fed a 0.5% cholesterol diet (HCD) (Gp 1), HCD with vitamin E (Gp 2), HCD with vitamin E and sarpogrelate (Gp 3), or HCD with sarpogrelate alone (Gp 4) for 8 weeks. The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate (16.9+/-2.0% in Gp 1 vs. 8.2+/-2.0% in Gp 3). Tone-related basal NO release was higher in Gps 3 and 4. Acetylcholine-induced relaxation tended to be improved in Gp 3. The amount of eNOS mRNA was increased in Gp 4, and aortic cyclic GMP concentration showed the same tendency. O(2)(-) release tended to be decreased in Gps 2 and 3. The matrix metalloproteinase-1 (MMP-1)-positive area was decreased, and the percentage ratio of cell numbers of smooth muscle cells/macrophages in the plaque was increased in Gp 3. The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits, and that this effect is enhanced by concomitant administration of vitamin E. Although upregulation of eNOS may play a role as one of the underlying mechanisms, our results suggest that an additional mechanism-possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages-may also play an important role.

Kushibiki S, Hodatet K, Shingu H, Hayashi T, Touno E, Shinoda M, Yokomizo Y. · Department of Animal Production, National Agricultural Research Center for Tohoku Region, Iwate, Japan. · J Anim Sci. · Pubmed #12211385 links to  free full text

Abstract: Endotoxin induces marked changes in lipid metabolism via its effects on cytokines. To evaluate the role of tumor necrosis factor-alpha (TNF) in mediating changes of lipid metabolism in ruminants, we performed a crossover saline-controlled study in Holstein heifers (n = 8; 394.0 kg average BW), investigating the metabolic effects of a single intravenous administration of recombinant bovine TNF (rbTNF, 5.0 microg/kg). Blood samples were taken from a jugular vein at 0 (1100, just before injection), 0.5, 6, 12, and 24 h after each treatment. Dry matter intake in the heifers was not affected by single administration of the rbTNF. The rbTNF produced early as well as later hypertriglyceridemia (P < 0.05) in dairy heifers. The rbTNF also induced an early and sustained rise (P < 0.05) in the plasma NEFA concentration. Plasma retinol concentration was decreased (P < 0.05) at 24 h after rbTNF injection, whereas the a-tocopherol concentration was not significantly affected by rbTNF treatment. At 0.5 and 24 h, there was an increase (P < 0.05) in the plasma concentration of the very-low-density lipoprotein (VLDL) fraction in rbTNF-treated heifers. Between 6 and 24 h after rbTNF treatment, concentration of the low-density lipoprotein fraction declined (P < 0.05) but the high-density lipoprotein fraction was not altered in the rbTNF-treated heifers. These results indicate that TNF produces a hypertriglyceridemic response associated with an increase of the VLDL fraction and a disturbance of retinol metabolism in dairy heifers.

Kanamasa K, Otani N, Ishida N, Inoue Y, Ikeda A, Morii H, Naito N, Hayashi T, Ishikawa K, Miyazawa M. · First Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan. · J Cardiovasc Pharmacol. · Pubmed #11209998 No free full text.

Abstract: Thrombus formation is a key component of the pathogenesis of restenosis after arterial balloon injury. The purpose of this study was to determine whether intimal hyperplasia could be attenuated by infusion of recombinant tissue plasminogen activator (tPA). Forty-two Kurosawa and Kusanagi hypercholesterolemic rabbits were divided into tPA (n = 20) and control (n = 22) groups, the former receiving 7 days of continuous tPA infusion (0.6 mg/kg/day) via ear veins. The walls of the common iliac arteries were injured using 2.5-mm balloon catheters and then examined histologically 7, 14, 21, and 28 days later. Cell proliferation was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and transforming growth factor (TGF)-beta immunohistochemistry was carried out to estimate cell proliferation and differentiation. It was observed that 28 days after balloon injury, intimal cross-sectional areas in the tPA group were significantly smaller than in controls (0.11 +/- 0.03 mm2 vs. 0.57 +/- 0.08 mm2, p < 0.01), as were ratios of the cross-sectional areas of the intima and media (0.21 +/- 0.07 vs. 1.06 +/- 0.18, p < 0.05). In addition, the numbers of PCNA-positive medial cells were significantly lower (0.06 +/- 0.01 vs. 0.36 +/- 0.08, p < 0.05) and TGF-beta-positive vessel wall areas were significantly smaller in tPA-treated animals 7 days after balloon injury (0.47 +/- 0.28% vs. 4.55 +/- 1.44%, p < 0.05). Thus infusion of tPA after arterial balloon injury appears to decrease medial cell proliferation and suppress intimal hyperplasia.

Arai I, Amagaya S, Komatsu Y, Okada M, Hayashi T, Kasai M, Arisawa M, Momose Y. · Central Research Laboratories, Tsumura & Company, Ibaraki, Japan. · J Ethnopharmacol. · Pubmed #10624893 No free full text.

Abstract: EtOH (70%) extracts from the leaves of Eugenia uniflora were separated into six fractions with different polarity and molecular size, i.e. NP-1-NP-6. In an oral glucose tolerance test, NP-1 and 4 inhibited the increase in plasma glucose level. However, in an intraperitoneal glucose tolerance test, such an inhibitory effect was not seen. Thus, the effects of NP-1 and 4 were apparently due to the inhibition of glucose absorption from the intestine. In a sucrose tolerance test, all fractions inhibited the increase in plasma glucose level. In an oral corn oil tolerance test, NP-3 and 4 showed an inhibitory effect on the increase in plasma triglycerides level. On the other hand, NP-3, 4, 5 and 6 inhibited maltase and sucrase activities and all fractions except for NP-1 showed an inhibitory effect on lipase activity dose-dependently. The inhibition of the increase in plasma glucose level by NP-3, 4, 5 and 6 in the oral sucrose tolerance test and the inhibition of the increase in plasma triglycerides by NP-3 and 4 in the oral corn oil tolerance test were apparently due to the inhibition of the decomposition of carbohydrates and fats in the intestine, respectively.

Hayashi T, Yamada K, Esaki T, Kano H, Asai Y, Kumar Thakur N, Jayachandran M, Sumi D, Iguchi A. · Department of Geriatrics, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan. · Atherosclerosis. · Pubmed #10559521 No free full text.

Abstract: We determined the role of ONOO(-) in nitric oxide (NO) mediated vascular response in atherosclerosis and regression following removal of dietary cholesterol. The effect of ONOO(-) on NO-mediated vascular responses was examined in vitro. Basal and stimulated NO release was estimated by an NO-selective electrode as well as vascular response and the plasma NO metabolites. An immunohistochemical study was also carried out. Responses were compared in normal controls, atherosclerotic rabbits fed 1% cholesterol diet for 6 or 9 weeks (atherosclerotic group) and animals fed a normal diet for 6-36 weeks after the high cholesterol diet for 6 or 9 weeks (regression group). ONOO(-) impaired the basal and acetylcholine-stimulated NO release, but did not affect endothelium-independent relaxation. After 15 weeks on a normal diet, the acetylcholine-stimulated and basal NO-mediated relaxation, which was diminished in the aorta induced by 6 weeks high cholesterol diet, became restored. However, the vascular response in the 9 weeks high cholesterol diet group did not return to normal after 36 weeks on a normal diet. iNOS was observed in atherosclerotic plaques in atherosclerotic and regression groups along with ONOO(-) in the 9 weeks high cholesterol diet group, but not in the 6 weeks group. Conclusively, ONOO(-) can play a role in impairment of NO-mediated vascular response during the regression of dietary cholesterol-induced atherosclerosis, not in the initiation of atherosclerosis.

Kano H, Hayashi T, Sumi D, Esaki T, Asai Y, Thakur NK, Jayachandran M, Iguchi A. · Department of Geriatrics, Nagoya University Graduate School of Medicine, 466-8550, Japan. · Biochem Biophys Res Commun. · Pubmed #10362523 No free full text.

Abstract: We determined the role of Fluvastatin: HMG-CoA reductase inhibitor on the regression of atherosclerosis following removal of dietary cholesterol. Male rabbits fed a 0.5% cholesterol diet for 12 weeks were divided into three groups: A1, hypercholesterolemic; A2, fed a regular diet for an 12 additional weeks; and A3, fed a regular diet with fluvastatin (2 mg/kg/day). Fluvastatin treatment (A3) did not affect serum lipid levels compared with A2. However, it decreased the atherosclerotic area in the aortic arch and decreased total and esterified cholesterol concentrations in the descending aorta. Tone-related basal NO release in the thoracic aorta was larger in A3 than in A2. eNOS mRNA in vessel was determined by competitive RT-PCR assay. It increased in A1, compared with normal aorta and decreased in A2; however, it did not decrease in A3. This is the first report of a decrease in eNOS mRNA in atherosclerosis after removal of dietary cholesterol and a reversal of it by a HMG-CoA reductase inhibitor, which may contribute to the regression of atherosclerosis.