摘要:

Indobufen is a reversible inhibitor of platelet prostaglandin G/H-synthase. To verify the dose dependence of the antiplatelet effect of indobufen on ex vivo and in vivo indexes of thromboxane (TX) biosynthesis and TXAj-dependent platelet function, we studied nine patients with non-insulin-dependent diabetes mellitus (NIDDM). This was a randomized, double-blind, crossover study in which each patient was treated with three different daily regimens (50 rag BID, 100 mg BID, and 200 mg BID) of indobufen for 1 week, with a 7-day washout period between treatments. Urinary 11-dehydro-TXBj excretion averaged 58.2 ± 21.8 ng/h at baseline. TX metabolite excretion was reduced dose dependently by indobufen: by 67% at 50 mg BID, 72% at 100 mg BID, and 81% at 200 mg BID. Platelet cyclooxygenase activity, ATP release, collageninduced platelet aggregation, and bleeding time also were modified dose dependently by indobufen. Biochemical demonstration of suppressed platelet TX A2 in vivo was accompanied by evidence of inhibited platelet function as assessed ex vivo. Under pathophysiological conditions, such as NIDDM, which are associated with enhanced TX A2 synthesis, more than 95% suppression of platelet cyclooxygenase activity may be necessary to produce virtually maximal inhibition of platelet TXA2 biosynthesis in vivo.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Thioglycolate-elicited mouse peritoneal macrophages were Incubated for 24 hours in serum-free Dulbecco- Vogt medium containing 0.5% fatty acid-poor bovine serum albumin. This conditioned medium, designated MP medium, was used for experiments with bovine aortic smooth muscle cells (SMCs) or human skin flbroblasts (HSFs). Dulbecco-Vogt medium of the same albumin content but without macrophages served as a control medium. In SMCs labeled from plating with [3H] cholesterol and incubated with hypercholesterolemic rabbit β-very-low-density lipoprotein O-VLDL) in Dulbecco-Vogt medium for 24 hours, there was an increase in cellular [3H] cholesteryl ester (CE) content compared with cells incubated without lipoprotein. When MP medium was used for the incubation of SMCs with β-VLDL, cellular [3H]cholesteryl ester content increased threefold compared with cells incubated with Dulbecco-Vogt medium. A smaller increase in cholesterol esterification in the presence of MP medium was also encountered with low-density lipoprotein (LDL). The MP medium-induced increase in [3H]cholesterol esterification was not evident up to 6 hours of incubation. Similar results were also obtained with HSFs. The increase in [3H] cholesterol esterification with MP medium in the presence of β-VLDL was also elicited in cells obtained from LDL receptor-negative donors with familial hypercholesterolemia (FH-HSF), even though in these cells significantly less [3H]cholesteryl ester was formed in the presence of 0-VLDL. MP medium contains numerous agents that could be responsible for the increase in cellular [3H] cholesteryl ester induced by lipoproteins. The first considered was lipoprotein lipase, but lack of inhibition of the MP medium effect by antiserum to lipoprotein lipase did not support this possibility. Recombinant apoprotein E, when added to β-VLDL and Dulbecco-Vogt medium, failed to mimic the MP effect, which argued against apoprotein E's being the "active" agent Since the increase in cellular [3H]cholesteryl ester in the presence of 0-VLDL and MP medium was more prominent in normal HSFs and SMCs than in FH-HSFs, it appears that although the LDL receptor may play a role, it is not absolutely necessary. The exact mode by which MP medium enhances cellular [3H] cholesteryl ester formation in the presence of 0-VLDL has not been elucidated, but it is important to conclude that this may occur through multiple pathways involving both the uptake of the whole particle and preferential uptake of the lipid moiety.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To assess the effect of exercise on the plasma concentration of cholesterol ester transfer protein (CETP) and its possible influence in mediating the exercise-associated redistribution of cholesterol among plasma lipoproteins, we measured plasma CETP in 57 healthy normolipidemic men and women before and after 9 to 12 months of exercise training. The training protocol resulted in significant changes in Vol., (mean±SD, +5-3±3.5 mL &#149; kg"1&#149; min"1), body weight (-2.5±3.5 kg), plasma triglycerides (-25.7±36J mg/dL), high-density lipoprotein cholesterol (HDL-C) (+2.6±62 mg/dL), and ratios of total cholesterol to HDL-C (-0.30±0.52) and low-density lipoprotein cholesterol (LDL-C) to HDL-C (-0.18±0.45) (all P$.05) but no change in lipoprotein(a). CETP concentration (in milligrams per liter) fell significantly in response to training in both men (n=28, 2.47±0.66 to 2.12±0.43; % A=14.2%;P<.005) and women (n=29, 2.72±1.01 to 2-J6±0.76; % A=13.2%;P<M7). The CETP change was observed both in subjects who lost weight (n=28, A mean weight=−5.0 kg; A CETP=−0.42±0.79; % A=15.4%;p<.009) and in those who were weight stable (n=29, A mean weight=−0.12 kg; A CETP =−0.29±0.78; % A=10.4%;p<.055). Pretraining plasma CETP concentration predicted training-associated changes in HDL-C (r= −.27,P<M) and ratio of LDL-C to HDL-C (r=+.40,p<.002). In a smaller study of 15 men, exercise training was associated with a decrease in levels of CETP, an increase in plasma postheparin lipoprotein lipase (LPL) activity, and a decrease in hepatic trigfyceride lipase (HTGL) activity. Overall, the data suggest that basal plasma CETP concentrations, in addition to LPL and HTGL activities, may contribute to determining the extent to which exercise redistributes cholesterol among plasma lipoproteins.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This study investigated the hypothesis that increased influx of low-density lipoprotein (LDL) accounts for the natural development of atherosclerosis in a characteristic (susceptible) site in the distal thoracic aorta of White Carneau (WC) pigeons and the exacerbation of atherosclerosis by cholesterol feeding. The influence of dietary cholesterol-induced changes in LDL composition on LDL influx into the artery was also investigated. As a measure of the influx of LDL into the artery, we determined the arterial accumulation of radiolabeled LDL after 1 hour. Nine 50-month-old WC pigeons with naturally occurring atherosclerosis and seven 14-month-old WC pigeons with atherosclerosis accelerated by 10 months of cholesterol feeding were studied. In the absence of atherosclerotic lesions, we found no evidence for increased accumulation of LDL at the susceptible site. In fact, more LDL accumulated in less susceptible normal arterial areas near the heart (=90 nl/h per square centimeter) than in the susceptible distal thoracic aorta (»35 nl/h per square centimeter). In the absence of atherosclerotic lesions, LDL accumulation (nanoliters per hour per square centimeter) was not influenced by hypercholesterolemia, although mass transport of LDL cholesterol into the artery was increased. Naturally occurring atherosclerotic lesions accumulated five times as much LDL as the adjacent normal arterial area (p<.001), whereas cholesterol-aggravated atherosclerotic lesions in different arterial sites accumulated four to 26 times as much LDL as the adjacent normal artery (p<.05). Cholesterol-aggravated atherosclerotic lesions at the most susceptible site accumulated five times as much LDL as naturally occurring atherosclerotic lesions in the corresponding arterial site (823±241 vs 175±45 nl/h per square centimeter, mean±SEM;p<.005). Arterial accumulation of LDL was influenced very little by changes in LDL composition induced by cholesterol feeding. In another study with young WC pigeons free of atherosclerosis and other WC pigeons with cholesterol-aggravated atherosclerosis, we injected differently labeled LDL 0.5 and 1 hour before sacrifice to investigate whether efflux of LDL from the artery was significant during a 1-hour period of LDL uptake. Although efflux of LDL from all arterial sites occurred during 1 hour, differential efflux could not account for regional differences in 1-hour arterial LDL accumulation. This study suggests that the characteristic susceptibility of the distal thoracic aorta of WC pigeons to atherosclerosis and the exacerbation of atherosclerosis by cholesterol feeding cannot be explained by differences in influx or efflux of LDL. Apparently, susceptibility to atherosclerosis in WC pigeons is determined by differences in other processes, such as metabolism of LDL after entering the artery or efflux of cholesterol from arterial cells.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Previous studies have demonstrated the presence of apoprotein (apo) E protein and message in arterial lesions. To determine the source of the synthesized apoE, we performed simultaneous in situ hybridization and immunocytochemistry on human and rabbit atherosclerotic tissue. Studies of serial sections of aortic atherosclerotic lesions from humans and hypercholesterolemic New Zealand White rabbits and Watanabe heritable hyperlipidemic rabbits revealed a similar pattern of macrophage-specifi c apoE expression in the rabbit and human lesions. In early lesions of rabbit atherosclerotic tissue, in which many macrophages were present, there was abundant expression of apoE mRNA. Northern blot analyses of total mRNA obtained from arterial macrophage-derived foam cells, freshly isolated from ballooned, cholesterol-fed New Zealand White rabbits, demonstrated positive hybridization with an apoE-specific riboprobe. Western blot analyses of conditioned media from the isolated foam cells placed in culture for up to 24 hours demonstrated the presence of secreted apoE. These studies demonstrated that in atherosclerotic lesions, arterial wall macrophages synthesize and secrete apoE and probably account for most of the apoE synthesized in the atherosclerotic artery.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID