Ageing of the blood vessel is defined as the agerelated structural and functional changes of the blood vessel. These include distension, or kinking of the wall of the blood vessel and increased stiffness of the blood vessel wall. These age-related change are frequently associated with arteriosclerosis. Both phenomena are similar and closely correlated in terms of pathogenetic mechanism. Morphologically, age-related changes in the artery are usually characterized as degenerative changes of smooth muscle cells associated with the deposition of collagen fibers and the fragmentation of elastic fibers. Research on this topic so far is reviewed and the clinical significance of these agerelated changes of artery is discussed. Reevaluation of an anti-atherosclerotic drug Elaszyme which has been classified as a hypocholesterolemic drug is also included.

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It was suggested that the induction of a poor down-regulation of LDL receptors, which was attributable to increased acyl coenzyme A: cholesterol acyltransferase activity, contributed to cholesteryl ester accumulation in differentiated monocyte-macrophage-like cells from U937 cells when incubated with apo B or apo E containing lipoproteins.

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It has been reported that the simplified fat emulsion tolerance test (FETT) has been evaluated as a tool for analysis of triglyceride-rich lipoprotein metabolism and pathogenesis in hyperlipoproteinemia. In the present study, the reproducibility of the removal rate (K₂) in FETT was investigated.
Twenty-one healthy subjects participated in this study. After an overnight fast, the subjects were injected with 0.25ml/kg weight of 10% Intralipid®, and blood was sampled 8 times during the following 20 minutes. K₂-value was determined by nephelometry as previously reported. FETT was repeated at the interval of 90 minutes.
The correlation coefficient between K₂ in the first and second FETT was 0.9057 (p<0.0001). K₂ was highly reproducible in FETTs repeated within a short time. The removal rate (K₂) was expressed as -b±Sb where Sb is the standard error of b. Student's t-value was calculated as b/Sb ratio, and was distributed by more than 5 in repeated FETTs. This high t-value indicates a high linearity of the semilogarithmic disappearance curves, and a high reliability of K₂.
These findings suggest that simplified FETT is a useful tool for the study of hyperlipoproteinemia and TG-rich lipoprotein metabolism.

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We examined the serum lipids, apoproteins and lipoproteins, and several neutral sterols including cholestanol, desmosterol, lathosterol, campesterol and β-sitosterol in 45 male patients with coronary artery disease (CAD) and 40 normal control male subjects. The results were as follows:
(1) Statistically significant differences between both groups were noted in triglycerides, high density lipoprotein cholesterol (HDL-Ch), low density lipoprotein cholesterol (LDL-Ch), β-lipoprotein (β-Lipo), apolipoprotein (Apo) A-I, Apo A-II, Apo B, β-Lipo/HDL-Ch, Apo B/Apo A-I, HDL-Ch/total cholesterol, and Atherogenic index, as reported previously.
(2) Serum Lp (a) levels were significantly higher (p<0.001) in the CAD group (162.0±120.7mg/l) than in the control group (76.0±64.1mg/l).
(3) No significant differences between both groups were noted in plant sterols (campesterol and β-sitosterol) and desmosterol. While, serum cholestanol, which was an intermediate metabolite in the cholesterol metabolic pathway, and lathosterol, which has been reported to be a good indicator of whole-body cholesterol synthesis, were significantly high in the CAD group.
These results showed that patients with CAD had multiple risk factors in the metabolism of lipids, particularly of cholesterol, and lipoproteins.

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Variant form of angina pectoris is known to be induced sometimes by alcohol ingestion. The author reported that patients attacked by alcoholinduced coronary spasm there was an association with a gradual decrease of cyclic GMP levels in the plasma before the induction of attack. To investigate the mechanism of alcohol-induced coronary spasm, we conducted an in vitro study on the effect of alcohol on cyclic GMP metabolism, using cultured smooth muscle cells isolated from porcine coronary artery.
The effects of ethanol and its metabolite, acetaldehyde, on guanylate cyclase activity and cyclic GMP were studied with or without sodium nitroprusside (SNP).
Ethanol at the concentration of 4.0mg/m/ was found to suppress guanylate cyclase activity. Enhanced accumulation of cyclic GMP by SNP was inhibited by a similar concentration of etha nol, whereas the basal level of cyclic GMP was suppressed by a concentration of 12mg/m/ or more. Acetaldehyde also showed both suppression of guanylate cyclase activity and inhibition of cyclic GMP accumulation, though it required rather high concentration to exert these eflects.
Cyclic GMP is known as a key substance in vasodilatation by endothelium-derived relaxing factor, atrial natriuretic factors and nitrovasodilators. The results of our in vitro study suggests that the effects of ethanol on cyclic GMP metabolism in smooth muscle cell could play an important role on ethanol-induced vasospastic angina.

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Hypo α-lipoproteinemia is often related to hypertriglyceridemia. Lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL) and cholesteryl ester transfer protein (CETP) may have a role in this state. We gave a oral fat load to hypertriglyceridemic subjects in order to investigate these relations.
There were no differences in either LPL and HTGL activities between the hypertriglyceridemia patients and normal controls. After fat load, serum triglyceride (TG) elevated and maintained the level for a longer period in the hypertriglyceridemic subjects than in the normolipidemic controls.
High density lipoprotein 3 (HDL₃) cholesterol decreased in both groups. HDL₃ cholesterol of the normolipidemic subjects recovered in 10 hours, while that of the hypertriglyceridemic subjects stayed at a low level until 12 hours after fat load. CETP activity did not change significantly. However, significant positive relationships were found between the Δ HDL₃-C Area (Δ HDL₃-C×hours) and TG Area (PlasmaTG×hours), and between the Δ HDL₃-C Area (Δ HDL₃-C×hours) and Δ VLDL-C Area (Δ VLDL-C×hours).
Based on these results, we conclude that hypo α-lipoproteinemia with hypertriglyceridemia may be related to increased transfer of cholesteryl ester (CE) from HDL to TG-rich lipoproteins, and that the transfer may be accelerated by an increased mass of TG-rich lipoproteins as an acceptor rather than the stimulation of CETP activity.

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High levels of lipoproteins (a) (Lp (a)) are strongly associated with atherosclerosis. We describe a case of diabetic nephropathy who suffered from myocardial infarction associated with hyper Lp (a) aemia. Plasma concentrations of Lp(a) were elevated in this patient compared with those of controls (76 vs. 18.3±10.4mg/dl, mean±SD). LDL-apheresis using a liposorber system was performed in this patient. Total and LDL-cholesterol levels decreased by 42 and 46%, respectively. Lp (a) levels decreased by 72%. Thallium-201 single photon emission computed tomographic images were remarkably improved during LDL apheresis.
These results suggest that LDL apheresis may be an alternative therapy in drug resistant hyperLp (a) aemia.

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Low density lipoprotein (LDL) in plasma has been known to fractionate into subgroups, and two distinct LDL subclasses identified using gradient polyacrylamide gel electrophoresis were named pattern A and B by Austin and Krauss in 1986. They demonstrated that individuals with pattern B were characterized by a preponderance of small and dense LDL particles which significantly increased the risk of myocardial infarction. It has also been proposed that these LDL subclass patterns are influenced by a genetic trait.
In this study, LDL patterns of 131 patients with non-insulin dependent diabetes mellitus (NIDDM) and 71 healthy controls were determined by gradient gel electrophoresis analyses. The results showed that the frequency of pattern B in the patients with NIDDM was greater (38.9%) than that in the controls (7.0%). Mean particle diameters for NIDDM patients with pattern A were 26.56±0.46nm and those with pattern B, 25.19±0.40nm. The interrelation between LDL subclass patterns and the clinical status showed that patients with pattern B had a higher body mass index (BMI) than those with pattern A. However, the mode of treatment and levels of blood glucose control were not different for the two groups of LDL subclass patterns. As far as plasma lipid and lipoprotein levels are concerned, total cholesterol, triglyceride and apolipoprotein B levels were significantly higher, but HDL-C and HDL2-C levels were significantly lower in patients with pattern B than those with pattern A. The study in the selected group of diabetic patients with normal triglyceridemia (<150mg/dl) also showed similar results.
The majority of the diabetic patients with pattern B showed no change in their LDL pattern, though their blood glucose had been controlled and triglyceride levels had decreased.
The families of 6 diabetic patients with pattern B were studied. As a result, a parent or a child in two families showed pattern B in their LDL. These findings suggest that LDL subclass pattern B is controlled by a genetic trait.

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Human plasma apolipoprotein A-I (apo A-I), the major protein component of high density lipoprotein (HDL), is a single polypeptide that consists of 243 amino acids and has a molecular weight of about 28, 000. It is secreted from the cells of the intestine and liver as proapo A-I which contains a six amino acid prosegment: Arg-His-Phe-Trp-Gln-Gln.
We describe a specific enzyme immunoassay (EIA) for quantification of plasma proapo A-I levels using monospecific antibodies raised against the synthetic peptide, copying a nine amino acid N-terminus of proapo A-I: Arg-His-Phe-Trp-Gln-Gln-Asp-Glu-Pro. The assay is a non-competitive sandwich EIA in which oligoclonal anti-proapo A-I antibodies are immobilized on the surface of polystyrene beads and other polyclonal anti-apo A-I antibodies are used as horseradish peroxidase conjugated antibodies. The working range of the assay was 10 to 500ng/ml of proapo A-I. Intraassay and interassay coefficients of variation were 5.8% and 7.0%, respectively. A delipidation step using diisopropylether-butanol was necessary to expose the antigen sites of proapo A-I in native lipoproteins.
In this assay, we determined plasma proapo A-I levels and the proapo A-I ratio (proapo A-I/total apo A-I) of patients with liver cirrhosis and chronic hepatitis. The mean levels of proapo A-I in 6 patients with decompensatory liver cirrhosis, in 17 with compensatory liver cirrhosis and in 9 with chronic hepatitis were higher than in 21 normal subjects (8.8±2.5, 10.5±3.6, 9.3±2.0, 6.9±2.5mg/dl, respectively). Furthermore, the mean proapo A-I ratio of each liver disease was higher than that in normal subjects (10.0±3.5, 10.2±3.9, 6.6±0.8, 4.6±1.6%, respectively). Proapo A-I levels indicated a positive correlation to HDL2-C levels (r=0.736), though they showed no correlation to biochemical indicators of residual hepatic functions, apo A-I and HDL₃-C levels. Proapo A-I ratios correlated positively with ICG-R₁₅ and HDL₂-C (r=0.544, r=0.508, respectively), and inversely with serum albumin, ChE, L-CAT and HDL₃-C (r=-0.456, r=-0.402, r=-0.395, r=-0.609, respectively).
We next measured proapo A-I converting enzyme activity in 10 normal subjects and 10 patients with liver cirrhosis. The activities were calculated on the basis of changes of serum proapo A-I levels during incubating for 6 hours at 37°C. Activities in patients with liver cirrhosis (6.2±3.0×10^-2nmol ml/hr) were significantly lower than those in normal subjects (17.2±5.5×10^-2nmol/ml/hr).
These results indicated that the elevations of plasma proapo A-I levels and ratios in patients with liver cirrhosis are caused by a decline of proapo A-I converting enzyme, which may be produced in the liver. The strong relationships of proapo A-I levels and proapo A-I ratios to HDL₂-, HDL₃-C levels indicated that proapo A-I may play an important role in the maturation and catabolism of HDL.

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The objective of this study was to clarify the actions of 3-isobutyryl-2-isopropylpyrazol [1, 5-a] pyridine (ibudilast) on calcium (Ca) and magnesium (Mg) contents in the central nervous system (CNS), heart, liver, kidney, muscle, abdominal aorta and bone of rabbits fed cholesterol-rich diets.
Thirty male rabbits were divided into five groups. Each group was fed standard diet (group A), standard diet containing 1.0% cholesterol (group B), standard diet containing 1.0% cholesterol plus oral administration of 2.5mg/kg/day of ibudilast (group C), standard diet containing 1.0% cholesterol plus oral administration of 10mg/kg/day of ibudilast (group D) and standard diet containing 1.0% cholesterol plus oral administration of 2.5mg/kg/day of ibudilast and 300mg/kg/day of nicomol (group E). After the three months, blood was collected by cardiocentesis using ether anesthesia. The rabbits were then sacrificed to remove the CNS and other tissues. Blood was left to stand for 1 hour at room temperature and serum was separated by centrifugation of 3000rpm for 10min. to determine total cholesterol, phospholipids, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, peroxide lipid, NEFA, thromboxane B₂ (TXB₂) and other biochemical indices. The pathological changes in each tissue were observed. Serum TXB2 levels were decreased in groups D and E, compared with those in Group B (p<0.05). The atherosclerotic changes in groups D and E were ameliorated, in comparison with the findings of group B and C. Ca contents in the frontal cortex and cerebellum of Groups A and E and in the pons of group E were significantly lower than those of group B (p<0.05). Ca content in the cerebellum showed lower values in groups C and D than those in group (B (p<0.05). Ca content in the abdominal aorta of groups A and D, and especially of group E, were decreased, compared with those contents of Groups B and C. However, there were no significant differences in the Mg contents of the CNS and other tissues in each group.
These results suggest that higher contents of Ca in the CNS and abdominal aorta were deposited and atherosclerotic changes were observed in rabbits fed cholesterol-rich diet. Furthermore, the actions of 10mg/kg/day of ibudilast and 2.5mg/kg/day ibudilast plus 300mg/kg/day nicomol exerted a scavenger effect on Ca deposition in the CNS and abdominal aorta.

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Effects of probucol administration (500mg/day for 12 weeks) on serum lipids, apolipoproteins and several parameters were studied in 17 patients with hypercholesterolemia, which consisted of type IIa-, IIb- and IV-hyperlipemia. Serum levels of total cholesterol and triglyceride decreased in all types. Apolipoprotein Al and B decreased in type IIa and IIb. HDL cholesterol decreased in type IIa and IV. Significant decreases in HDL cholesterol/apolipoprotein A1 ratio and LDL cholesterol/apolipoprotein B ratio were seen only in type IIa. In type ha, it appears that probucol decreases the particle number of lipoproteins such as HDL and LDL which is abnormally high by nature, and also decreases their cholesterol contents.

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Apoprotein A-1- and B-100-containing particles were isolated by selective affinity columns prepared with monoclonal antibodies. The effects of probucol and clinofibrate on cholesterol and protein concentrations in these particles were studied in non insulin dependent diabetic patients. Total plasma cholesterol levels in the 2 groups were both reduced significantly after 8 weeks of treatment, but during this period, fasting blood glucose and hemoglobin HbA-1 levels were almost unchanged in the 2 groups. Cholesterol and protein contents in apoprotein A-1 particles after treatment with probucol were both reduced, but not significantly. Cholesterol and protein contents in apoprotein A-1 particles after treatment with clinofibrate were both significantly increased (p<0.05). Cholesterol contents in apoprotein B-100 particles after treatment with probucol or clinofibrate were both reduced (p<0.05) significantly. Cholesterol contents in other lipoprotein fractions after treatment with probucol or clinofibrate were both reduced (p<0.05) significantly. Protein contents in apoprotein B-100 particles were significantly increased (p<0.05) after treatment with probucol, and were reduced after treatment with clinofibrate, but not significantly. The ratio of esterified cholesterol/free cholesterol in apoprotein A-1 or B-100 were almost unchanged with probucol or clinofibrate, but the ratio of total cholesterol/protein in apoprotein B-100 was reduced (p<0.05) with probucol and the ratio in apoprotein A-1 was increased (p<0.05) with clinofibrate. It may be important for preventive treatment of atherosclerosis to analyze apoprotein A-1 and B-100 particles.

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We studied the erect of large doses of niceritrol in 120 patients with hypercholesterolemia. The dose of niceritrol was increased every 4 weeks from 750mg, through 1, 500mg and 2, 250mg to 3, 000mg/day. The final dose was adjusted to obtain good control or good compliance of each patient. Four groups of patients were established according to the final dose.
Serum cholesterol decreased 1.8%, 8.1 %, 11.9%, and 13.2%, and HDL-cholesterol increased 6.3%, 16.9%, 18.4%, and 13.8% with the dose of 750mg, 1, 500mg, 2, 250mg, and 3, 000mg/day, respectively. In 23 patients at the final dose of 2, 250mg/day, whose initial cholesterol levels were higher than 240mg/dl, the serum cholesterol level reduced 16%. In 21 patients of the same group, whose initial LDL-cholesterol levels were higher than 150mg/dl, the reduction rate in LDL-cholesterol was 21%.
Side effects were found in 17.5% of the subjects. There was no difference in the frequency of the side effects among the 4 groups.
This study indicates that a large dose of niceritrol administer in gradually increasing doses leads to a significant reduction in serum cholesterol and LDL-cholesterol levels and a significant increment in HDL-cholesterol level without increased side effects.

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Dai-Saiko-Toh is a traditional Chinese drug and has been noted to exhibit anti-atherogenesity. Following administration, aortas from fifty-one male New Zealand white (NZW) rabbits were studied to determine the drug's effect compared to controls, groups given feed containing 1.5% cholesterol and others. A group: Dai-Saiko-Toh administration (Tsumura, Tokyo, 1, 000mg/kg/day) for 3 or 6 months respectively after giving feed containing 1.5% cholesterol for 3 months, B group: simultaneous cholesterol containing feed and Dai-Saiko-Toh administration for 3 months, C group (control): normal diet feeding (vehicle, CR-1, Nihon-Kurea, Tokyo) for 3 or 6 months after giving feed containing 1.5% cholesterol for 3 months, D group: feed containing 1.5% cholesterol through the 3-month experimental period, and other groups. Body weight, levels of serum total cholesterol (TC), triglyceride (TG), cholestrol ester (CE), and others parameters were periodically monitored until sacrifice. Serum lipids and aortic tissue lipids were analysed, and the samples from the aortas were processed for pathomorphological analyses, including Surface Involvement (SI) and Atherosclerotic Index (AI) with the point counting method after Sudan IV staining.
Dai-Saiko-Toh administration for 6 months showed that serum levels of TC (71.4mg/dl, A group) tended to be lower than in the C group (128.0mg/dl), and serum TG (41.0mg/dl, A group) was significantly lower than in the C group (72.1mg/dl). The B group at termination of administration at 3 months exhibited trends of decreasing serum TC and TG compared to those of the D group. Dai-Saiko-Toh administration showed a significantly decreased value of CE in aortic tissue (215.3mg/g, A group) than that of the D group, but no significant decrease of CE compared with the C group (227.7mg/g). FC/PL ratio in the aortic intima-medial cells of the A group (3.55 at 6 months) was markedly lowered than in the C group (5.21). The value of AT in the A group (4.98 at 6m) was markedly decreased than in both the C (6.32) and D (7.09) groups. No significant differences were noted in SI among each group. Microscopically, the lesions tended to exhibit decreased foam cells, calcium deposition, and collagen synthesis with Dai-Saiko-Toh administration than in the C group.
Six-month administration of Dai-Saiko-Toh is less effective for 1.5% cholesterol induced-atherosclerosis in NZW rabbit aorta. However, Dai-Saiko-Toh may have a preventive effect or antiatherogenesity for initial atherosclerotic lesions by lowering serum TC and TG.

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