Effects of dietary Angelica keiskei on lipid metabolism in stroke-prone spontaneously hypertensive rats

1. The effect of dietary Angelica keiskei on lipid metabolism was examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Six-week-old male SHRSP were fed diets containing 0.2% A. keiskei extract (ethyl acetate extract from the yellow liquid of stems) for 6 weeks with free access to the diet and water. 3. Elevation of systolic blood pressure tended to be suppressed on and after 2 weeks; however, this effect was not statistically significant. 4. Serum levels of cholesterol and phospholipid in SHRSP were significantly elevated after treatment with A. keiskei extract and this effect was accompanied by significant increases in serum apolipoprotein (Apo) A-I and ApoE concentrations. These changes in the serum were due to increases in high-density lipoprotein (HDL) containing ApoA-I and ApoE. 5. In the liver, significant decreases in relative weight and triglyceride content were observed in SHRSP after treatment with A. keiskei extract. An investigation of mRNA expression of enzymes involved in hepatic triglyceride metabolism indicated a decreased level of hepatic Acyl-coenzyme A synthetase mRNA expression. 6. In conclusion, dietary A. keiskei produces elevation of serum HDL levels and a reduction of liver triglyceride levels in SHRSP.     

Hypotensive and lipid regulatory actions of 4-hydroxyderricin, a chalcone from Angelica keiskei, in stroke-prone spontaneously hypertensive rats

1. Previously, we found that Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems) elevated serum high-density lipoprotein (HDL) levels and reduced liver triglyceride content in stroke-prone spontaneously hypertensive rats (SHRSP). To identify the active substance in A. keiskei extract, we examined the effect of 4-hydroxyderricin, a characteristic chalcone isolated from the yellow liquid of stems, on blood pressure and lipid metabolism in SHRSP. 2. Six-week-old male SHRSP were fed diets containing 0.07% 4-hydroxyderricin for 7 weeks with free access to the diet and water. Elevation of systolic blood pressure was significantly suppressed after 7 weeks treatment. Serum very low-density lipoprotein (VLDL) levels were significantly reduced, without any effect on HDL levels, and were associated with a significant decrease in the serum concentration of free fatty acids. 3. In the liver, significant decreases in relative liver weight and triglyceride content were found after treatment with 4-hydroxyderricin for 7 weeks. 4. An investigation of hepatic mRNA expression of proteins involved in lipid metabolism indicated that a significant decrease in microsomal triglyceride transferprotein may be responsible for the decrease in serum VLDL levels and that significant decreases in adipocyte determination and differentiation factor 1 and fatty acid synthase may be responsible for the decrease in hepatic triglyceride content. 5. In conclusion, dietary 4-hydroxyderricin produces suppression of the elevation of systolic blood pressure, reduction of serum VLDL levels and a decrease in hepatic triglyceride content in SHRSP.     

Beneficial effect of xanthoangelol, a chalcone compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats

1. Recently, we reported that 4-hydroxyderricin, one of the major chalcones in Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems), exerted hypotensive and lipid regulatory actions in stroke-prone spontaneously hypertensive rats (SHRSP). In the present study, we isolated xanthoangelol, another major chalcone in A. keiskei extract, and examined the effect of dietary xanthoangelol on blood pressure and lipid metabolism in SHRSP. 2. Six-week-old male SHRSP were fed diets containing 0.02% or 0.1% xanthoangelol (0.02 and 0.10 Xan, respectively) for 7 weeks, with free access to the diet and water. There were no significant changes in daily food intake, bodyweight or systolic blood pressure throughout the experimental period. Serum total cholesterol levels tended to decrease in the two experimental groups (albeit not significantly), which was due to a dose-dependent decrease in the cholesterol content of the low-density lipoprotein (LDL) fraction. These results suggest that dietary xanthoangelol decreases serum LDL levels. 3. In the liver, significant dose-dependent decreases in relative liver liver weight and total triglyceride content were seen in the 0.02 and 0.10 Xan groups. In addition, a significant decrease in total cholesterol content was found in the 0.10 Xan group, which may be due to an elevation of faecal cholesterol excretion in addition to the decrease in liver weight. 4. Investigation of the hepatic mRNA expression of proteins involved in lipid metabolism indicated that there was a significant increase in peroxisome proliferator-activated receptor (PPAR) alpha mRNA expression associated with the tendency for increases in acyl-coenzyme A (CoA) synthetase and acyl-CoA oxidase mRNA expression in the 0.10 Xan group, which may be responsible, at least in part, for the decrease in hepatic triglyceride content in the xanthoangelol-treated rats. In addition, a significant increase in LDL receptor mRNA expression in the 0.10 Xan group may be responsible, at least in part, for the decrease in serum LDL levels in the xanthoangelol-treated rats. 5. In conclusion, dietary xanthoangelol results in a reduction of serum LDL levels and decreases in total cholesterol and triglyceride contents in the liver of SHRSP. These beneficial effects are more effective following consumption of diet containing 0.10% xanthoangelol.     

Hypocholesterolaemic effects of an ethanol precipitate of Kabosu juice in stroke-prone spontaneously hypertensive rats fed a cholesterol-free diet

1. We have previously identified strong inhibitory effects of Kabosu (Citrus sphaerocarpa Hort.) juice precipitate (KJP) on cholesterol elevation in stroke-prone spontaneously hypertensive rats (SHRSP) fed a cholesterol diet. In the present study, to elucidate the hypocholesterolaemic mechanism, we examined the effect of dietary KJP on lipid metabolism by using SHRSP fed a cholesterol-free diet. 2. Compositions of the experimental diet containing 10% KJP powder were adjusted to those of the control diet. Seven-week-old male SHRSP were fed control or experimental diet for 2 weeks with free access to the diet and water. 3. Serum levels of cholesterol, phospholipid and triglyceride of the KJP group were significantly reduced, which was due to decreases in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions. 4. Serum concentrations of apolipoproteins A-I and E (apoA-I and E) of the KJP group were significantly lower than those of the control group, whereas no significant differences were observed in serum apoB and apoA-IV between the two groups. 5. In liver, there were no significant differences in the contents of lipids or relative liver weight between the two groups. The activity of microsomal cholesterol 7alpha-hydroxylase of the KJP group tended to increase, whereas that of microsomal acyl-coenzyme A : cholesterol acyltransferase was significantly reduced, compared with the control group. 6. These results indicate that dietary KJP produces reductions of serum lipid levels, which are due to reductions in VLDL, apoE HDL and apoA-I HDL, and may promote catabolism and excretion of hepatic cholesterol in SHRSP fed a cholesterol-free diet.     

Low density lipoprotein-lowering and high density lipoprotein-elevating effects of nicardipine in rats

Oral administration of a calcium antagonist, nicardipine hydrochloride (simply designated as nicardipine), in doses of 10-100 mg/kg tended to decrease total serum cholesterol and to increase high density lipoprotein (HDL) cholesterol in the normal rat. These effects of nicardipine were much greater than those of clofibrate, a standard cholesterol-lowering drug. Neither nicardipine nor clofibrate caused significant alteration in serum triglyceride and phospholipid. In hypercholesterolemic rats, nicardipine increased significantly HDL cholesterol with a reduction of total serum cholesterol, whereas clofibrate did not change HDL cholesterol. Separation of serum lipoproteins either by ultracentrifugation in various densities of KBr-NaCl solution or by polyacrylamide gel electrophoresis demonstrated that nicardipine increased preferentially HDL2 (density: 1.063-1.125), with a reduction of the low density lipoprotein (LDL) (density: 1.006-1.063) level in hypercholesterolemic rats. Serum triglyceride and liver phospholipid were increased slightly by nicardipine with no clear dose-dependency. Clofibrate also increased serum triglyceride. In normal rats, neither nicardipine nor nicotinic acid inhibited sterol biosynthesis from [1-14C]acetate in the liver, whereas clofibrate inhibited sterol production. Oral administration of [4-14C]cholesterol to hypercholesterolemic rats indicated that nicardipine had no inhibitory effect on the intestinal absorption of cholesterol.     

Effect of nicardipine on cholesterol-fed S.H.R

The effect of nicardipine on experimental hyperlipemia induced by a 1% cholesterol diet in spontaneously hypertensive rats (SHR) was investigated by the change of hemodynamics and the determination of lipid contents of the serum, liver, heart and aorta. Nicardipine increased liver weight and liver weight per body weight ratio, and it decreased heart and kidney weight significantly. Nicardipine inhibited the increase in blood pressure with cholesterol and normal diets. Nicardipine decreased heart rate in SHR fed the normal diet, and it inhibited the increase in heart rate in SHR fed the cholesterol diet. Serum lipid levels significantly increased with the cholesterol diet. Nicardipine significantly increased cholesterol in high density lipoprotein (HDL-C) and phospholipid in HDL (HDL-PL) with cholesterol and normal diets, and it decreased triglyceride and improved the atherogenic index "(total cholesterol-HDL-C)/HDL-C" with the normal diet. Serum GOT and GPT significantly increased with the cholesterol diet. Nicardipine significantly enhanced an increase in GOT and GPT levels with the cholesterol diet. Nicardipine increased phospholipid content in the liver, triglyceride in the heart, and it decreased total cholesterol in the aorta. A morphologic study showed a fatty liver in SHR fed the cholesterol diet, but nicardipine had no effect on the morphological changes in the liver, heart and aorta. These results suggest that nicardipine may prevent atherosclerotic degeneration by the inhibition of hypertension, increase in serum HDL and decrease in total cholesterol in the aorta.     

Altered bile acid metabolism in alloxan diabetic rats

Changes of cholesterol, phospholipid, triglyceride or bile acid levels in serum liver, bile and feces after the treatment with alloxan were examined in Wistar strain male rats. Serum cholesterol, phospholipid and triglyceride levels and liver cholesterol level markedly increased but liver phospholipid and triglyceride levels remained unchanged. The lipid levels in serum very low density and low density lipoproteins were elevated but those in high density lipoprotein were not. Bile flow was not changed but biliary secretion of cholesterol, phospholipid and bile acids markedly increased. Among the biliary bile acid components, cholic acid markedly increased but the amount of chenodeoxycholic acid was similar to that of normal rats. Fecal excretion of deoxycholic acid increased but that of lithocholic and hyodeoxycholic acids decreased, and alpha, beta- and omega-muricholic acids did not change, thus, the total amount of fecal bile acids remained unchanged. Hepatic cholesterol synthesis was markedly depressed, while cholesterol 7 alpha-hydroxylase activity did not change and cytochrome P-450 content was elevated by about 40%. From such evidence, it was apparent that synthesis of cholic acid increased while that of chenodeoxycholic acid decreased and the total amount of bile acids synthesized did not change in the diabetic rats. Furthermore, marked increase of the pool size of cholic acid and hepatic secretion of cholic acid stimulated the absorption of lipids and produced a hyperlipidemia in the diabetic rats.     

Lipid-lowering properties of TAK-475, a squalene synthase inhibitor,in vivo and in vitro

1. Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED(50), 2.9 mg kg(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3. In marmosets, TAK-475 (30, 100 mg kg(-1), p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg(-1), p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4. TAK-475 (60 mg kg(-1), p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5. In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of (125)I-low-density lipoprotein (LDL) to LDL receptors. 6. These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.     

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high‐cholesterol‐fed rats. Male Sprague‐Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high‐cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high‐cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine‐treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine‐conjugated bile acids by 61% and decreased glycine‐conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine‐conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α‐hydroxylase (CYP7A1), the rate‐limiting enzyme for bile acid synthesis, by three‐ and two‐fold, respectively. Taurine also decreased the enzymatic activity of acyl‐CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine‐conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.     

Synthesis and Hypolipidemic Activity of 3-Imino-l-oxoisoindolines in Rodents

A series of substituted 3-imino-l-oxoisoindolines derivatives demonstrated significant hypolipidemic activity, lowering both serum cholesterol and triglycerides levels after 16 days of dosing at 20 mg/kg/ day ip in CF₁ mice. 2-Butyl-3-butylimino-l-oxoisoindoline lowered serum cholesterol levels 52% and serum triglyceride 42%. 2-Pentyl-3-imino-l-oxoisoindoline lowered serum cholesterol levels 42% and serum triglyceride 61%. These derivatives resulted in better activity than the parent compound, 3-imino-1-oxoisoindoline. These studies showed that compounds with N-alkyl substitution of nitrogen atoms in the ring and outside the ring possessed potent hypolipidemic activity at the low dose of 20 mg/kg/day ip in normolipidemic CF₁ mice. Studies with 2-butyl-3-butylimino-l-oxoisoinodine in rats showed that serum cholesterol was reduced 60% and serum triglyceride 43% after 14 days of dosing at 20 mg/kg/day, orally. Treatment with this agent lowered lipid levels in the liver and aorta tissue, with increases in lipid levels in the small intestine tissue. Higher levels of cholesterol and phospholipids were excreted in the feces of treated animals compared to the control. Cholesterol levels of the very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) fractions were reduced, whereas the HDL cholesterol levels were elevated significantly. This ratio of low-density lipoprotein (LDL) cholesterol:HDL cholesterol levels suggests that the agent may be effective in treating hyperlipidemic states in humans.     

Effect of medroxyprogesterone acetate on hepatic lipid profile of female rats under various states of nutrition

The effect of medroxyprogesterone acetate (MPA) treatment on hepatic lipid profile was studied in female rats kept on protein-deficient diet, on normal restricted diet and on normal, ad libitum diet. A significant decline in total and free cholesterol levels was observed in rats kept on protein-deficient diet and on normal, restricted diet. However, protein-deficient animals exhibited a significant rise in the liver triglyceride level. In rats on normal, ad libitum diet only, MPA treatment resulted in elevated levels of triglycerides and increased esterification of cholesterol. This was mostly due to increased incorporation of acetate into esterified cholesterol and triglyceride as evident from studies using the labelled precursor. Total phospholipid content was found to be unaffected by MPA in all the groups suggesting that the drug and dietary protein level have no effect on hepatic phospholipid content.     

Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits.

The effects of atorvastatin (3 mg kg(-1)) and simvastatin (3 mg kg(-1)) on hepatic enzyme activities involved in very low density lipoprotein metabolism were studied in coconut oil/cholesterol fed rabbits. Plasma cholesterol and triglyceride levels increased 19 and 4 fold, respectively, after 7 weeks of feeding. Treatment with statins during the last 4 weeks of feeding abolished the progression of hypercholesterolaemia and reduced plasma triglyceride levels. 3-Hydroxy-3-methyl-glutaryl Coenzyme A reductase, acylcoenzyme A:cholesterol acyltransferase, phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities were not affected by drug treatment. Accordingly, hepatic free cholesterol, cholesteryl ester and triglyceride content were not modified. Simvastatin treatment caused an increase (72%) in lipoprotein lipase activity without affecting hepatic lipase activity. Atorvastatin caused a reduction in hepatic phospholipid content and a compensatory increase in CTP:phosphocholine cytidylyl transferase activity. The results presented in this study suggest that, besides the inhibitory effect on 3-hydroxy-3-methyl-glutaryl Coenzyme A reductase, simvastatin and atorvastatin may have additional effects that contribute to their triglyceride-lowering ability.     

Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits

MK-733 was found to prevent an increase of serum cholesterol levels in cholesterol-fed rabbits, and lovastatin also markedly inhibited their increase. MK-733 and lovastatin inhibited the increase of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, and it slightly affected the high density lipoprotein (HDL) cholesterol levels. MK-733 and lovastatin suppressed the increase of serum phospholipid levels and slightly affected the triglyceride levels. MK-733 suppressed the development of atherosclerosis in coronary arteries and aorta, and lovastatin also diminished their development.     

Hypolipidemic and antioxidant effects of mulberry (Morus alba L.) fruit in hyperlipidaemia rats

The phytochemical constituents of a freeze-dried powder of mulberry (Morus alba L.) fruit (MFP) were determined. The hypolipidemic and antioxidant effects of the MFP as a dietary supplement were evaluated in rats who were fed 4 weeks of either a high-fat or a normal diet supplemented with 5% or 10% MFP. Administration of MFP to rats on a high-fat diet resulted in a significant decline in levels of serum and liver triglyceride, total cholesterol, serum low-density lipoprotein cholesterol, and a decrease in the atherogenic index, while the serum high-density lipoprotein cholesterol was significantly increased. In addition, the serum and liver content of thiobarbituric acid related substances, a lipid peroxidation product, significantly decreased, while the superoxide dismutase (SOD) of red blood cell and liver, as well blood glutathione peroxidase (GSH-Px) activities significantly increased. No significant changes in lipid profile in the serum and liver were observed in rats on a normal diet supplemented with MFP, but blood and liver antioxidant status improved, as measured by SOD and GSH-Px activity, and lipid peroxidation was reduced. These beneficial effects of MFP on hyperlipidaemia rats might be attributed to its dietary fiber, fatty acids, phenolics, flavonoids, anthocyanins, vitamins and trace elements content.     

Stroke-prone spontaneously hypertensive rats have reduced hydroxysteroid 17-β dehydrogenase 7 levels for low cholesterol biosynthesis

Reduced serum cholesterol content was recently reported to be one of the factors responsible for cerebral haemorrhage. Stroke-prone spontaneously hypertensive rats (SHRSP) are known to have lower serum cholesterol content than normotensive Wistar-Kyoto rats (WKY). We previously reported that lower levels of mevalonate pyrophosphate decarboxylase (MPD) and squalene epoxidase (SQE), which are associated with cholesterol biosynthesis in the liver, are involved in the low serum cholesterol content in SHRSP. Here, we investigate the levels of sterol 14-demethylase (CYP51), methylsterol monooxygenase (SC4MOL), and hydroxysteroid 17-β dehydrogenase 7 (HSD17B7), which contribute to the cholesterol synthesis pathway in the conversion of lanosterol to zymosterol, in SHRSP and WKY. The HSD17B7 mRNA levels in the liver of SHRSP were markedly lower than those in WKY, whereas no significant differences were observed in CYP51 and SC4MOL levels in the two types of rats. The relative levels of protein, heteronuclear RNA, and mRNA of HSD17B7 were also significantly lower in SHRSP than in WKY. The degradation rates of HSD17B7 were the same in SHRSP and WKY. The protein levels of HSD17B7 were not significantly reduced in tissues other than the liver, including the brain, lung, heart, spleen, kidney, and testis, in SHRSP. Moreover, HSD17B7 activity was significantly lower in SHRSP than in WKY. Thus, our results indicated that low protein levels and activity of HSD17B7 are responsible for the reduced cholesterol content in SHRSP, indicating that HSD17B7, along with MPD and SQE, is involved in the decreased cholesterol synthesis in the liver of SHRSP.     

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor,in animal models of familial hypercholesterolemia

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.     

Hypolipidemic activity of N,N-dimethyl-n-octadecylamine borane in rodents

N,N-Dimethyl-n-octadecylamine borane proved to be an effective hypolipidemic agent in rodents, lowering both serum cholesterol and triglyceride levels by greater than 40% after 16 d of administration. The agent lowered serum lipid levels by inhibiting the enzymatic activity of rate-limiting enzymes of both de novo cholesterol and triglyceride pathways in the liver. The reduction led to lower levels of lipids in the liver and small intestine tissues, with a reduction of the cholesterol and triglyceride levels of the serum low density lipoprotein (LDL) fraction. Concurrently, the cholesterol level of high density lipoproteins (HDL) was significantly elevated in rats after 14 d of treatment. The drug caused an increased rate of cholesterol clearance from the body, essentially via the feces. The ability of the agent to modulate the cholesterol levels of LDL and HDL fractions suggests that the agent should be an effective agent for the treatment of hyperlipidemic states in humans.     

海南狗牙花总生物碱对兔实验性动脉粥样硬化的影响

本文报告海南狗牙花总生物碱(以下称总碱)对实验性动脉粥样硬化兔血清、主动脉和肝脏脂质含量,以及对动脉粥样硬化的影响。总碱能明显降低血清胆固醇(S-Ch)和甘油三酯(S-TG)含量,增加血清高密度脂蛋白胆固醇(HDL-Ch)含量和游离胆固醇(FC)与胆固醇酯(CE)的比值;能使主动脉壁胆固醇含量降低,FC与CE的比值增加,亦能明显减轻动脉粥样硬化的发展。总碱对肝脏脂质含量无明显影响。     

Long-term low-dose treatment with reserpine of cholesterol-fed rabbits reduces cholesterol in plasma,non-high density lipoproteins and arterial walls

The effects of long-term low-dose treatment with reserpine on plasma lipoproteins and arterial cholesterol were determined in cholesterol-fed rabbits. Hepatic low-density lipoprotein (LDL) receptors; uptake of LDL by liver, heart, and kidneys; plasma fibrinogen; blood pressure; and heart rate were also determined. Reserpine at 43 microg/kg. d was continuously infused subcutaneously via implanted minipumps for 6 weeks into conscious unrestrained male New Zealand White rabbits (n = 5) fed a 0.2% cholesterol-enriched diet. Compared with controls, reserpine (n = 4) significantly reduced the elevated levels of plasma total cholesterol and esterified and unesterified cholesterol throughout the study, and at 6 weeks of treatment these reductions were 42, 41, and 49%, respectively. The increased cholesterol in the aortic walls (n = 5) produced by the atherogenic diet was reduced by 73% (p < 0.004) and 125I-tyramine cellobiose-labeled LDL by 67 to 86% (0.05 < p <0.004), respectively. The aortic intimal-medial thickness ratio was reduced by 70%. The decrease in elevated plasma total cholesterol was mainly due to cholesterol reductions in both LDL (41%) and non-high density lipoprotein (HDL) of density < 1.019 g/ml (51%). HDL cholesterol and triglyceride levels were unchanged. Reserpine had no significant effects on the clearance of 125I-tyramine cellobiose-LDL from plasma and there was a trend towards an increase in hepatic LDL receptor expression. Heart rate was decreased by 28%. There were no significant effects on blood pressure, liver and heart lipids, hematocrit, or plasma fibrinogen. The results suggest that treatment of cholesterol-fed rabbits with reserpine at a low dose over a long period prevents increases in plasma atherogenic lipoproteins. Reserpine decreases the cholesterol in aortic walls and the intima-media thickness ratio. This anti-atherosclerotic effect of reserpine may have therapeutic implication.