Ethanol-extracted soy protein isolate does not modulate serum cholesterol in golden Syrian hamsters: a model of postmenopausal hypercholesterolemia.

Soy protein consumption has been linked to reduction in hypercholesterolemia, a risk for coronary heart disease. However, to what extent soy protein itself or its non-nutritive components, e.g., isoflavones and saponins, exert this cholesterol-lowering effect requires further investigation. To evaluate the effect of the protein component alone on lipid variables, ethanol-extracted, isoflavone-depleted soy protein isolate (SPe) was studied in ovarian hormone-deficient hamsters. Forty-eight 6-month-old female Golden Syrian hamsters were either sham-operated or ovariectomized and fed casein-based or SPe-based diets for 70 d. Ovariectomy, but not protein source, significantly (P < 0.05) increased serum phospholipids and total, non-high density lipoprotein, free and esterified cholesterol concentrations. Serum HDL cholesterol concentrations were not altered with either treatment. No significant differences were observed in liver total lipids or liver total cholesterol among the groups. Soy protein isolate, however, lowered serum triglyceride concentrations in both sham-operated and ovariectomized hamsters. These findings confirm the ovariectomized hamster as a model of postmenopausal hypercholesterolemia. The results are consistent with earlier observations that isoflavones or other nonprotein components, perhaps in combination with soy protein, play an important role in exerting this hypocholesterolemic effect. Further studies are needed to investigate whether isolated nonprotein components of soy would be able to prevent the ovarian hormone deficiency-associated rise in serum cholesterol regardless of dietary protein source.

Statistical optimization of gastric floating system for oral controlled delivery of calcium.

The development of an optimized gastric floating drug delivery system is described. Statistical experimental design and data analysis using response surface methodology is also illustrated. A central, composite Box-Wilson design for the controlled release of calcium was used with 3 formulation variables: X1 (hydroxypropyl methylcellulose [HPMC] loading), X2 (citric acid loading), and X3 (magnesium stearate loading). Twenty formulations were prepared, and dissolution studies and floating kinetics were performed on these formulations. The dissolution data obtained were then fitted to the Power Law, and floating profiles were analyzed. Diffusion exponents obtained by Power Law were used as targeted response variables, and the constraints were placed on other response variables. All 3 formulation variables were found to be significant for the release properties (P <.05), while only HPMC loading was found to be significant for floating properties. Optimization of the formulations was achieved by applying the constrained optimization. The optimized formulation delivered calcium at the release rate of 40 mg/hr, with predicted n and T50% values at 0.93 and 3.29 hours, respectively. Experimentally, calcium was observed to release from the optimized formulation with n and T50% values of 0.89 (+/- 0.10) and 3.20 (+/- 0.21) hours, which showed an excellent agreement. The quadratic mathematical model developed could be used to further predict formulations with desirable release and floating properties.

High-molecular-weight hydroxypropylmethylcellulose taken with or between meals is hypocholesterolemic in adult men.

Hydroxypropylmethylcellulose (HPMC) is a food gum that shares certain characteristics, such as high viscosity, with soluble fibers. In this trial, the safety and cholesterol-lowering efficacy of HPMC consumed with and between meals was evaluated in free-living male volunteers with mild-to-moderate hypercholesterolemia. After a 14-d baseline period, men (n = 51) with LDL cholesterol between 3.36 and 4.91 mmol/L and triglycerides <3.95 mmol/L were randomly assigned to consume 5.0 g/d HPMC in 240 mL of orange drink, taken either with or between meals, for a 2-wk treatment period. In the Between Meals group, total cholesterol was reduced by 8.0% vs. baseline in wk 1 of treatment (P < 0.05) and 5.1% in wk 2 (P < 0.01). LDL cholesterol concentrations fell by 12.0 and 7.7% (P < 0.01). In the With Meals group, reductions were 9.5 and 8.3% for total cholesterol, and 12.5 and 12.8% for LDL cholesterol (wk 1 and 2, respectively, P < 0.01). In both groups, HDL cholesterol decreased by approximately 5% during wk 1 of treatment (P < 0.01), but the wk 2 concentrations were not significantly different from baseline. There were no significant differences between groups in lipid responses, although there was a trend for a smaller LDL cholesterol-lowering effect during wk 2 of treatment in the Between Meals group (P < 0.06). Gastrointestinal-related adverse experiences (mostly mild) were twice as common among participants who ingested HPMC with meals (P < 0.05). These results suggest that HPMC has a lipid-lowering effect, which may be more consistent when taken with meals.

Review article: alginate-raft formulations in the treatment of heartburn and acid reflux.

Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.

Cholesterol lowering with high-viscosity hydroxypropylmethylcellulose.

Hydroxypropylmethylcellulose (HPMC) is a food gum having several structural and functional properties in common with hypocholesterolemic soluble fibers. The safety and cholestero-lowering efficacy of HPMC, incorporated into a National Cholesterol Education Program Step I diet, was compared with placebo in patients with mild to moderate hypercholesterolemia. After an 8-week National Cholesterol Education Program Step I dietary lead-in phase, 160 patients with low-density lipoprotein (LDL) cholesterol between 130 and 200 mg/dl and triglycerides <300 mg/dl were randomized to placebo, 2.5, 5.0, or 7.5 g/day of HPMC for a 6-week treatment period. Patients returned to the clinic every 2 weeks for lipid measurements and safety assessments. HPMC significantly lowered total, LDL, and non-high-density lipoprotein (HDL) cholesterol. LDL cholesterol concentrations (average of weeks 4 and 6) decreased by 3.0% (4.9 mg/dl), 5.9% (10.3 mg/dl), 12.1% (20.4 mg/dl), and 11.7% (20.3 mg/dl) from baseline levels in the placebo and 2.5, 5.0, and 7.5 g/day HPMC treatment groups, respectively. Statistically significant (p<0.05) reductions in LDL cholesterol were observed in the 5.0 and 7.5 g/day HPMC groups compared with placebo and 2.5 g/day HPMC treatment groups. Total and non-HDL cholesterol responses paralleled those of LDL cholesterol. There were no significant differences between the treatment groups in HDL cholesterol or triglyceride responses, incidence of adverse experiences, or gastrointestinal-related adverse experiences. These results suggest that HPMC is a well-tolerated and effective adjunct to diet for lowering LDL cholesterol in patients with mild to moderate hypercholesterolemia.

Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia.

BACKGROUND: Water-soluble dietary fibers decrease postprandial glucose concentrations and decrease serum cholesterol concentrations. This study examined the effects of administering psyllium to men with type 2 diabetes. OBJECTIVE: The objective was to evaluate the safety and effectiveness of psyllium husk fiber used adjunctively to a traditional diet for diabetes in the treatment of men with type 2 diabetes and mild-to-moderate hypercholesterolemia. DESIGN: After a 2-wk dietary stabilization phase, 34 men with type 2 diabetes and mild-to-moderate hypercholesterolemia were randomly assigned to receive 5.1 g psyllium or cellulose placebo twice daily for 8 wk. Serum lipid and glycemic indexes were evaluated biweekly on an outpatient basis and at weeks 0 and 8 in a metabolic ward. RESULTS: In the metabolic ward, the psyllium group showed significant improvements in glucose and lipid values compared with the placebo group. Serum total and LDL-cholesterol concentrations were 8.9% (P < 0.05) and 13.0% (P = 0.07) lower, respectively, in the psyllium than in the placebo group. All-day and postlunch postprandial glucose concentrations were 11.0% (P < 0.05) and 19.2% (P < 0.01) lower in the psyllium than in the placebo group. Both products were well tolerated, with no serious adverse events related to treatment reported in either group. CONCLUSION: The addition of psyllium to a traditional diet for persons with diabetes is safe, is well tolerated, and improves glycemic and lipid control in men with type 2 diabetes and hypercholesterolemia.

Ovariectomized hamster: a potential model of postmenopausal hypercholesterolemia.

A suitable and economical animal model of ovarian hormone deficiency can greatly enhance the understanding of postmenopausal-elevated risk of coronary heart disease. The male Golden Syrian hamster is a well-established small animal model of hypercholesterolemia, but the effect of ovariectomy on lipid profile in the female hamster is unclear. The objective of this study was to determine whether ovariectomized hamsters develop hypercholesterolemia and experience changes in body fat distribution consistent with changes observed in postmenopausal women. Twenty-two 90-day-old female Golden Syrian hamsters were divided into two groups and were either ovariectomized or sham-operated and given free access to a standard cholesterol-free laboratory diet for 65 days. Ovariectomized hamsters had significantly (P < 0.05) elevated serum total cholesterol concentrations (16.6%) as well as abdominal fat mass (56%; P< 0.01) despite equal food intake compared with the sham-operated group. In contrast, the mean intestinal weight and in vivo rate of sterol biosynthesis were significantly (P < 0.002 and P = 0.01, respectively) lower in the ovariectomized compared with the sham-operated group. In vivo rates of hepatic sterol biosynthesis were directionally lower (P = 0.1) in the ovariectomized group. No significant differences were observed in final body weight, serum triglycerides, or liver total cholesterol and lipids between the two groups. In conclusion, ovariectomized hamsters undergo changes in serum cholesterol and fat distribution similar to those experienced by postmenopausal women, and thus may serve as an appropriate model for postmenopausal hypercholesterolemia.

Psyllium is superior to docusate sodium for treatment of chronic constipation.

BACKGROUND: Stool softening is a physician's first step in the management of chronic constipation. AIM: To compare stool softening (stool water content) and laxative efficacy of psyllium hydrophilic mucilloid vs. docusate sodium. METHODS: The multi-site, randomized, double-blind, parallel-design study of 170 subjects with chronic idiopathic constipation involved a 2-week baseline (placebo) phase followed by 2 weeks of treatment. The treatment phase compared psyllium (5.1 g b.d.) plus docusate placebo to docusate sodium (100 mg b.d.) plus psyllium placebo. Stools were collected and assessed. RESULTS: Compared to baseline, psyllium increased stool water content vs. docusate (psyllium 2.33% vs. docusate 0.01%, P = 0.007). Psyllium also increased stool water weight (psyllium 84.0 g/BM; docusate 71.4 g/BM; P = 0.04), total stool output (psyllium 359.9 g/week: docusate 271.9 g/week; P = 0.005), and O'Brien rank-type score combining objective measures of constipation (psyllium 475.1; docusate 403.9; P = 0.002). Bowel movement (BM) frequency was significantly greater for psyllium (3.5 BM/week) vs. docusate (2.9 BM/week) in treatment week 2 (P = 0.02), with no significant difference (P > 0.05) between treatment groups in treatment week 1 (3.3 vs. 3.1 BM/week). CONCLUSION: Psyllium is superior to docusate sodium for softening stools by increasing stool water content, and has greater overall laxative efficacy in subjects with chronic idiopathic constipation.

Additive hypocholesterolemic effect of psyllium and cholestyramine in the hamster: influence on fecal sterol and bile acid profiles.

Recent findings suggest that the effects of cholestyramine and psyllium in combination could be additive for cholesterol-lowering. We therefore examined the effect of both agents, alone and in combination, on lipoprotein cholesterol and neutral and acidic steroid excretion in the hamster. Animals (n = 8/group) were fed for 21 days, either a basal chow diet supplemented with 10% palm oil and 0.2% cholesterol, or one of four treatments consisting of the basal diet plus: 5.5% cellulose; 5% psyllium with 0.5% cellulose; 0.5% cholestyramine with 5% cellulose; or 5% psyllium with 0.5% cholestyramine. Psyllium and cholestyramine both had significant hypocholesterolemic effects, but in combination produced additive reductions in lipoprotein and hepatic cholesterol. Psyllium, cholestyramine, and the combination increased total bile acid excretion by 26%, 57%, and 79%, respectively. Psyllium affected only unconjugated bile acid excretion while cholestyramine also increased the excretion of conjugated and primary bile acids. Neither agent, nor the combination, affected fecal neutral sterol excretion. We conclude that, while both agents lower cholesterol by a mechanism of increased bile acid excretion, these studies indicate that psyllium does not bind bile acids in vivo and lend further support for the concomitant use of these agents for cholesterol-lowering.

Native and partially hydrolyzed psyllium have comparable effects on cholesterol metabolism in rats.

This study was conducted to determine whether the storage conditions and the levels of psyllium in the diet modulate its hypocholesterolemic effects. Seventy-five male Sprague-Dawley rats, age 90 d, were randomly divided into five treatment groups and were fed cholesterol-containing diets for 21 d. Diets included 10% cellulose (control); 5 or 10% psyllium stored 8 mo at 5 degrees C (PS5); or 5 or 10% psyllium stored 8 mo at 40 degrees C (PS40). The higher storage temperature caused a gradual decrease in molecular weight of the psyllium, as measured by changes in solution viscosity. Hepatic rates of sterol synthesis were significantly (P < 0.001) higher in all of the psyllium-fed rats compared with control rats [21 +/- 2, 312 +/- 35, 464 +/- 40, 328 +/- 49 and 439 +/- 57 nmol [3H]digitonin-precipitable sterol (DPS)/(g liver x h), respectively, for control, 5% PS5, 10% PS5, 5% PS40 and 10% PS40]. A similar trend was observed in intestinal rates of sterol synthesis, and the difference was significant (P < 0.05) for all treatment groups except the 5% PS5-fed group compared with the control group. Liver total cholesterol and total lipid concentrations were significantly lower in all psyllium-fed rats compared with controls. There were no significant differences in serum total cholesterol concentrations among the psyllium-fed groups, although serum cholesterol levels in both the PS5-fed groups were significantly (P < 0.05) lower than that in the control group (2.66 +/- 0.18, 2.62 +/- 0.15 and 3.26 +/- 0.12 mmol/L, respectively, for 5% PS5, 10% PS5 and control). Serum triglyceride and HDL cholesterol concentrations did not vary significantly among groups. The findings of this study indicate that the cholesterol-lowering activity of psyllium is unaltered by storage conditions shown to cause a moderate degree of hydrolysis.

Effect of feeding psyllium and cholestyramine in combination on low density lipoprotein metabolism and fecal bile acid excretion in hamsters with dietary-induced hypercholesterolemia.

We wished to determine the effectiveness of submaximal doses of cholestyramine and psyllium given in combination in reversing dietary-induced hypercholesterolemia in Golden Syrian hamsters, and to investigate the mechanism or mechanisms of action through which these agents together decrease plasma low density lipoprotein cholesterol (LDL-C) levels in this model. For 30 days, male hamsters were fed a cholesterol-rich cereal-based diet containing either a submaximal dose of cholestyramine (1% wt/wt) alone or in combination with psyllium (either 2 or 4%), or a high dose of cholestyramine (3%) alone. Although the greatest cholesterol-reducing action was achieved with 3% resin alone, in the animals fed one third as much cholestyramine combined with psyllium (4%) LDL-C production decreased from 288 +/- 15 to 187 +/- 17 micrograms/h per 100 g body weight, the suppression of LDL-receptor activity was almost fully reversed, plasma LDL-C levels were reduced from 90 +/- 8 to 41 +/- 5 mg/dl, and hepatic cholesterol content decreased from 17.1 +/- 1.9 to 2.4 +/- 0.1 mg/g. In the group that received 1% resin alone, the plasma LDL-C and hepatic cholesterol levels were 60 +/- 3 mg/dl and 7.2 +/- 0.6 mg/g, respectively. As compared with animals that received 1% resin alone, those fed both agents manifested higher rates of fecal bile acid excretion and lower levels of intestinal cholesterol absorption. A significant cholesterol-lowering benefit can be derived from using these nonsystemic agents in combination at lower, more tolerable doses.

Psyllium augments the cholesterol-lowering action of cholestyramine in hamsters by enhancing sterol loss from the liver.

BACKGROUND/AIMS: Psyllium hydrophilic mucilloid is a nonabsorbable soluble fiber that lowers plasma cholesterol levels in several species, including humans. However, its mechanism of action has not been fully elucidated. Therefore, using a hamster model, experiments were performed to determine whether psyllium given alone or in combination with a submaximal dose of cholestyramine blocks intestinal cholesterol absorption. METHODS: The efficiency of cholesterol absorption and concentrations of plasma and hepatic total cholesterol were measured in male hamsters fed a cholesterol-enriched chow diet (0.1%) that contained either avicel (cellulose) (7.5%), surfomer (3%), cholestyramine (1% or 3%), or psyllium (7.5%) as single agents or a fixed level of cholestyramine (1%) combined with variable levels of psyllium (2%, 4%, 6%, or 8%). RESULTS: Psyllium, cholestyramine, and surfomer, when given alone, markedly lowered plasma and hepatic cholesterol concentrations. Surfomer, and cholestyramine at the higher dose (3%), blocked cholesterol absorption by 54% and 75%, respectively, whereas psyllium had no effect. Combining psyllium with a submaximal dose of cholestyramine augmented the cholesterol-lowering action of the resin without effecting any marked change in the level of cholesterol absorption, except at the highest dose used. CONCLUSIONS: Psyllium, given either as a single agent or as an adjunct to treatment with cholestyramine, exerts a significant hypocholesterolemic effect by enhancing net negative sterol balance across the liver.

Effects of psyllium hydrophilic mucilloid on LDL-cholesterol and bile acid synthesis in hypercholesterolemic men.

The goal of the current study was to determine the mechanism of the hypocholesterolemic effect of psyllium using a randomized, double-blind, crossover design. Twenty males (age 44 +/- 4 yr, weight 79 +/- 10 kg) with moderate hypercholesterolemia (total 265 +/- 17 mg/dl, low density lipoprotein (LDL) 184 +/- 15 mg/dl) were studied at baseline (B) and after randomization to receive a 40-day course of 15 g/day of either psyllium (Ps) or placebo (Pl) (cellulose). After a washout period (11 +/- 2 days), subjects were crossed over to the other fiber treatment for an additional 40 days and restudied. Intestinal cholesterol absorption, cholesterol synthesis in isolated peripheral blood mononuclear cells, bile acid kinetics, gallbladder motility, and intestinal transit were measured at each study period. Psyllium lowered LDL cholesterol (x:184 (B), 169 (Ps), and 179 (Pl) mg/dl; Ps vs. B,Pl: P less than 0.004, P less than 0.02), decreased relative cholesterol absorption (x:51 (B), 45 (Ps), and 49 (Pl) %; Ps vs. B,Pl: P less than 0.03, P less than 0.03), did not alter absolute cholesterol absorption, and increased the fractional turnover of both chenodeoxycholic acid (x:0.176 (B), 0.203 (Ps), and 0.170 (Pl) day-1; Ps vs. B,Pl: P less than 0.0001, P less than 0.01) and cholic acid (x:0.303 (B), 0.411 (Ps), and 0.301 (Pl) d-1; Ps vs. B, Pl: P less than 0.006, P less than 0.002). Bile acid synthesis increased in subjects whose LDL cholesterol was lowered by more than 10% (Ps vs. B: 1304 +/- 489 vs 992 +/- 307 mumol/day, P less than 0.006; Ps vs. PI: 1304 +/- 489 vs. 914 +/- 321 mumol/day, P less than 0.0002). We conclude that psyllium lowers LDL cholesterol primarily via stimulation of bile acid synthesis.

Cholesterol-lowering action of psyllium mucilloid in the hamster: sites and possible mechanisms of action.

These studies were undertaken to examine and compare the metabolic effects of psyllium mucilloid and two other nonabsorbable polymers (cholestyramine and surfomer) on sterol metabolism in the hamster. These three agents all significantly lowered the plasma total cholesterol concentration and the level of cholesterol carried in low-density lipoproteins (LDL). Rates of cholesterol synthesis were markedly increased in the livers of the psyllium-fed animals, but not in other tissues. In contrast, cholestyramine and surfomer feeding increased both hepatic and intestinal sterol synthesis. When cholesterol and saturated triacylglycerols were added to the diet, psyllium feeding essentially completely blocked the increase in the plasma cholesterol concentration and hepatic cholesterol content and the suppression of cholesterol synthesis. The pool of bile acid in the small intestine was increased from the control value (17.9 mumol/animal) by both psyllium (23.0 mumol) and cholestyramine (21.9 mumol) feeding. However, this pool was readily absorbed and secreted into the bile in the psyllium-fed animals (27.9 mumol/4 h), but not in the cholestyramine-treated hamsters (13.0 mumol/4 h). This was consistent with the further observation that there was no binding of bile acid by psyllium under in vitro conditions. Thus, these findings indicate that all three polymers lower plasma cholesterol concentrations by inducing a net negative cholesterol balance across the liver. With psyllium, this effect is presumably articulated through a reduction in cholesterol absorption, as well as an increase in the rate of degradation of cholesterol to bile acids.

Effects of dietary cholesterol and fasting on hamster plasma lipoprotein lipids.

Hamsters are commonly utilized for comparative study of cholesterol metabolism. The present study was conducted to assess the effects of fasting on the plasma lipoprotein cholesterol concentrations of hamsters. Over a period of 3 weeks, adult male Golden Syrian hamsters (n = 32) were fed chow with or without the addition of 2 g/kg cholesterol. Half of the animals consuming each diet were fasted for 18 hours prior to blood sampling. Comparison of diets showed the following increases in those animals receiving cholesterol: total plasma cholesterol (180%) and triacylglycerols (75%), high density (75%), low density (250%), and very low density (560%) lipoprotein cholesterol. Compared with fasted animals, total plasma triacylglycerols were higher in both non-fasted diet groups. Compared with fasted hamsters that had received cholesterol, total plasma cholesterol (mean +/- SE mmol/l) was greater (6.36 +/- 0.18 vs 5.43 +/- 0.21; p less than or equal to 0.05) in the non-fasted group, due primarily to higher VLDL cholesterol (2.07 +/- 0.18 vs 1.58 +/- 0.18; p less than or equal to 0.05). There were no differences in HDL cholesterol (2.07 +/- 0.05 vs 2.17 +/- 0.08) or LDL cholesterol (1.29 +/- 0.08 vs 1.37 +/- 0.05) between fasted and non-fasted hamsters fed cholesterol. Fasting is not necessary for the study of the plasma HDL cholesterol and LDL cholesterol of hamsters fed cholesterol.

Enrichment of apolipoprotein B-48 in the LDL density class following in vivo inhibition of hepatic lipase.

In order to explore the in vivo function of hepatic lipase, rats were injected with goat anti-rat hepatic lipase serum which produced a complete and specific inhibition of heparin-releasable hepatic lipase. In the fasting rats, protein, phospholipid and free cholesterol expressed as either mass or percent weight increased significantly in low-density lipoprotein (LDL) and high-density lipoprotein 2 (HDL-2) fractions. These three constituents were not affected in the VLDL and HDL-3 lipoproteins. In the fat-loaded (1 ml corn oil) rat, 6 h post inhibition of hepatic lipase triacylglycerol, phospholipid and free cholesterol concentrations in the d less than 1.006 fraction were 2.5-fold higher in the inhibited animals than in the control rats. The composition of the d less than 1.006 fraction was also affected. Expressed as percent mass, protein was lower (5.2 +/- 1.2 vs. 10.3 +/- 1.5, P less than 0.001) as was cholesteryl ester (1.7 +/- 0.7 vs. 2.6 +/- 0.4, P less than 0.01); triacylglycerol was elevated (77.2 +/- 4.0 vs. 72.6 +/- 2.4, P less than 0.025), as was free cholesterol (3.0 +/- 0.6 vs. 2.4 +/- 0.2, P less than 0.025). Overall, inhibition lowered the ratio of surface-to-core constituents suggesting a larger mean particle diameter. SDS-polyacrylamide gel electrophoresis showed the intermediate- and low-density lipoprotein from treated rats to be significantly enriched in apolipoprotein B-48. In the LDL fraction, apolipoprotein B-48 accounted for 62 +/- 14% of the total apolipoprotein B in the inhibited rats, vs. 12 +/- 2% in the control rats. The above results support the previously described in vivo function of hepatic lipase as a phospholipase. In addition, the results demonstrate a role of hepatic lipase in the catabolism of chylomicrons. Since removal of apolipoprotein B-48-containing lipoproteins is dependent upon apolipoprotein E, their appearance in the LDL fraction implies a masking of apolipoprotein E-binding determinants.

Hepatic blood flow in phenobarbital-pretreated rats during halothane anesthesia and hypoxia.

Centrilobular liver necrosis results when halothane is administered to rats pretreated with phenobarbital. Using radioactive microspheres in Wistar rats weighing 300 to 360 g each, the authors determined cardiac output and hepatic arterial and portal blood flows in normoxic (FlO2 = 0.20) unanesthetized animals pretreated with phenobarbital and in similarly pretreated animals that received halothane with adequate oxygen (FlO2 = 0.50) and while hypoxic (FlO2 = 0.08 to 0.10). Cardiac output averaged 122 +/- 8 ml/min (mean +/- SEM) in unanesthetized normoxic rats and 119 +/- 23 ml/min in unanesthetized hypoxic rats. When halothane, 0.6% in 50% oxygen, was administered cardiac output decreased significantly to 89 +/- 8 ml/min and when halothane was administered during hypoxia cardiac output was decreased further to 80 +/- 11 ml/min. During hypoxia without halothane portal venous blood flow decreased significantly but the percentages of cardiac output delivered to the hepatic artery and portal vein were not significantly different from the normoxic awake animals. When halothane was administered with adequate oxygen the percentage of the cardiac output delivered to the hepatic artery significantly increased but there was no change in absolute blood flow to either the hepatic artery or portal vein. When hypoxic animals received halothane the percentage of the cardiac output delivered to the hepatic artery and portal vein was unchanged but the absolute blood flows to the hepatic artery and portal vein decreased significantly. It is concluded that halothane combined with hypoxia is associated with changes in hepatic blood flow but that these changes are similar to changes caused by hypoxia alone. It is unlikely that hemodynamic factors account for the liver injury seen after halothane and hypoxia in phenobarbital-treated rats.