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Biomedical subjects

R L Gebhard

Publications and source records attributed to R L Gebhard.

At least 19 recordsLinked to original sources
PubMed1997

Oral acetylsalicylic acid induces biliary cholesterol secretion in the rat.

Several agents can alter biliary cholesterol secretion, critical for cholesterol excretion and gallstone formation. Although salicylate effects on bile formation and gallstones have been studied, biliary lipid secretion has not been measured during oral aspirin treatment. We examined whether oral acetylsalicylic acid affects bile lipid secretion. Three groups of young rats were fed chow for 3 wk. Two of the groups then received aspirin at either 1.67 or 3.33 g/kg diet for 4 d. Serum, hepatic, and bile lipids were measured, as were enzymes of cholesterol synthesis and esterification. With oral aspirin, bile cholesterol secretion increased by 42% and hepatic cholesteryl ester content decreased by 40%. Serum cholesterol and hepatic free cholesterol did not change. To evaluate mechanisms of the cholesterol hypersecretion, hypothyroid animals fed low-fat or fish oil diets and repleted with triiodothyronine were also studied. Aspirin stimulated cholesterol secretion to a degree similar to triiodothyronine. An additive response was seen in fish oil-fed rats. Aspirin did not appear to have a primary action on 3-hydroxy-3-methylglutaryl-CoA reductase or acyl CoA:cholesterol acyltransferase activities, and had no direct effect on esterification of cholesterol by isolated hepatocytes. Aspirin may directly increase cholesterol transport into bile or have cell membrane effects which alter cholesterol transport. It remains to be determined whether the observed alterations in bile cholesterol secretion are specific to the rat or also apply to humans.

Administration, Oral↗
PubMed1997

Sclerotherapy for actively bleeding esophageal varices in male alcoholics with cirrhosis. Veterans Affairs Cooperative Variceal Sclerotherapy Group.

BACKGROUND: Male alcoholics hospitalized with actively bleeding esophageal varices were treated with sclerotherapy or sham sclerotherapy and the outcomes during the index hospitalization were compared. METHODS: The 87 patients were a subset of 253 patients enrolled in a prospective, randomized, single-blind, multicenter, controlled trial conducted in 12 VA medical centers. The patients (44 sclerotherapy, 43 sham therapy) were actively bleeding from esophageal varices at either randomization endoscopy (49) or follow-up endoscopy (38). Events and resource use during the index hospitalization were recorded. RESULTS: In 40 (91%) of the sclerotherapy and 26 (60%) of the sham therapy patients, bleeding was stopped during the endoscopy session (p < 0.001). During the hospitalization, 10 (25%) sclerotherapy and 21 (49%) sham therapy patients died (p = 0.04, relative risk 2.17, 95% CI [1.02, 4.61]); 9 sclerotherapy and 22 sham therapy patients rebled (p = 0.005). The median transfusion requirement was higher for sham therapy (8 vs 4 units, p = 0.001), the number of median ICU hours was greater (101 vs 55, p < 0.001), and more patients in this group required shunt surgery (6 vs 0, p = 0.01). CONCLUSION: Sclerotherapy, compared to no sclerotherapy, stops hemorrhage from actively bleeding esophageal varices and reduces use of resources. Sclerotherapy significantly increased hospital survival.

Alcoholism↗
PubMed1996

The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss.

Obese persons are at risk for cholesterol gallstones because their bile is saturated with cholesterol. The risk increases during rapid weight loss by means of certain very-low-calorie diets or gastric bypass surgery. Gallstone risk factors during rapid weight loss include increased bile cholesterol saturation index and gallbladder stasis. Obese subjects were randomized to one of two low-calorie liquid diets for rapid weight loss: a 520-kcal diet with less than 2 g fat/d, and a 900-kcal diet with 30 g fat/d (including one 10-g fat meal to stimulate maximal gallbladder emptying). Bile and blood lipids, saturation index, leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity, and ultrasonographic gallbladder emptying were measured repeatedly during dietary treatment. Both diets produced comparable weight loss of 22%. Bile cholesterol saturation index increased during both diets (26%), but fell to 15% below prediet level after weight loss. Compared with subjects' maximal gallbladder emptying fraction of 66%, the 520-kcal diet provided poor gallbladder emptying (35%), whereas the 10-g fat meal of the 900-kcal diet provided maximal emptying. Gallstones developed in four of six 520-kcal subjects and none of seven 900-kcal subjects (P = .021), an unanticipated difference that resulted in premature study termination for ethical reasons. Blood lipids and HMG CoA reductase activity in mononuclear leukocytes fell at week 8 during both diets, but recovered while weight was still being lost. The findings suggest that gallstone risk during rapid weight loss may be reduced by maintenance of gallbladder emptying with a small amount of dietary fat. Ultimately, weight loss reduced bile cholesterol saturation and improved highdensity lipoprotein (HDL) levels.

Adult↗
PubMed1996

Gallstones in chronic spinal cord injury: is impaired gallbladder emptying a risk factor?

OBJECTIVE: To confirm that spinal cord injured persons are susceptible to gallstones and to evaluate the role of gallbladder stasis as a risk factor. STUDY DESIGN: Twenty-nine subjects with chronic spinal cord injury underwent fasting ultrasonography to determine the incidence of gallstones and to quantitate gallbladder emptying response to a 20g fat liquid meal. Gallbladder emptying fraction was compared to that of healthy subjects studied concurrently. RESULTS: Gallstones or sludge were found in 6 spinal cord injured men, a minimal prevalence of 21%. Four additional subjects had prior cholecystectomy for stones, giving a potential maximal prevalence of 30%. Four of the 6 subjects had gallstone risk factors of diabetes, obesity, and/or family history. Gallbladder stasis was not apparent in chronic spinal cord injured subjects. Only 5 subjects had poor gallbladder emptying, and 4 of them had diabetes and/or obesity. CONCLUSIONS: The study confirms an increased prevalence of gallstones after spinal cord injury. However, gallbladder stasis did not appear to be etiologic, and most gallstones were associated with conventional risk factors. The results do not support a general policy of gallstone screening or prophylactic therapy after spinal cord injury.

Adult↗
PubMed1995

Thyroid hormone is required for dietary fish oil to induce hypersecretion of biliary cholesterol in the rat.

In the rat, both fish oil diet and thyroid hormone replacement are reported to augment bile cholesterol secretion out of proportion to bile flow or secretion of other bile lipids. We sought common mechanisms for these effects and evaluated the role of phospholipid fatty acid composition in the process. Methimazole-treated hypothyroid rats were fed low-fat chow or chow supplemented with 10% corn oil or fish oil, and were studied before and after thyroid hormone treatment. Serum, hepatic, and bile lipids were measured, phospholipid fatty acid composition determined, and hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity assayed. Fish oil diet stimulated cholesterol secretion into bile only after thyroid hormone was given, and this action was synergistic with that of thyroid hormone. Reduced serum cholesterol in fish oil-treated rats was associated with increased biliary cholesterol secretion and diminished hepatic cholesterol content. This suggests that augmented biliary cholesterol secretion may contribute to the fish oil-induced reduction of serum cholesterol. No definite relationship between hepatic or biliary phospholipid fatty acid composition and biliary secretion was apparent, although high bile cholesterol secretion was associated with a low percentage of hepatic and bile phospholipid linoleic acid.

Animals↗
PubMed1992

Gallbladder emptying stimuli in obese and normal-weight subjects.

Gallbladder stasis may be an important factor in the pathogenesis of cholesterol-gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone-free, healthy subjects with normal (22 +/- 1 kg/m2) and high (36 +/- 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 +/- 4.4 ml) and residual volume after maximal emptying (8.4 +/- 2.3 ml) in high-body-mass index subjects were not significantly different from those of normal-body-mass index subjects (20.5 +/- 2.5 ml and 4.2 +/- 1.3 ml, respectively). The percentage of gallbladder emptying (71% +/- 5%) and the rate of gallbladder emptying (-1.9 +/- 0.3 x 10(-2) min-1) in high-body-mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78% +/- 6%) and rate of emptying (-2.3 +/- 0.6 x 10(-2) min-1) in normal-body-mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal-stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose-response relationships to fat are similar in obese and normal-weight individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Thyroid hormone differentially augments biliary sterol secretion in the rat. I. The isolated-perfused liver model.

Thyroid hormone lowers serum cholesterol and alters sterol metabolic processes. This laboratory has previously reported increased biliary lipid secretion as an early effect of triiodothyronine (T3) in the rat. To evaluate whether the bile lipid action of T3 is a primary or secondary effect, the isolated-perfused rat liver model was used. Red blood cells in lipid-free buffer were used to perfuse livers of euthyroid and methimazole-hypothyroid rats, as well as hypothyroid rats given T3 at intervals before perfusion. Bile flow was maintained by taurocholate perfusion. Hypothyroid rats had elevated pre-perfusion serum cholesterol compared to euthyroid (107 +/- 4 vs. 65 +/- 2 mg/dl) and decreased biliary cholesterol (0.016 +/- 0.001 vs. 0.031 +/- 0.004 mumol/g liver/h) secretion. Serum cholesterol decreased to euthyroid levels by 18 h after T3, an effect that was prevented by bile duct ligation. Bile cholesterol secretion doubled by 18 h, and reached levels twice euthyroid by 42 h, while phospholipid secretion doubled to levels just above euthyroid. The fourfold increase in biliary cholesterol secretion occurred with lipid-free perfusion and unchanging bile acid uptake or output. It occurred without a fall in hepatic lipoprotein cholesterol secretion. Blockade of cholesterol synthesis with lovastatin failed to alter T3-augmented bile cholesterol secretion. We conclude that T3 induces biliary cholesterol secretion concomitantly with the fall in serum cholesterol. This augmented biliary secretion did not appear to depend upon lipoprotein uptake, increased bile acid transport, or cholesterol synthesis. It did not occur at the expense of hepatic lipoprotein secretion. Facilitated biliary lipid secretion may be a primary effect of T3.

Animals↗
PubMed1992

Thyroid hormone differentially augments biliary sterol secretion in the rat. II. The chronic bile fistula model.

To further define thyroid hormone effects on bile acid synthesis and biliary lipid secretion, studies were done in chronic bile fistula rats. Euthyroid and methimazole-hypothyroid rats, with and without triiodothyronine (T3) injection, had total bile diversion for timed bile collections. With interrupted enterohepatic circulation, cholesterol absorption is negligible and bile acid secretion equals bile acid synthesis rate. Hypothyroid rats had diminished levels of bile acid synthesis and biliary secretion of cholesterol and phospholipid. Single dose T3 injection produced a 13-fold increase in bile cholesterol secretion and a 3-fold increase in phospholipid secretion, both initiated 12 h after T3. Bile acid synthesis increased by 50%, but the increase did not begin until 24 h after T3. Neither hypothyroidism nor T3 treatment abolished diurnal rhythms of bile acid synthesis and biliary lipid secretion. Inhibition of cholesterol synthesis with lovastatin resulted in a persistent 33% decrease in bile acid synthesis in euthyroid and hypothyroid rats, while bile cholesterol secretion only transiently decreased. Inhibition of cholesterol synthesis did not alter T3-induced bile cholesterol secretion, with a 10-fold increase seen. However, bile acid synthesis was not stimulated by T3 in the presence of lovastatin. We conclude that facilitated bile acid synthesis and biliary cholesterol secretion are early effects of T3 and may account for the hypocholesterolemia of T3. Cholesterol synthesis does not appear to be required for the T3-induced bile cholesterol secretion.

Animals↗
PubMed1991

Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition on human gut mucosa.

Mevalonic acid is an important biochemical intermediate in cholesterol synthesis and other processes involved in cell replication. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the enzyme which catalyzes mevalonic acid synthesis. To determine whether a potent competitive inhibitor of this enzyme, the drug simvastatin, may have an adverse effect on enterocyte cell replication and cholesterol metabolism, small intestinal biopsies from nine hypercholesterolemic subjects were obtained before and during treatment with simvastatin as a lipid-lowering agent. Histologic review of biopsies in a blinded manner detected no change in ratio of villous length to crypt length or in mitotic index which might indicate altered cell replication. Similarly, no significant change in measured activity of HMG-CoA reductase activity was observed. In spite of the high exposure of jejunal mucosal cells to this potent competitive inhibitor of a key enzyme, no adverse effect on growth could be detected.

Anticholesteremic Agents↗
PubMed1991

Effect of probucol on blood cholesterol and basal and lovastatin-induced 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in mice.

The drug probucol is known to reduce levels of blood cholesterol and to have antioxidant effects on lipoproteins that may alter their metabolism. While studying probucol feeding in mice, we observed that the drug lowered total hepatic, but not gut, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase activities during the diurnal cycle. Hepatic fatty acyl:cholesterol acyl transferase activity and cholesterol content were not measurably affected by probucol. Probucol also abolished the induction of HMG CoA reductase activity that resulted from feeding of lovastatin, when activity was measured in microsomes washed free of drugs. These effects are consistent with previous reports that probucol increases fractional clearance of lipoprotein cholesterol by the liver. The findings raise the possibility that some patients with hypercholesterolemia may benefit from combined therapy with lovastatin plus probucol.

Animals↗
PubMed1989

Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension.

The effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, "high-carbohydrate" diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each). Mean pulmonary arterial pressures were lower in the chronically hypoxic rats fed fish oil (19.7 +/- 1.8 mm Hg) than in the rats fed corn oil (25.3 +/- 1.6 mm Hg) or regular diets (27.5 +/- 1.5 mm Hg, P less than 0.05). The fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain. The finding that a fish oil diet can reduce the hemodynamic and morphological sequelae of chronic hypoxia may have therapeutic significance.

Animals↗
PubMed1989

Time course of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothyronine administration: possible linkage of cholesterol synthesis to biliary secretion.

In an effort to define the mechanism by which thyroid hormone increases the synthesis of hepatic cholesterol, we have investigated both in hypophysectomized and methimazole-treated hypothyroid rats the time course of T3 effects on plasma cholesterol concentration, total hepatic cholesterol, the rate of biliary secretion of cholesterol, bile acids, and phospholipids, and the activity and mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme in the hepatic synthesis of cholesterol. A single dose of 200 micrograms T3 was estimated to maintain at least 90% nuclear occupancy for the ensuing 54 h of the experiment. In both preparations the relative rise in biliary secretion of cholesterol exceeded that of other biliary constituents and preceded by 12 h an increase in HMG-CoA reductase enzyme activity and its mRNA. The level of total hepatic cholesterol remained constant throughout the experiment. We interpret these findings to suggest that T3-stimulated cholesterol synthesis is mediated by an antecedent T3-induced rise in biliary cholesterol secretion. We postulate that biliary cholesterol secretion is augmented by an intrahepatic shift of cholesterol and depletion of the hepatic sampling center responsible for the feedback regulation of cholesterol synthesis. The level of HMG CoA reductase mRNA appeared to govern enzyme activity in both preparations, but the ratio of mRNA to hepatic enzyme activity was substantially greater in the methimazole-treated compared with the hyphophysectomized animals.

Animals↗
PubMed1989

Lovastatin treatment inhibits sterol synthesis and induces HMG-CoA reductase activity in mononuclear leukocytes of normal subjects.

The mechanism by which competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decrease serum cholesterol is incompletely understood. The few available data in humans suggest that chronic administration of the competitive inhibitor, lovastatin, decreases serum cholesterol with little or no change in total body sterol synthesis. To further define the effect of lovastatin on cholesterol synthesis in normal subjects, we investigated the effect of a single oral dose of lovastatin and a 4-week treatment period of lovastatin on mononuclear leukocyte (ML) sterol synthesis as a reflection of total body sterol synthesis. In parallel, we measured serum lipid profiles and HMG-CoA reductase activity in ML microsomes that had been washed free of lovastatin. ML sterol synthesis did not significantly decrease (23 +/- 5%, mean +/- SEM) at 3 h after a single 40-mg dose of lovastatin. With a single oral 80-mg dose, ML sterol synthesis decreased by 57 +/- 10% (P less than 0.05) and remained low for the subsequent 6 h. With both doses, total HMG-CoA reductase enzyme activity in microsomes prepared from harvested mononuclear leukocytes was induced 4.8-fold (P less than 0.01) over baseline values. Both the 20-mg bid dose and the 40-mg bid dose of lovastatin administered for a 4-week period decreased serum cholesterol by 25-34%. Lovastatin at 20 mg bid decreased ML sterol synthesis by 23 +/- 6% (P less than 0.02) and increased ML HMG-CoA reductase 3.8 times (P less than 0.001) the baseline values. Twenty four hours after stopping lovastatin, ML sterol synthesis and HMG-CoA reductase enzyme activity had returned to the baseline values. The higher dose of lovastatin (40 mg bid) decreased ML sterol synthesis by 16 +/- 3% (P less than 0.05) and induced HMG-CoA reductase to 53.7 times (P less than 0.01) the baseline value at 4 weeks. Stopping this higher dose effected a rebound in ML sterol synthesis to 140 +/- 11% of baseline (P less than 0.01), while HMG-CoA reductase remained 12.5 times baseline (P less than 0.01) over the next 3 days. No rebound in serum cholesterol was observed. From these data we conclude that in normal subjects lovastatin lowers serum cholesterol with only a modest effect on sterol synthesis. The effect of lovastatin on sterol synthesis in mononuclear leukocytes is tempered by an induction of HMG-CoA reductase enzyme quantity, balancing the enzyme inhibition by lovastatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Inhibition of mammary carcinogenesis in rats by dietary restriction.

Mammary tumors were induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Sprague-Dawley female rats kept under different dietary restrictions. Starting at 40 days of age, 4 groups of rats were either full-fed or fed 25%, 50% or 80% of their daily ration. At 55 days of age DMBA was given by intravenous injection. Rats were continued on the restricted diet until 150 days after carcinogen treatment. Rats on 25% diet lost weight rapidly and the experiment had to be terminated. Rats on the 50% diet maintained a lower body weight throughout the experiment; only 12% developed tumors. Rats on the 80% diet lost weight initially, but at the termination of the experiment, there was no significant difference in body weight between this group and the full-fed controls. Of the rats on 80% diet, 34% developed tumors, compared to 92% tumor incidence in the full-fed controls. Vaginal smears were normal in the animals fed the 80% diet, while some irregularity was observed in the 50% group. Breeding capability in rats on the 80% diet was not affected, since there was no observable difference in the pregnancy rate between these animals and their controls. There was also no difference in plasma level of estrogen between the 80% diet group and the full-fed controls at the time of carcinogen treatment. [3H]Thymidine labelling index was significantly affected by 50% restriction of diet while there was no significant change in the 80% group.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Intestinal HMG-CoA reductase activity is low in hypercholesterolemic patients and is further decreased with lovastatin therapy.

Significant cholesterol synthesis occurs in gut mucosa of animals and humans. However, the role of gut synthesis in hypercholesterolemia and the effect of drugs on this function have not been defined. We obtained jejunal biopsies and bile samples from 21 Type II hypercholesterolemic subjects (mean serum cholesterol = 331 mg/dl) on a low fat diet after an over-night fast. Whole gut mucosal homogenate was assayed for activity of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-determining enzyme of cholesterol synthesis. Mean reductase activity (pmol/mg per min) was 5.5 +/- 1.0 (n = 21) in hypercholesterolemic subjects versus 11.3 +/- 1.0 in 52 normal subjects (P less than 0.01). This is consistent with the hypothesis that the primary defect in these patients is not excessive cholesterol synthesis but decreased low density lipoprotein (LDL) clearance. It implies that high LDL levels down-regulate gut reductase activity. After treatment of 7 patients with lovastatin (40-80 mg/day for at least 6-13 weeks), gut reductase activity decreased from 7.7 +/- 2.6 to 3.6 +/- 0.5 (P less than 0.05), in biopsies obtained 12 hr after the last drug dose. Inhibition of reductase activity by this drug was detected 12 hr after a dose, and the enzyme was not measurably induced during 6-13 weeks of therapy. In keeping with the decrease in serum cholesterol (332----239 mg/dl) and mucosal reductase activity during lovastatin therapy, mean gallbladder bile cholesterol saturation index also decreased (1.045 +/- 0.112 vs. 0.883 +/- 0.109, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Bile↗
PubMed1987

Transport of circulating serum cholesterol by human renal cell carcinoma.

Clear cell renal cancer contains a large quantity of cholesterol ester (300-mg./gm. protein). To determine whether abnormalities in cholesterol transport could account for this sterol accumulation, the uptake, release, and imaging capabilities of intravenously injected 131I-6-iodomethyl-29-norcholesterol, a cholesterol analogue, were studied preoperatively in five patients with clear cell renal cancer. At surgery, samples of the liver, tumor, adrenal, and non-tumor kidney were obtained for analysis. 131I-sterol uptake by the tumor, when normalized for cholesterol content, was less than for adrenal, liver or kidney. In contrast, release of preloaded 131I-sterol from the human tumors was consistently slower than for normal kidney. The reduced release of free cholesterol from renal cancer cells may, in part, be responsible for the accumulation of cholesterol in human renal cancer.

Adosterol↗