Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 199 records · Page 11Linked to original sources

PubMed1987

Protective effect of gamma-linolenic acid on aspirin-induced gastric hemorrhage in rats.

The effects of feeding with gamma-linolenic acid (GLA) in comparison with linoleic acid on aspirin-induced gastric hemorrhage were studied in the rat. Gastric damage was examined macroscopically and histologically. Intragastric administration of 100 mg aspirin daily for 4 weeks produced hemorrhage in 3 of 8 rats receiving a linoleic-acid-enriched diet, but none in 8 rats receiving GLA-enriched diet. The levels of linoleic acid in plasma and liver phospholipids were significantly increased, whereas those of arachidonic acid (AA) were reduced in plasma and liver phospholipids of aspirin-treated animals fed linoleic acid. Similar, more pronounced changes occurred in those animals with hemorrhage. The reduced ratios of arachidonate/linoleate suggest that fatty acid desaturation in these animals was depressed. Treatment with GLA prevented these changes. Our results demonstrated that GLA could protect the gastric mucosa from aspirin-induced damage by bypassing the depressed delta-6-desaturation and thus providing a precursor for the synthesis of AA and prostaglandins.

Animals↗

PubMed1987

Sex differences in n-3 and n-6 fatty acid metabolism in EFA-depleted rats.

We studied the effect of sex on the distribution of long-chain n-3 and n-6 fatty acids in essential fatty acid-deficient rats fed gamma-linolenate (GLA) concentrate and/or eicosapentaenoate and docosahexaenoate-rich fish oil (FO). Male and female weanling rats were rendered essential fatty acid deficient by maintaining them on a fat-free semisynthetic diet for 8 weeks. Thereafter, animals of each sex were separated into three groups (n = 6) and given, for 2 consecutive days by gastric intubation, 4 g/kg body wt per day of GLA concentrate (containing 84% 18:2n-6), n-3 fatty acid-rich FO (containing 18% 20:5n-3 and 52% 22:6n-3), or an equal mixture of the two oil preparations (GLA + FO). The fatty acid distributions in plasma and liver lipids were then examined. GLA treatment increased the levels of C-20 and C-22 n-6 fatty acids in all lipid fractions indicating that GLA was rapidly metabolized. However, the increases in 20:3n-6 were less in females than those in males, while those in 20:4n-6 were greater, suggesting that the conversion of 20:3n-6 to 20:4n-6 was more active in female than in male rats. FO treatment increased the levels of 20:5n-3 and 22:6n-3 and reduced those of 20:4n-6. The increase in n-3 fatty acids was greater in females than that in males and the reduction in 20:4n-6 was smaller. Consequently, the sum of total long-chain EFAs incorporated was greater in females than that in males. The administration of n-3 fatty acids also reduced the ratio of 20:4n-6 to 20:3n-6 in GLA + FO-treated rats indicating that n-3 fatty acids inhibited the activity of delta-5-desaturase. However, this effect was not affected by the sex difference.

Animals↗

PubMed1987

Selective incorporation of n-3 and n-6 fatty acids in essential fatty acid deficient rats in response to short-term oil feeding.

Essential fatty acid deficient male Sprague Dawley rats were fed for 7 days a fat-free semi-synthetic diet supplemented with 10% by weight of different oil supplements. The oil supplement was a mixture of olive, safflower and linseed oils prepared at different proportions so the dietary n-9/n-6/n-3 ratios were approximate 2/1/1, 1/2/1, 1/1/2, and 1/1/1. The fatty acid compositions of plasma and liver lipids were then examined. Our results show polyunsaturated n-6 and n-3 fatty acids were selectively incorporated into plasma and liver phospholipids, and also into plasma cholesteryl esters. A preferential incorporation of n-6 over n-3 fatty acids into plasma cholesteryl esters and phospholipids was also observed.

Animals↗

PubMed1987

Effect of dietary cholesterol on the release of prostacyclin from the mesenteric vascular bed in diabetic rat.

Streptozotocin-induced diabetic female rats and age-matched control rats were fed a regular chow with or without the addition of 1% cholesterol in the diet. The release of 6-keto-PGF1 alpha, a prostacyclin metabolite, from the mesenteric vascular bed was significantly increased in diabetic rats. The production of PGI2 in diabetic rats was significantly reduced whereas that in the control was not affected by cholesterol feeding. The examination of the fatty acid composition of phospholipids from the mesenteric vascular bed indicated that proportions of stearic (18:0), linoleic (18:2n-6) and dihomo-gamma-linolenic (20:3n-6) acids were higher whereas those of oleic (18:1n-9) was lower in diabetic rats than those in the controls. Cholesterol feeding had no significant effect on the levels of arachidonic acid (20:4n-6) in the controls but it significantly decreased those in diabetic rats. It is suggested that cholesterol feeding lowers the release of PGI2 from the mesenteric vascular bed possibly because of a reduced level of arachidonic acid, the major precursor for prostaglandin synthesis. This could be due to an impairment of delta-5 desaturase.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Changes of plasma lipids and long-chain n-3 and n-6 fatty acids in plasma, liver, heart and kidney phospholipids of rats fed variable levels of fish oil with or without cholesterol supplementation.

Diets supplemented with 10% by weight of oil, either wholly safflower oil or proportinally (25, 50, 75 or 100%) replaced by fish oil, were given to 60 rats which had previously been deprived of dietary fat for 6 weeks. Half the animals on each dietary regimen were also given 1% of cholesterol. After 4 weeks of feeding, the plasma lipid contents and the phospholipid fatty acid compositions of plasma, liver, heart and kidney were determined. In general, the concentrations of plasma lipids were significantly reduced in animals fed a diet containing 5% or more of fish oil in comparison with those fed only safflower oil. Cholesterol feeding increased the levels of plasma cholesterol, whereas it lowered those of plasma triacylglycerols and phospholipids. The levels of 20:4(n - 6) in all four tissues were sharply reduced, whereas those of 18:2(n - 6) increased when 25% of dietary safflower oil was replaced by fish oil. Both 18:2(n - 6) and 20:4(n - 6) were decreased as the contents of dietary fish oil were further increased. The levels of long-chain n-3 fatty acids, e.g., 20:5(n - 3), 22:5(n - 3) and 22:6(n - 3) were increased as the intake of fish oil increased. The incorporation of 22:6(n - 3) was greater in plasma, liver and heart phospholipids, whereas that of 20:5(n - 3) was greater in kidney phospholipids. Cholesterol feeding also increased the levels of 18:2(n - 6) and 20:5(n - 3), whereas it decreased the levels of 20:4(n - 6) and 22:6(n - 3) in plasma and liver. However, these changes were not observed in heart and kidney.

Animals↗

PubMed1986

The influence of dietary manipulation with n-3 and n-6 fatty acids on liver and plasma phospholipid fatty acids in rats.

The interrelations between linoleic acid (LA) metabolites and fish oil fatty acids were studied. Sprague-Dawley rats (200-220 g) were fed a fat-free semisynthetic diet supplemented with 10% (by weight) of different combinations of evening primrose oil (EPO), a rich source of LA and gamma-linolenic acid, and polepa (POL), a marine oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. The combinations of supplement were as follows: 9% EPO-1% POL, 8% EPO-2% POL, 7% EPO-3% POL, 6% EPO-4% POL and 5% EPO-5% POL. After two weeks on the respective diets, the animals were killed, and the fatty acid compositions of liver and plasma phospholipids were examined. The results showed that animals fed higher proportions of POL consistently contained higher levels of dihomo-gamma-linolenic acid (DGLA) (p less than 0.05), a metabolite of LA and GLA, and lower levels of arachidonic acid (AA) (p less than 0.01), a metabolite of DGLA through delta-5-desaturation. Thus, an inverse relationship between AA/DGLA ratio and EPA levels was found to exist (r = -0.765 in plasma and -0.792 in liver). However, there was no such relationship between AA/DGLA ratio and DHA levels. This result suggested that EPA but not DHA in fish oil exerts an inhibitory effect on the conversion of DGLA to AA.

Animals↗

PubMed1986

Dietary manipulation of ethanol preference in the Syrian golden hamster.

Male Golden Syrian hamsters, in which ethanol preference was previously established, were fed a basal diet supplemented with essential fatty acid-rich oils (increased weekly from 10-160 g/kg diet), cholesterol (10 g/kg diet) or retinol palmitate (100 or 200 mg/kg diet), each in an independent study. Within 4-5 weeks, all three supplements were associated with significantly decreased ethanol preference. No consistent change in the fatty acid composition of liver or brain was associated with the decrease in ethanol preference but, in ethanol-fed hamsters, each of the supplements was associated with an increase in total cholesterol and the cholesterol/phospholipid ratio in liver. The essential fatty acid-induced reduction in ethanol preference was not associated with a significant change in blood ethanol elimination rate or time.

Alcohol Drinking↗

PubMed1986

Increased release of prostaglandins from the mesenteric vascular bed of diabetic animals: the effects of glucose and insulin.

To study prostaglandin (PG) metabolism in peripheral vascular beds, PGs and TxB2 released from perfused mesenteric tissues were measured in both normal and streptozotocin (STZ)-induced diabetic rats. The release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) was significantly increased in mesenteric vascular beds from diabetics in comparison with control rats. The 6-keto-PGF1 alpha/TxB2 ratio was decreased in diabetics. In order to clarify the mechanism of this imbalanced synthesis of eicosanoids, we infused buffer with 500 mg/dl glucose which was similar to the concentration of blood glucose in the diabetic rats. In response to this high glucose concentration, TxB2 released into the effluent from the mesenteric beds of normal animals was increased to the diabetic level. The release of the other PGs was not changed significantly. The 6-keto-PGF1 alpha/TxB2 ratio was decreased in control rats perfused with buffer containing 500 mg/dl glucose. We also investigated the effect of insulin (50 and 100 microU/ml) in the diabetic mesenteric vascular beds, but there were no changes in prostaglandin or TxB2 release. These data suggest that a high glucose level may have an important role in regulating TxA2 synthesis and in modulating the balance between PGI2 and TxA2 in diabetes. It is postulated that an increase in the micro-circulation of PGI2 may partially be protective against the progression of angiopathy.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Free radicals as possible mediators of the actions of interferon.

Interferons (IFNs), in addition to their antiviral action, have been shown to inhibit cell proliferation, induce differentiation of some tumor cells, activate NK cells and macrophages, and modulate phagocytosis. The exact mechanism(s) by which IFN can bring about these pleiotropic actions is not known. Recent studies, including our own (presented here), showed that IFN can augment free radical generation in the cells. Free radicals can stimulate lymphocytes mitogenically and activate macrophages and NK cells. It is also known that activated machophages and polymorphs produce oxidative metabolites, such as hydrogen peroxide, which is responsible for sterilizing action against microorganisms and cytotoxic activity against tumor cells. Free radicals are also known to inhibit cell division. Since IFN can augment free radical generation, it is suggested that free radicals mediate some of the actions of IFN.

Cell Division↗

PubMed1986

n-3 Essential fatty acids decrease weight gain in genetically obese mice.

1. Lean (ln/ln) and obese (ob/ob) mice were given diets containing a fat source of 100 g evening primrose (Oenothera biennis) oil (fatty acids 18:2n-6, 18:3n-6; EPO) or 100 g cod liver oil (20:5n-3, 22:6n-3; CLO)/kg diet. 2. Weight gain was lower in the ob/ob mice fed on CLO, an effect unrelated to food intake. 3. In the ob/ob mice fed on CLO, thromboxane synthesis by clotting platelets was reduced compared with that in ob/ob mice fed on EPO. 4. The ob/ob CLO-fed mice had lower arachidonic acid but higher levels of n-3 fatty acids in liver, brown adipose tissue and white adipose tissue. 5. The n-3 fatty acids in CLO therefore replaced the n-6 fatty acids in tissue lipids and reduced synthesis of '2 series' prostaglandins in addition to causing lower weight gain in the CLO-fed ob/ob mice.

Animals↗

PubMed1986

Influence of different dietary fatty acid sources on erythrocyte lipids and plasma and liver essential fatty acids in hamsters fed ethanol.

Hamsters fed ethanol were given three different dietary sources of essential fatty acids; safflower oil, evening primrose oil (both mainly n-6 fatty acids) or linseed oil (mainly n-3 fatty acids). After 7 weeks, plasma, erythrocyte and liver lipids and fatty acids were analyzed. Plasma and liver lipids were not significantly different in the ethanol-fed hamsters compared to the controls. Erythrocyte total phospholipid was increased only in the ethanol-fed groups given n-6 but not n-3 fatty acids. Some fatty acid changes induced by ethanol were predictable, e.g. lower 20:4 n-6 in hamsters fed n-6 fatty acids, but others were not predictable, e.g. higher 22:6 n-3 in all the ethanol-fed groups. The effect of ethanol on hamster lipids and fatty acid composition appears dependent on the predominant class of dietary fatty acids.

Alcohol Drinking↗

PubMed1986

Effect of different dietary proteins on plasma and liver fatty acid compositions in growing rats.

Weanling male rats were fed semipurified diets containing 20% protein derived from casein, soy protein, or wheat gluten for 5 weeks. The fat source was 2% safflower oil (containing 79.4% 18:2n-6). In comparison with the casein-fed rats, the growth rate of rats fed plant proteins was slower, particularly that of rats fed the wheat gluten diet. The plasma cholesterol levels were significantly lower in rats fed wheat gluten than in those fed the other dietary protein regimens. The fatty acid compositions of plasma and liver lipids were also examined. The ratios of 16:1/16:0, 18:1/18:0 and 20:4n-6/18:2n-6 in both plasma and liver phospholipids and cholesteryl esters were consistently reduced in animals fed plant protein suggesting a reduced activity of fatty acid desaturation. The reduction of fatty acid desaturation may possibly be attributed to the low lysine/arginine ratio in plant proteins.

Adipose Tissue↗

PubMed1986

Essential fatty acid and prostaglandin metabolism in Sjögren's syndrome, systemic sclerosis and rheumatoid arthritis.

Evidence from biochemical studies and from experimental animals indicates that abnormalities of essential fatty acid (EFA) and eicosanoid metabolism could lead to salivary and lacrimal gland atrophy and to immunological and cardio-vascular defects. Measurements of EFA levels in erythrocytes from patients with primary Sjögren's syndrome have shown that abnormalities are indeed present. Controlled clinical trials of supplementation with gamma-linolenic acid (GLA) as evening primrose oil (Efamol) in both primary Sjögren's syndrome and systemic sclerosis have given positive results. There are strong arguments to indicate that sophisticated manipulation of EFA metabolism may have a role to play, not only in Sjögren's syndrome but also in other rheumatological disorders.

Erythrocyte Membrane↗

PubMed1986

Hydralazine inhibits vascular reactivity by a mechanism independent of vascular prostaglandin biosynthesis: role of thromboxane synthetase in blocking hydralazine actions.

To explore the mechanism of action of hydralazine on vascular reactivity of small vessels we have examined its actions in the isolated perfused mesenteric vascular bed. In buffer perfused preparations hydralazine inhibited responses to nondepolarizing stimuli at concentrations comparable to those achieved in vivo. Inhibition of cyclo-oxygenase activity enhanced hydralazine's action as did inhibition of thromboxane synthetase. Hydralazine stimulated mesenteric vascular bed prostaglandin biosynthesis (6-keto PGF1a and PGE2 determined by radio-immunoassay) and stimulated aorta PG12 synthesis (monitored by platelet bioassay). Extracellular calcium opposed hydralazine's action by a mechanism sensitive to cyclo-oxygenase inhibition. Concentrations of hydralazine substantially greater than those effective in the perfused vascular bed were required to demonstrate inhibition of platelet aggregation and ram seminal vesicles cyclooxygenase activity. These data indicate: Hydralazine acts directly on the smooth muscle to attentuate responses to nondepolarizing stimuli. Hydralazine does not inhibit vascular reactivity by a PG12 dependent mechanism although it stimulates prostaglandin biosynthesis. Reduction of vascular bed prostaglandin and thromboxane A2 biosynthesis enhances hydralazine actions. Hydralazine appears to act at a thromboxane A2 sensitive site however it is not a nonselective prostaglandin antagonist. Hydralazine is effective at concentrations which do not inhibit either platelet aggregation or ram seminal vesicle cyclooxygenase. These data suggest that hydralazine is a potent direct acting vasodilator which stimulates prostaglandin biosynthesis and whose potency may in turn be attenuated by the production of proconstrictory prostaglandins.

Animals↗

PubMed1986

Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids.

The effects of essential fatty acids on cell proliferation and cell viability of 3 human tumor and 4 normal cell lines were tested in vitro. It was found that n-3 and n-6 fatty acids supplemented at 20 micrograms/ml killed human breast, lung, and prostate cancer cells selectively. Normal human fibroblasts and other normal cells were not killed, but their rate of division was lowered. The most selective cytotoxic effects were obtained with fatty acids containing 3, 4, and 5 double bonds. The degree of inhibition of growth and/or loss of viability depended on a given fatty acid, on cell density, on fatty acid concentration, and on the type of cell. When eicosapentaenoate, gammalinolenate, or arachidonate was added to cocultures made of human cancer cells with normal fibroblasts, the cancer cells were selectively eliminated. These results, combined with the observation that certain fatty acids coupled to cytotoxic agents may enhance the cytotoxic activity, suggest that treatment of cancer with polyunsaturated fatty acids containing 3, 4, and 5 double bonds has potential clinical usefulness.

Animals↗

PubMed1985

Effects of dietary saturated, N-6 and N-3 polyunsaturated fats on blood pressure and prostaglandins outflow from perfused mesenteric vascular bed in rats.

Effects of the dietary administration of saturated fat and of n-6 and n-3 polyunsaturates on blood pressure, prostaglandin metabolism in small vessels, tissue fatty acid distribution and urinary PGE2 excretion were compared. Rats were divided into three groups. Diets contained 10% hydrogenated coconut oil (HCO), 10% safflower oil (SFO) or 10% cod liver oil (CLO) added to a basic fat free diet for 10 weeks. Systolic blood pressure was increased in the CLO group animals. Urinary PGE2 excretion was decreased in the HCO and CLO groups as compared to that in the SFO group animals. PGE2, 6-keto-PGF1 alpha and thromboxane (Tx) B2 outflow from isolated perfused mesenteric arterial beds were extremely decreased in the CLO group animals, and to a lesser extent in the HCO group as compared to the SFO animals. In the tissue phospholipid, 20:3n-9/20:4n-6 ratios were increased in the HCO group indicating essential fatty acid deficiency, and n-6 and n-3 polyunsaturates were elevated in the SFO and the CLO group animals respectively. Arachidonic acid concentration was highest in the SFO group, while there was no significant differences between the HCO and the CLO group. These results suggest that dietary fatty acid manipulation affects urinary PGE2 excretion and PGI2, PGE2 and TxA2 synthesis in mesenteric arterial beds and also changes the tissue fatty acid distribution. Furthermore, n-3 polyunsaturates caused an extreme reduction of 2-series PGs synthesis in small resistance vessels.

Animals↗

PubMed1985

Prostaglandins and thromboxane outflow from the perfused mesenteric vascular bed in spontaneously hypertensive rats.

To clarify the metabolism of PGE2, prostacyclin (PGI2) and thromboxane A2 (TxA2) in small vessels in spontaneously hypertensive rats (SHR), we removed superior mesenteric vascular beds from 10 week old SHR and age matched normotensive controls (WKY). The mesenteric artery was perfused with Krebs-Henseleit buffer and samples of effluent collected every 15 minutes during 3 hours perfusion for analysis of PGE2, 6-keto-PGF1 alpha (a stable metabolite of PGI2) and TxB2 (a stable metabolite of TxA2) by specific radioimmunoassays. Levels of all three arachidonic acid (AA) metabolites, PGE2, 6-keto-PGF1 alpha and TxB2, in the mesenteric effluent were significantly reduced in SHR as compared to WKY. TxB2 was detected in all samples throughout the perfusion. 6-keto-PGF1 alpha/PGE2 ratios and TxB2/PGE2 ratios were significantly increased in SHR. 6-keto-PGF1 alpha/TxB2 ratios in the first four samples were significantly decreased in SHR as compared to WKY. These data suggest that there may be reduced availability of PG precusor AA and unbalanced synthesis of PGs in small vessels in SHR. Both may have relevance to the development of hypertension in the animals.

Animals↗

PubMed1985

Plasma essential fatty acids in pure and mixed race American Indians on and off a diet exceptionally rich in salmon.

Eskimos on a traditional diet have unusually low prevalences of cardiovascular disease and cancer. One possible reason is the high intake of eicosapentaenoic acid (EPA) which is thought to account for the high EPA and low arachidonic acid (AA) levels in Eskimo plasma. People who also consume a traditional diet exceptionally rich in EPA are the Indians of the west coast of Vancouver Island. There are about 12,000 of these people and their traditional diet has been affected much less than that of the Eskimos. When on their traditional diet the Vancouver Island Indians, like the Eskimos, have high EPA and low AA levels in plasma. When eating European food, EPA levels are in the European range, but AA levels are still exceptionally low, a finding also reported from Eskimos living in Denmark. In a small mixed race group, AA levels were intermediate between those in pure Indians and in Europeans. The high EPA levels in Eskimos and West Coast Indians are related to diet. The low AA levels, in contrast, are probably genetically determined. Unusual disease patterns in these populations cannot be entirely attributed to diet.

Adult↗