gamma-linolenic-acid and Thrombosis

Celecoxib, a selective cyclooxygenase-2 inhibitor, produces thrombotic events in patients predisposed to cardiovascular risk factors. One theory reported an increase in endothelial expression of tissue factor (TF) as a predisposing factor. This work explored the effect of evening primrose oil (EPO), a source of prostaglandin E1, and forskolin (a cyclic adenosine monophosphate stimulator) against the prothrombotic effect of celecoxib in mice. Lipopolysaccharide mouse model of endotoxemia was used to induce an upregulation of TF activity. Male mice received celecoxib (25 mg/kg), celecoxib plus EPO, or celecoxib plus forskolin for 4 weeks and then subjected to a prothrombotic challenge in the form of an intraperitoneal injection of lipopolysaccharide. Results showed an increase in plasma TF activity, endothelial TF expression, and thrombin-antithrombin (TAT) but lower antithrombin III (ATIII) level in mice that received celecoxib in comparison to those that received the vehicle. Adding EPO or forskolin to celecoxib regimen significantly decreased the prothrombotic effect of celecoxib. A positive correlation (r = 0.8501) was found between TF activity and TAT. Co-administration of EPO or forskolin decreased the activity of TF and mitigated the prothrombotic effect of celecoxib. Therefore, these combinations may have the utility to abrogate the prothrombotic adverse effect of celecoxib in clinical setting.

Topics: Animals; Antithrombin III; Blood Coagulation; Celecoxib; Colforsin; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Endotoxemia; Fibrinolytic Agents; gamma-Linolenic Acid; Linoleic Acids; Lipopolysaccharides; Lung; Male; Mice; Oenothera biennis; Peptide Hydrolases; Plant Oils; Thromboplastin; Thrombosis; Up-Regulation

Experimental data raised the specter of increased cardiovascular risk with selective cyclooxygenase-2 inhibitors. The study aimed to investigate the cardiovascular risk caused by celecoxib by studying its effect on blood pressure (BP) and thrombogenesis in rats. We tested the possible protective effects of evening primrose oil (EPO) or ω-3 polyunsaturated fatty acids (n-3 PUFAs). Male Wistar rats were assigned to the following groups: vehicle, celecoxib, celecoxib/n-3 PUFAs, celecoxib/EPO, n-3 PUFAs, and EPO. The rats were treated with celecoxib (20 mg·kg(-1)·d(-1)) by gastric gavage for 6 weeks. The mean BP was recorded, and blood samples were collected for testing prothrombin time and activated partial thromboplastin time. Platelet aggregation assay and collagen-induced platelet consumption test were used as models of thrombogenesis. Celecoxib increased the BP without affecting coagulation parameters and accelerated thrombogenesis by increasing platelet aggregation and collagen-induced thrombocytopenia. EPO and n-3 PUFAs decreased the celecoxib-induced elevation in BP. Although EPO significantly decreased platelet aggregation and collagen-induced thrombocytopenia, n-3 PUFAs did not. Celecoxib elevated BP and increased the risk of thrombogenesis in rats. A combination of celecoxib and the selected natural supplements is suggested as a novel approach to minimize cardiovascular risk caused by celecoxib.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Celecoxib; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; gamma-Linolenic Acid; Linoleic Acids; Male; Oenothera biennis; Plant Oils; Pyrazoles; Random Allocation; Rats; Rats, Wistar; Risk Factors; Sulfonamides; Thrombosis; Treatment Outcome

The dietary intake of saturated fatty acids affects arteriosclerosis. We studied the effect of supplementation (15% wt/wt) of a hyperlipemic diet (1.3% cholesterol) with evening primrose oil (Oenothera biennis) in four groups of 10 rabbits each. After 6 weeks the aortic endothelium was analyzed morphologically with scanning electron microscopy, and the arterial wall was studied with morphometric techniques and cell nucleus counts. Endothelial functioning was analyzed by measuring prostacyclin synthesis, and thrombogenicity of the subendothelium was studied by perfusion in a Baumgartner annular chamber. Evening primrose oil reduced hypercholesterolemia (from 29 +/- 3 to 12 +/- 2 nmol/l), increased HDL-cholesterol (from 0.5 +/- 0.06 to 0.8 +/- 0.09 nmol/l) and doubled prostacyclin synthesis (from 2.7 +/- 2 to 6.2 +/- 0.7 ng/mg aorta) in rabbits on the hyperlipemic diet, reduced subendothelial surface occupied by platelets (from 6.9 +/- 0.4 to 4.8 +/- 0.3%), and reduced human platelet adhesion on the subendothelium (from 53.3 +/- 6% to 38 +/- 8%, respect to total occupation). Morphological analyses showed that evening primrose oil diminished endothelial lesions caused by the atherogenic diet, reducing area of the arterial wall (from 6.9 +/- 0.2 to 4.7 +/- 0.2 microm2 x 10(6)) and the degree of neointimal proliferation (from 0.6 +/- 0.02 to 0.4 +/- 0.09 microm2 x 10(6)). We conclude that in our experimental model, this dietary supplement enhanced the antithrombotic capacity of the endothelium, reduced subendothelial thrombogenicity, and diminished the extent of vascular wall lesions caused by the hyperlipemic diet.

Topics: Animals; Diet, Atherogenic; Dietary Supplements; Fatty Acids, Essential; Fibrinolytic Agents; gamma-Linolenic Acid; Humans; Hyperlipidemias; Hypolipidemic Agents; Linoleic Acids; Oenothera biennis; Plant Oils; Rabbits; Thrombosis

Evening primrose oil (Oenothera biennis) is a rich source of omega-6 series fatty acids. We report here the effects of dietary supplementation with evening primrose oil (EPO) on platelet aggregation as the main factor in arterial thrombus formation in an experimental model of atherogenesis in rabbits. A total of 40 male white New Zealand rabbits were divided into four groups (n = 10 animals/group): 1: normal diet, 2: atherogenic diet (ATD), 3: normal diet enriched with 15% EPO, 4: ATD + EPO. Each group was kept on the diet for 6 weeks. We determined serum lipid profile, platelet aggregation in whole blood, platelet thromboxane B2 production and platelet lipid peroxides. The atherogenic diet increased platelet aggregation (135% when ADP was used, and 185% when collagen was used as the inducer). Evening primrose oil reduced hyperaggregation to the values obtained in rabbits fed with the normal diet. Thromboxane synthesis was increased from 0.18 to 2.28 nmol/10(9) platelets); EPO reduced this value to 1.38 nmol/10(9) platelets. Lipid peroxides were increased by ATD from 0.27 to 0.81 nmol/10(8) platelets; EPO prevented this increase (0.35 nmol/10(8) platelets). In conclusion, EPO reduced platelet hyperaggregability in rabbits fed an atherogenic diet.

Topics: Animals; Arteriosclerosis; Diet, Atherogenic; Fatty Acids, Essential; gamma-Linolenic Acid; Linoleic Acids; Male; Oenothera biennis; Plant Oils; Platelet Aggregation; Rabbits; Thrombosis

Diet including mold oil from a lipid accumulative fungus, containing gamma-linolenic acid, showed an inhibitory effect on thrombus formation in the microvessels of rats by the light/dye method of the authors. Male Wistar rats were fed for 3 to 4 weeks with two series of experimental diets and were examined for thrombus formation. The thrombus formation times to totally occlude, ts, were 347 sec for (mold + soybean)-oil and 236 sec for (palm + soybean)-oil in the first series of diets and 1288 sec for mold oil, 538 sec for olive oil and 575 sec for safflower oil in the second series of diets. Fatty acid composition of plasma, erythrocyte and liver lipids showed an increase in arachidonate content with the diet including the mold oil. Higher arachidonate content seem favorable in inhibiting thrombus formation with increasing PGI2 formation. In terms of the level of lipid hydroperoxides, indicated as a desaturation index of constituent fatty acids, the higher desaturation index with safflower oil gave shorter ts, which suggested some oxygen derived free radicals from polyunsaturated fatty acids were involved in the mechanism of thrombogenesis study by this method.

Topics: Animals; Blood Pressure; Dietary Fats; Fluorescein; Fluoresceins; Free Radicals; Fungi; gamma-Linolenic Acid; Light; Linolenic Acids; Lipid Peroxidation; Male; Mesenteric Vascular Occlusion; Plant Oils; Rats; Rats, Inbred Strains; Thrombosis; Weight Gain