Many clinical studies are being carried out to see if enrichment of the Western diet with w-3 fatty acids found in fish oil will prevent the development of atherosclerosis and its complications. This notion is based on the epidemiologic suggestion that populations with a high dietary intake of such fatty acids (eg. Eskimos and coastal Japanese) have a low incidence of stroke and myocardial infarction. These data are amplified by the finding that Eskimos and volunteers who consume fish oil develop prolonged bleeding times and apparently altered platelet function ex vivo, since recent evidence strongly suggests a role for chronic platelet activation and endothelial damage in the development of atherosclerosis. Very few studies have been performed on the effects of fish oil (or eicosapentaenoic acid, EPA) supplementation on indices of platelet-vascular interactions which accurately reflect alterations in prostanoid metabolism in vivo, or which assess the effects of increased dietary EPA on the many pathways of arachidonic acid (AA) metabolism in intact animals or man. Since EPA supplementation probably will have different effects on antagonistic AA metabolic pathways (eg. proaggregatory) thromboxane vs antiaggregatory prostacyclin) the net biologic result of altering the prostaglandin precursor pool by dietary means is unpredictable. We propose to assess the effects of feeding w-3 fatty acids on in vivo production of AA and EPA derived prostanoids by measuring the excretion of urinary metabolites with state-of-the-art methods during fish oil feeding as well as to study alterations in leukotriene and hydroxy fatty acid metabolism induced in human cells by such feeding. After establishing the biochemical changes which take place in normal volunteers and asymptomatic atherosclerotics, we will attempt to assess changes in biologic function by investigating whether EPA supplementation lowers blood pressure in atherosclerotics with mild untreated hypertension and whether EPA influences the early or late phase bronchial responses after allergen challenge in allergic asthmatics. During these studies newly developed capillary column GC/negative ion chemical ionization MS methods will be employed to assess changes in the types and amounts of cyclo and lipoxygenase products released in vivo and by cells isolated from volunteers after EPA feeding. By clarifying the clinical pharmacology of w-3 fatty acids in man in regards to both the cyclo and lipoxygenase pathways, a rational basis for clinical applications can be developed, allowing well-designed clinical studies to assess their potential in modifying the cause of human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035380-03
Application #
3349210
Study Section
Nutrition Study Section (NTN)
Project Start
1985-12-01
Project End
1988-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
van Sorge, Nina M; Cole, Jason N; Kuipers, Kirsten et al. (2014) The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe 15:729-740
Knapp, H R; Murray, J J (1994) Leukotrienes as mediators of nasal inflammation. Adv Prostaglandin Thromboxane Leukot Res 22:279-88
Knapp, H R; Sladek, K; Fitzgerald, G A (1992) Increased excretion of leukotriene E4 during aspirin-induced asthma. J Lab Clin Med 119:48-51
Knapp, H R (1991) Hypotensive effects of omega 3 fatty acids: mechanistic aspects. World Rev Nutr Diet 66:313-28
Greene, H L; Swift, L L; Knapp, H R (1991) Hyperlipidemia and fatty acid composition in patients treated for type IA glycogen storage disease. J Pediatr 119:398-403
Braden, G A; Knapp, H R; FitzGerald, G A (1991) Suppression of eicosanoid biosynthesis during coronary angioplasty by fish oil and aspirin. Circulation 84:679-85
Knapp, H R; Miller, A J; Lawson, J A (1991) Urinary excretion of diols derived from eicosapentaenoic acid during n-3 fatty acid ingestion by man. Prostaglandins 42:47-54
Knapp, H R (1990) Polyunsaturates, endogenous eicosanoids, and cardiovascular disease. J Am Coll Nutr 9:344-51
Knapp, H R (1990) Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 323:1745-8
Knapp, H R (1990) Prostaglandins in human semen during fish oil ingestion: evidence for in vivo cyclooxygenase inhibition and appearance of novel trienoic compounds. Prostaglandins 39:407-23

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