PubMed Health⌕ Search

Biomedical subjects

H R Knapp

Publications and source records attributed to H R Knapp.

At least 37 records · Page 2Linked to original sources
PubMed1993

14,15-Epoxyeicosatrienoic acid metabolism in endothelial cells.

Epoxyeicosatrienoic acid (EET) metabolism was studied in endothelial cells to determine whether this tissue may influence their vasoactive properties. Porcine aortic endothelial cells rapidly took up all four EET regioisomers. The uptake of [1-14C]14,15-EET reached a maximum in 15-30 min, and saturation was not observed with concentrations up to 5 microM. More than 70% of the incorporated 14,15-EET was contained in choline and inositol glycerophospholipids, most of it in the form of an EET ester. A metabolite, 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), accumulated in the medium during incubation, and products with similar chromatographic properties also were formed from 5,6-, 8,9-, and 11,12-EET. Much of the 14,15-EET taken up was only temporarily retained by the cells, and in 2 h half was released into the medium as 14,15-DHET. Bovine aortic and human umbilical vein endothelial cells also took up 14,15-EET, incorporated it into choline glycerophospholipids, and converted it to 14,15-DHET. These findings suggest that the endothelium may limit the vascular actions of EETs through rapid uptake, hydration, and release of DHETs into the circulation. Some vasoactive effects of EETs may result from their temporary accumulation in endothelial phospholipids involved in stimulus-response coupling.

8,11,14-Eicosatrienoic Acid↗
PubMed1992

Increased excretion of leukotriene E4 during aspirin-induced asthma.

The etiology of aspirin-sensitive asthma is unknown, but a plausible hypothesis is that the inhibitory effect of aspirin on the cyclooxygenase enzyme increases formation of bronchoconstrictor leukotrienes via "shunting" of unmetabolized arachidonic acid into metabolism by the 5-lipoxygenase enzyme. The severity and rapidity of bronchospasm that is induced by cyclooxygenase-inhibiting drugs in aspirin-sensitive asthmatics is directly related to the dose and to the potency of the drug to inhibit the cyclooxygenase enzyme. Since increased leukotriene synthesis has recently been shown to occur during allergen-induced asthma, we have examined whether altered leukotriene synthesis correlates with the degree of either cyclooxygenase inhibition or bronchospasm during asthma that is induced by doses of aspirin that range from 30 to 365 mg in individual patients. Excretion of leukotriene E4 was increased by a mean of 361% +/- 76% (p less than 0.05) during aspirin-induced asthma episodes, but the degree of increase for individual patients did not correlate with the degree of bronchospasm or inhibition of platelet thromboxane B2 formation. Thus although the endogenous synthesis of potent bronchoconstrictor leukotrienes increases during aspirin-induced bronchospasm, it appears unlikely that a direct "shunting" of unmetabolized arachidonate into leukotriene synthesis represents the mechanism of aspirin-induced asthma.

Aspirin↗
PubMed1991

Urinary excretion of diols derived from eicosapentaenoic acid during n-3 fatty acid ingestion by man.

Epoxides and fatty acid diols derived from arachidonate by the action of cytochrome P-450 appear in human urine and have biological activities. Dietary eicosapentaenoic acid gives rise to prostaglandins in vivo, but vascular effects of n-3 supplements do not all correlate with altered types or amounts of in vivo cyclooxygenase products. We investigated whether dietary eicosapentaenoic acid could also be metabolized by cytochrome P-450, by assessing the excretion of its vicinal diols. Utilizing gas chromatography/negative chemical ionization mass spectrometry, we have found that humans ingesting n-3 fatty acids excrete vicinal diols of eicosapentaenoic acid in substantial quantities.

Chromatography, Gas↗
PubMed1991

Hyperlipidemia and fatty acid composition in patients treated for type IA glycogen storage disease.

Because glycogen storage disease type IA (GSD-IA) is characterized by recurrent episodes of hypoglycemia that promote a marked elevation in blood triglyceride levels, we evaluated plasma lipid levels in 12 patients with GSD-IA on a regular basis. Six of the 12 patients had plasma fatty acid composition measured; because of possible essential fatty acid deficiency, urinary prostaglandin excretion was also measured. All patients had triglyceride levels between 1440 and 6120 mg/dl (16.25 to 69.09 mmol/L) before treatment. After treatment to promote blood glucose levels of 75 to 85 mg/dl (4.2 to 4.7 mmol/L), triglyceride levels in each of 11 patients were between 189 +/- 31 (2.13 +/- 0.35 mmol/L) and 510 +/- 60 mg/dl (5.76 +/- 0.68 mmol/L). The lipoprotein fatty acid composition in six patients showed a substantial elevation in C16:0, C16:1 omega 7, and C18:1 omega 9, but no increase in C20:3 omega 9 (the fatty acid that characteristically increases in essential fatty acid deficiency). In addition, each of the six patients had normal 24-hour urinary excretion of prostaglandin. One patient, whose triglyceride levels remained elevated despite dietary treatment, was given either clofibrate, lovastatin, niacin, or fish oil. With the exception of lovastatin, these agents produced a decrease in triglyceride values for 1 to 2 months; however, by 3 months triglycerides reached pretreatment levels. Combined treatment with clofibrate and niacin resulted in a sustained decrease in plasma triglyceride levels for 4 months. The findings indicate that dietary management of GSD-IA is usually associated with improvements in triglyceride levels; however, patients maintain triglyceride values between 300 and 500 mg/dl (3.38 to 5.65 mmol/L). No patient had biochemical evidence of essential fatty acid deficiency.

Adolescent↗
PubMed1991

Suppression of eicosanoid biosynthesis during coronary angioplasty by fish oil and aspirin.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is an acute, localized stimulus to platelet and vascular function. Periprocedural cardiovascular complications are reduced by moderate-dose aspirin (ASA), presumably due to inhibition of thromboxane (TX) A2. METHODS AND RESULTS: Excretion of TXA2 and prostacyclin (PGI2) metabolites in urine increased during PTCA. Pretreatment for 3 days with either moderate- (325 mg/day) or low-dose (80 mg/day) ASA inhibited the increase in both eicosanoids. Pretreatment for 3 weeks with fish oil (10 g/day) only partially suppressed TXA2. Formation of trienoic eicosanoids and accumulation of omega-3 fatty acids in platelet membranes confirmed fish oil ingestion. Although basal PGI2 was not inhibited, the PTCA-related increment was suppressed. CONCLUSIONS: PTCA results in an acute, transient alteration of eicosanoid biosynthesis consistent with accelerated platelet-vascular interactions. Pretreatment for 3 days with moderate or low doses of ASA suppresses TXA to a similar extent during PTCA, and their effects on acute cardiovascular complications of this procedure are likely to be comparable. It is unlikely that even prolonged pretreatment with fish oil can substitute for the platelet inhibitory action of ASA during PTCA. Suppression of PGI2 may contribute to the residual acute periprocedural complication rate in patients taking ASA.

Angioplasty, Balloon, Coronary↗
PubMed1990

Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor.

BACKGROUND AND METHODS: The clinical importance of leukotrienes in human allergy has not been defined, in part because there have been no selective 5-lipoxygenase inhibitors that have been effective and safe for use in humans. To address the hypothesis that stimulated leukotriene synthesis causes symptoms of immediate-hypersensitivity reactions in vivo, I investigated the effects of a new 5-lipoxygenase inhibitor, A-64077, on provoked allergic nasal symptoms and mediator release in a double-blind, randomized, placebo-controlled study. Eight subjects with allergic rhinitis underwent nasal challenge on two occasions after an oral dose of 800 mg of A-64077 or an identical-appearing placebo. RESULTS: Allergen-induced nasal congestion was significantly attenuated (P less than 0.02) by A-64077; peak levels of leukotriene B4 (median, 684 pg per milliliter) and 5-hydroxyeicosatetraenoic acid (median, 704 pg per milliliter) in nasal-rinse fluids were markedly reduced (to 67 and 185 pg per milliliter, respectively; P less than 0.01), whereas levels of prostaglandin D2 were not. Histamine release and sneezing were not reduced significantly by A-64077, but there was a significant correlation (P less than 0.01) between the changes in these variables within subjects. The mean (+/- SEM) stimulated synthesis of leukotriene B4 in whole blood ex vivo was markedly reduced by A-64077 (from 153 +/- 19 to 20 +/- 9 ng per milliliter, P less than 0.01), and the specificity of A-64077 for 5-lipoxygenase inhibition was verified by its lack of effect on the synthesis of serum thromboxane B2 or 12-hydroxyeicosatetraenoic acid. CONCLUSIONS: These results provide direct evidence of an important role for the 5-lipoxygenase products of arachidonic acid in allergic rhinitis and support the notion that further experiments in this area may lead to new therapeutic approaches to allergic disorders.

Double-Blind Method↗
PubMed1990

Prostaglandins in human semen during fish oil ingestion: evidence for in vivo cyclooxygenase inhibition and appearance of novel trienoic compounds.

Marine oils may offer cardiovascular benefits, but inhibition of prostaglandin E and prostaglandin F synthesis by fish oil has been found in animal studies, and such effects could alter physiological responses in man to a clinically significant degree. Since greater amounts of E and F-type prostaglandins are made in human seminal vesicles than in the rest of the body combined, the influence of n-3 supplements upon semen prostaglandins was assessed in 10 subjects before and after one month of taking 50 ml menhaden oil daily. Prostaglandins E1, E2 and their 19-hydroxy derivatives were measured by HPLC-UV as PGB's, and prostaglandin E3, 19-OH PGE3, and analogous PGF's by gas chromatography/mass spectrometry. Fish oil ingestion reduced concentrations of one- and two series prostaglandins (mean reduction in PGE's = 37%, in PGF's = 20%, p less than 0.05), while more than doubling the low amounts of PGE3 and PGF3 alpha, and their previously undescribed 19-hydroxy derivatives. Semen phospholipids were enriched in eicosapentaenoic acid after dietary fish oil, but sperm counts and motility were not altered during the study. Since dietary fish oil reduces prostaglandin concentration in semen, clinical trials of n-3 fatty acids should also evaluate other possible results of in vivo cyclooxygenase inhibition.

Adult↗
PubMed1990

Polyunsaturates, endogenous eicosanoids, and cardiovascular disease.

The role of dietary polyunsaturated fats in the prevention of human vascular disease has not been defined, but population and intervention studies have suggested that omega-3 fatty acids (FAs) from marine lipids may have a number of potentially beneficial effects. Eicosanoids are extremely potent autacoids made from polyunsaturated fatty acids and have effects on many vascular parameters, so that the physiological effects of dietary supplementation with polyunsaturated fats are often attributed to alterations in endogenous eicosanoid production. Few studies have attempted to correlate in vivo eicosanoid synthesis and functional effects during such dietary maneuvers, however. This article reviews the relationship between dietary polyunsaturates and endogenous eicosanoid synthesis in man, with particular emphasis on recent studies of the effects of omega-3 FAs. Data on omega-3 FAs and platelet-vascular interactions, blood pressure, and vascular reactivity in human subjects are also summarized, with interpretation of recent work addressing a number of controversial points. A discussion of the significance and future direction of such investigations concludes that further clinical trials in selected patient groups are warranted.

Blood Pressure↗
PubMed1990

Dietary fish oil accelerates the response to coronary thrombolysis with tissue-type plasminogen activator. Evidence for a modest platelet inhibitory effect in vivo.

To assess the platelet inhibitory effect of high doses of fish oils and relate it to alterations in eicosanoid synthesis, we used a canine model in which coronary thrombosis, the time to reperfusion induced by recombinant tissue-type plasminogen activator (rt-PA), and the rate of spontaneous reocclusion are sensitive to platelet inhibition. In the animals fed fish oil, the time to rt-PA induced thrombolysis was accelerated (mean, 63 vs. 27 minutes; p less than 0.003). The time to thrombotic occlusion and the rate of reocclusion were unaltered. The ratio of eicosapentaenoic acid (EPA) to arachidonic acid rose in platelet and endothelial cell membranes, whereas serum thromboxane (Tx) B levels fell a mean 86%, and basal excretion of 2,3-dinor-TxB2 (TxA2-M) declined. Basal prostaglandin (PG) I2 formation was unaltered, whereas biosynthesis of EPA-derived TxA3 and PGI3 increased. In control animals, TxA2 formation increased during thrombosis; there was a further, more marked rise during reperfusion. PGI2 formation also increased, probably as a response to platelet-vascular interactions. Stimulated production of both eicosanoids was strikingly suppressed in the animals fed fish oil. Fish oils significantly enhance the efficacy of rt-PA in vivo, albeit to a modest extent. Because the time to reperfusion is highly sensitive to Tx-dependent platelet activation, this effect is likely to reflect the demonstrated suppression of TxA2 biosynthesis by fish oils.

Animals↗
PubMed1990

Polyunsaturated fatty acids and cardiovascular function in man.

Dietary supplementation with either n-6 or n-3 polyunsaturated fatty acids has been reported to lower blood pressure in man, and to confer benefits in atherosclerotic vascular disease. Such effects have been suggested to be due to altered in vivo production of vasoactive prostaglandins, but this hypothesis has not been tested previously. Epidemiologic data are often quoted as showing lower blood pressure in populations with a high consumption of fish, but such conclusions are less clear from the primary data. This review presents some of the population studies on the relationship between fish intake, hypertension and vascular disease, discusses problems in studying blood pressure in dietary intervention trials, and reviews the published literature on reducing blood pressure and vascular reactivity with dietary n-3 supplements in volunteers. Recent work addressing a number of controversial points is presented, with the conclusion that pharmacologic doses of n-3, but not n-6, fatty acids can lower blood pressure in humans, but probably do not do so through directly lowering vascular reactivity to catecholamines or increasing the synthesis of vasodilator prostaglandins.

Blood Pressure↗
PubMed1989

The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension.

Both n-3 and n-6 polyunsaturated fats have been suggested to lower blood pressure, an effect ascribed to altered biosynthesis of eicosanoids. To test these hypotheses, we studied blood pressure and eicosanoid production during supplementation of dietary fat for four weeks in 32 men with mild essential hypertension. Supplementation was preceded and followed by four-week run-in and recovery periods. Groups of eight subjects received either 10 ml or 50 ml of fish oil (3 or 15 g of n-3 fatty acids) daily, 50 ml of safflower oil (39 g of n-6 fatty acids), or 50 ml of a mixture of oils that approximated the types of fat present in the American diet. The biosynthesis of eicosanoids was assessed by the measurement of urinary metabolites. Blood pressure decreased in the men who received the high dose of fish oil (systolic pressure by a mean of 6.5 mm Hg [P less than 0.03] and diastolic pressure by 4.4 mm Hg [P less than 0.015]), but not in the other groups. Although the formation of vasodilatory prostacyclins (prostaglandins I2 and I3) increased initially, this increase was not maintained as blood pressure fell. The level of thromboxane A2 metabolites fell; metabolites of thromboxane A3 were detected in the groups receiving fish oil. The formation of prostaglandin E2 increased during supplementation with safflower oil and tended to decrease with fish oil; no prostaglandin E3 metabolite was detected. Our data indicate that high doses of fish oil can reduce blood pressure in men with essential hypertension. However, the clinical usefulness and safety of fish oil in the treatment of hypertension will require further study.

Blood Pressure↗
PubMed1989

Formation of PGI3 in the rat during dietary fish oil supplementation.

Conflicting results exist in the literature on the conversion of eicosapentaenoic acid (EPA) to trienoic prostaglandins and its influence on the formation of dienoic prostaglandins from arachidonic acid (AA). Tissues from animals fed fish oils produce little, if any, trienoic prostaglandins and reduced amounts of dienoic ones. Excretion of the major urinary metabolite of PGI2 is not reduced in humans taking fish oil, however, and substantial amounts of one derived from PGI3 have been found, by GC/MS. We have addressed this possible species difference by examining the urine of rats fed fish oil for 2.3 dinor-6-keto-PGF1 alpha and its delta 17 analog, formed from PGI2 and PGI3, respectively, and compared them with rats fed corn oil. Fatty acid differences in erythrocyte and aortic lipids were also determined. Rats fed fish oil do make PGI3 from eicosapentaenoic acid in vivo and do not suppress their production of PGI2, despite having more EPA than AA in aortic lipids.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Fish oils in cardiovascular disease.

Although several studies have reported an inverse relationship between the dietary history of fish intake and the prospective incidence of death from coronary heart disease, it is unclear whether these results represent the effects of n-3 fatty acids themselves or whether they merely reflect a more fundamental alteration in diet, such as a reduction in saturated fatty acids. n-3 fatty acids alter platelet eicosanoid formation, replacing arachidonate derived thromboxane (Tx)A2 with the biologically inert TxA3. However, they are a relatively inefficient approach to platelet inhibition. This is evident from results obtained in a model of coronary thrombosis followed by thrombolysis with tissue plasminogen activator (tPA). By contrast, high doses of n-3 fatty acids (15 g day-1) significantly reduced blood pressure in mild hypertensives in a double-blind, controlled study characterized by a prolonged run-in period and adequate follow-up. Fish oils inhibit the vascular proliferative response to injury in a variety of animal models, apparently independently of their effects on lipoprotein metabolism. Recent results imply that they may selectively interfere with the vascular expression of mitogenic peptides.

Arteriosclerosis↗
PubMed1988

Effects of low-dose aspirin on endogenous eicosanoid formation in normal and atherosclerotic men.

We have investigated the effects of a low-dose aspirin regimen (120 mg orally, then 20 mg twice daily) on the in vivo synthesis of prostacyclin, thromboxane and prostaglandin E in man by measurement of their urinary metabolites (PGI2-M, TxB2-M, PGE-M) using gas chromatography-mass spectrometry. A comparison was made between the selectivity of low-dose aspirin for thromboxane vs prostacyclin synthesis in patients with atherosclerosis, age-matched controls without vascular disease, and young healthy volunteers. After one week of treatment, aspirin reduced TxB2-M synthesis to a similar extent in the three groups (mean declines of 86, 84 and 78% respectively), while there was an unexpected difference in effect on PGI2-M, with only a 27% fall in the young volunteers but 53% and 54% declines in the patients with vascular disease and their age-matched controls. Serum TxB2 was reduced greater than 98% in all groups while PGE-M excretion was unchanged. These results indicate that bioselectivity for inhibition of Tx synthesis by aspirin is more difficult to achieve in older subjects than in the young volunteers previously studied and that very low, frequent dosing, or a sustained-release preparation of aspirin would be needed to achieve bioselectivity for Tx inhibition in patients with vascular disease.

Adult↗