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Biomedical subjects

H R Knapp

Publications and source records attributed to H R Knapp.

At least 55 records · Page 3Linked to original sources
PubMed1988

Leukotriene B4 synthesis and neutrophil chemotaxis in chronic granulocytic leukaemia.

A sensitive gas chromatography-mass spectrometric method was used to measure the generation in whole blood of leukotriene B4 (LTB4), a potent stimulator of neutrophil chemotaxis, in eight patients with chronic granulocytic leukaemia (CGL) and 12 healthy controls. LTB4 was detectable in unstimulated samples from all the patients (mean 194 (70 SEM) pg/ml), and the capacity for LTB4 production after stimulation with calcium ionophore (A23187) was similar in patients (32.1 (11) ng/10(6) leucocytes) and controls (38.1 (4) ng/10(6) leucocytes). In response to stimuli which induce neutrophil activation, LTB4 production was significantly greater in the patients than in controls: 35.6 (13) v 13.0 (3) ng/ml, p less than 0.05 (f-met-leu-phe); and 42.4 (16) v 14.7 (4) ng/ml, p less than 0.02 (opsonised zymosan). Anti-IgE stimulated considerably more LTB4 production in patients with CGL than in controls (3.86 (1.6) v 0.83 (0.43) ng/ml; p less than 0.005) and this correlated significantly (p less than 0.05) with the basophil count. Neutrophil chemotaxis to LTB4, however, was significantly impaired in the patients with CGL even at the highest concentration of LTB4 (10(-5) M). Chemotaxis to f-met-leu-phe, phagocytosis, and bacterial killing were normal. Thus although LTB4 synthesis is normal or even enhanced in patients with CGL, specific defects in LTB4-mediated responses may contribute to neutrophil dysfunction in this disease.

Adult↗
PubMed1986

In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis.

Populations that consume a diet rich in marine lipids may have a lower risk of atherosclerotic disease. Fish oil contains the N-3 polyunsaturated fatty acid eicosapentaenoate, and the biosynthesis of thromboxanes and prostacyclins from eicosapentaenoate (thromboxane A3 and prostaglandin I3), rather than from the usual precursor arachidonate (thromboxane A2 and prostaglandin I2), may help to reduce the risk. To examine this hypothesis, we studied the effect of eicosapentaenoate supplementation (10 g per day) for one month on the synthesis of thromboxanes and prostacyclins, as assessed by urinary metabolite excretion, in six patients with peripheral vascular disease and seven normal controls. Supplementation markedly increased the eicosapentaenoate content of phospholipids from red cells and platelets. Synthesis of the platelet agonist thromboxane A2, which was elevated in the patients at base line, declined by 58 percent during supplementation but did not reach normal values. The decline in thromboxane A2, which is synthesized from arachidonate, coincided with the formation of the inactive thromboxane A3, which is synthesized from eicosapentaenoate. A lower dose of eicosapentaenoate (1 g per day) was not sufficient to maintain the changes in thromboxane A2 synthesis. Platelet function was only moderately inhibited during eicosapentaenoate supplementation, consistent with incomplete suppression of thromboxane A2 synthesis. These studies show that a high dose of eicosapentaenoate alters the pattern of synthesis of thromboxanes and prostacyclins. However, effects comparable to those of aspirin require long-term administration in high doses. Whether other properties of fish oil might render it a more attractive antithrombotic therapy remains to be determined.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Bactericidal effects of polyunsaturated fatty acids.

Bactericidal effects of polyunsaturated fatty acids were investigated by using an in vitro killing assay. All gram-positive species tested were extremely susceptible to 10(-5) M arachidonic acid as were Neisseria, Branhamella, and Haemophilus spp. Pseudomonas aeruginosa and and members of the Enterobacteriaceae were resistant. The toxicity of polyunsaturated fatty acids for Staphylococcus aureus was dependent upon time, concentration, and fatty acid unsaturation. Arachidonic acid underwent peroxidation when incubated with S. aureus, but arachidonic acid peroxidation products had low bactericidal activity. Catalase protected S. aureus, whereas superoxide dismutase was ineffective. Scavengers of hydroxyl radicals or singlet oxygen or removal of halide ions had little effect on arachidonic acid-induced killing of bacteria, whereas transition metal chelators and some thiols were highly protective. S. aureus grown in iron-supplemented broth had increased iron content and arachidonic acid susceptibility. Ascorbate also potentiated arachidonic acid-induced killing of S. aureus. These observations indicate that bactericidal effects of polyunsaturated fatty acids are mediated by a peroxidative process involving H2O2 and bacterial iron.

Arachidonic Acid↗
PubMed1985

Endogenous biosynthesis of prostacyclin during cardiac catheterization and angiography in man.

The potent platelet inhibitory and vasodilator properties of prostacyclin suggest that levels of this substance may be of relevance to drug action and pathologic processes in the coronary vascular bed. Attempts to estimate the coronary secretion rate of prostacyclin have relied on measurements of metabolites obtained via cardiac catheter, usually as an adjunct to coronary angiography. To test the hypothesis that such procedures might themselves perturb endogenous biosynthesis of prostacyclin we used mass spectrometry to measure plasma levels of 6-keto-prostaglandin (PG) F1 alpha across the coronary vascular bed, as well as to assess the excretion of a major urinary metabolite, 2,3-dinor-6-keto-PGF1 alpha (PGI-M), in patients undergoing cardiac catheterization. PGI-M excretion increased variably from a median 100 to 205 pg/mg creatinine (p less than .01) during catheterization with angiography and remained elevated 2 to 4 hr after initiation of the procedure. However, cardiac catheterization without angiography also stimulated metabolite excretion, perhaps reflecting catheter-induced vascular trauma. The direct effect of radiocontrast media on vascular release of prostacyclin was indicated by increased PGI-M excretion in healthy volunteers administered intravenous radiocontrast and by studies of the canine coronary artery and jugular vein in vitro. Measurement of plasma 6-keto-PGF1 alpha after left heart catheterization showed that levels in aortic (21 +/- 8 pg/ml) and coronary sinus (14 +/- 2 pg/ml) blood were increased compared with peripheral venous levels (less than or equal to 4 + 1 pg/ml) determined before this procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Hypertensive crisis in prazosin-treated pheochromocytoma.

The selective alpha1-adrenergic antagonist prazosin has recently been recommended for the preoperative management of pheochromocytoma, but we have observed a hypertensive crisis in a patient with such a tumor, despite prazosin therapy. Her blood pressure was easily controlled with small doses of phenoxybenzamine, suggesting that less selective alpha-adrenergic blockade might be advantageous in this situation. The involvement of alpha 2-adrenoreceptors in pressor responses and a lack of evidence for presynaptic alpha 2 control of peripheral sympathetic tone in man suggest that selective alpha 1-blockade is not the optimal treatment of hypertension due to high levels of circulating catecholamines.

Adrenal Gland Neoplasms↗
PubMed1978

Effects of feeding ethyl-dihomo-gamma-linolenate on rabbit renomedullary lipid composition and prostaglandin production in vitro.

Feeding the ethyl ester of dihomo-gamma-linolenic acid for 25 days to rabbits resulted in increased PGE1 (20 to 30-fold) and PGE2 (1.5-fold) output by a hormone responsive, in vitro, renal papilla preparation. The relative amount of PGE1 increased from less than 5% of PGE2 in controls to 25-35% of PGE2 in the papillae of 20 : 3 omega 6-supplemented animals. During the study renomedullary tri glycerides in the 20 : 3 omega 6-supplemented animals increased 2.8-fold compared to animals fed an equal amount of a control fatty acid mixture, and in addition to a marked enrichment in 20 : 3 omega 6, also contained increased proportions of 20 : 4 omega 6 and longer chain polyenes. The increase in triglyceride content found in the renal medulla was not seen in the renal cortex or liver. There was no increase in renomedullary phospholipid content during the study, and phopholipids of treated animals contained increased proportions of 20 : 3 omega 6 and 20 : 4 omega 6, but not longer chain polyenes. The results indicate that enriching the prostaglandin precursor pool by feeding 20 : 3 omega 6 can alter the type and amount of prostaglandin released by the renal papilla, at least in vitro. Also, the selective changes in amount and long chain polyene content of renomedullary triglycerides during the study suggest some special functions for this lipid class in prostaglandin precursor metabolism.

8,11,14-Eicosatrienoic Acid↗
PubMed1978

Synthesis and metabolism of prostaglandins E2, F2alpha and D2 by the rat gastrointestinal tract. Stimulation by a hypertonic environment in vitro.

Whole cell preparations of rat stomach corpus, jejunum, and colon were incubated and the released prostaglandin E2 (PGE2), PGF2alpha, PGD2, 15 keto-13,14 dihydro PGE2, and 15 keto-13, 14 dihydro PGF2alpha were measured by combined gas chromatography-mass spectrometry. All regions made PGD2 and possessed a high capacity for production 15 keto-13,14 dihydro derivatives of both PGE2 and PGF2alpha. Hypertonic sucrose solutions resulted in concentration-dependent increases in prostaglandin release, particularly of PGE2 and its metabolite. It is suggested that PG's may play a role in the local effects of luminal hyperosomolarity on digestive tract functions.

Animals↗
PubMed1977

Biosynthesis of prostaglandin D2. 1. Formation of prostaglandin D2 by human platelets.

Formation of prostaglandin D2 (PGD2) during the aggregation of platelets was determined, employing a specific bioassay. PGD2 was synthesized in human platelet rich plasma (PRP) in response to thrombin, collagen and epinephrine. Indomethacin pretreatment abolished the biosynthesis of PGD2. When thrombin treated PRP was incubated for different periods of time and denatured in the presence of SnCl2 to prevent the formation of PGD2 from endoperoxides during the extraction procedure, PGD2 formation was noted within the first minute of incubation and reached a peak level after 4 minutes. PGD2 from thrombin stimulated PRP was conclusively identified by gas chromatography-mass spectrometry. The formation of PGD2 during platelet aggregation could represent a mechanism of feedback inhibition of aggregation.

Adenosine Diphosphate↗
PubMed1977

Ionophores stimulate prostaglandin and thromboxane biosynthesis.

The role of calcium in triggering prostaglandin and thromboxane synthesis was studied in several systems with ionophores of different ion specificities. Divalent cationophore A23187 stimulates prostaglandin and thromboxane production by washed human platelets in a concentration-dependent manner (0.3-9 muM). A23187 also induces an antimycin A-insensitive burst in oxygen utilization which is partially blocked by 5 mM aspirin or 10 muM indomethacin. Under our conditions, A23187 (up to 10 muM) does not appear to damage platelet membranes since it does not cause appreciable loss of lactate dehydrogenase or beta-glucuronidase. Mono- and divalent cationophore X537A also stimulates platelet thromboxane B(2) production and oxygen utilization, but monovalent cationophores nigericin, monensin A, A204, and valinomycin have no effect. The synthesis of prostaglandins E(2), D(2), and F(2alpha) by rat renal medulla mince is stimulated by 1 and 5 muM A23187 without changes in tissue ATP content, lactate output, or K(+) efflux. X537A, monensin A, and nigericin (all 5 muM) stimulate both prostaglandin output and K(+) efflux from renal medulla, while 5 muM valinomycin or A204 has no effect on either. None of the ionophores stimulates renomedullary prostaglandin production if calcium is omitted from the incubation medium. A23187 also stimulates prostaglandin production by human lymphoma cells, rat stomach and trachea preparations, and guinea pig polymorphonuclear leukocytes. These observations suggest a major role for Ca(2+) in stimulating prostaglandin and thromboxane biosynthesis, and also indicate that prostaglandin and/or thromboxane release may partially mediate some of the previously described effects of ionophores on cells and tissues.

Arachidonic Acids↗
PubMed1977

An effect of estradiol and testosterone on the calcium pump activity and phospholipid fatty acid composition of rat liver microsomes.

Castration of the male rat resulted in a 28% reduction of the specific activity of liver microsomal calcium uptake, three weeks after castration. Treatment of the castrated animals with testosterone during this period returned calcium uptake to control levels. Treatment with estradiol resulted in a reduction of calcium uptake to a level less than 25% of that seen in the normal male. Although testosterone treatment had only a small effect on the fatty acid composition of liver microsomal phospholipids in the castrated male, there were significant changes of linoleic acid (18:2) in phosphatidylcholines and of palmitic acid (16:0) in phosphatidylethanolamines, when compared to the untreated castrated male rat. Administration of estradiol to the castrated male rat resulted in a marked decrease of palmitic acid (16.0) and linoleic acid (18.2) in all three phospholipid fractions studied. Stearic acid (18.0) was significantly increased in the phosphatidylcholines and phosphatidylethanolamines by estradiol treatment. The phospholipid and calcium uptake changes seen after treatment of the castrated rat with testosterone or estradiol are consistent with the sex-related differences observed in the intact, adult rat liver microsomes.

Animals↗
PubMed1976

Effects of feeding ethyl-dihomo-gamma-linolenate on prostaglandin biosynthesis and platelet aggregation in the rabbit.

1. The ethyl ester of dihomo-gamma-linolenic acid (20:3omega6) (1 g/kg/day) was fed to rabbits for 25 days. Plasma lipids and platelet aggregation were analyzed on day 1, 11, 16, 21 and 26. 2. All plasma lipid classes were greatly enriched with 20:3omega6. Arachidonic acid levels were elevated to a smaller extent. The different platelet phospholipid fractions analyzed were also highly enriched with 20:3omega6, whereas the arachidonic acid content in platelet phospholipids was significantly lower than in control animals. 3. The excretion of 7 alpha-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid, the major urinary metabolite of prostaglandin E1 and E2 was increased 4.6 fold by the treatment. 4. Platelet aggregation in response to ADP, collagen and arachidonic acid did not differ at any time betweeen 20:3omega6 treated rabbits and controls. 5. It is concluded that prostaglandin E biosynthesis can be increased by enriching the prostaglandin precursor pool. Platelet aggregation in vitro is not altered by feeding ethyl 20:3omega6.

Animals↗
PubMed1975

Energy-dependent calcium sequestration activity in rat liver microsomes.

MgATP-dependent calcium sequestering activity of rat liver microsomes has been characterized. This activity is linear over a 90-min period and specifically requires MgATP. Substitution of CTP, UTP, GTP, or ADP will not support calcium uptake. Oxalate, which serves as a trapping agent in calcium uptake of skeletal muscle microsomes, is required to maintain net accumulation of calcium. The reaction is temperature-dependent and has an apparent Vmax of 11.2 nmol/mg of protein/min. The apparent Km for calcium is 23.2 muM calculated from total calcium concentration, and approximately 4.6 muM based on free calcium concentration, and apparent Km for ATP is 1.8 mM. Calcium uptake activity normally measured in presence of 100 mM KCl is only slightly depressed if 100 mM NaCl is substituted and is considerably depressed when 200 mM sucrose replaces KCl. An appropriate hydrolysis of ATP is associated with the calcium uptake. Separation of smooth and rough endoplasmic reticulum on sucrose gradients indicates a considerably lower specific activity per mg of protein in the fraction enriched with rough endoplasmic reticulum. Azide, at a level which completely inhibits liver mitochondrial calcium sequestration, has no effect on the liver microsomal system. Oligomycin, which inhibits ATP-dependent calcium uptake of liver mitochondria, has a considerably lesser effect on calcium uptake of liver microsomes. p-Chloromercuribenzoate and mersalyl inhibit the liver microsomal calcium pump at levels as low as 10- minus 7 M. Calcium uptake activity is considerably reduced in adult female rats. Weanling rats, both male and female, have calcium uptake activities like that of the adult males. Because of the higher activity in the male rat, the fatty acid composition of the liver microsomal phospholipids was analyzed. The male rat had a higher percentage of linoleic and palmitic acids in the microsomal phospholipids. Endoplasmic reticulum and plasma membrane are postulated to play a role in regulation of the levels of free cytoplasmic calcium in the mammalian liver.

Adenosine Triphosphate↗