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Biomedical subjects

F A Fitzpatrick

Publications and source records attributed to F A Fitzpatrick.

At least 109 records · Page 6Linked to original sources
PubMed1980

Albumins stabilize prostaglandin I2.

We monitored the chemical stability of prostaglandin I2 in the presence of different plasma proteins. PGI2 hydrolyzes by first order reaction kinetics, dependent on the albumin concentration in aqueous buffers. Chemical analysis shows that vertebrate albumins prolong the half-life of prostaglandin I2. The degree of stabilization varies quantitatively among different species. The results indicate that prostaglandin I2 may persist in its active form longer than previously supposed in some experimental conditions.

Animals↗
PubMed1980

Hydrolysis of an orally active platelet inhibitory prostanoid amide in the plasma of several species.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGE1-amide (OI-PGE1-amide) has a prolonged duration of oral platelet aggregation inhibitory activity when compared to the parent free acid (OI-PGE1) in the rat. When incubated in rat plasma at 1 microgram/ml for 30 seconds prior to addition of ADP, OI-PGE1-amide inhibits in vitro rat platelet aggregation approximately 50%. OI-PGE1 inhibits at 1 ng/ml. Inhibition of platelet aggregation by plasma incubated with OI-PGE1-amide (1 microgram/ml) increases with time and the rate of this increase differs with species. Incubation of OI-PGE1 in plasma does not result in an increase of platelet inhibitory activity with time. The increase of platelet inhibitory activity was assumed to indicate hydrolysis of OI-PGE1-amide to the more active OI-PGE1. A compound, different from OI-PGE1-amide, was isolated by an ion exchange/silica gel separation sequence from an incubation of OI-PGE1-amide in rat plasma. It had potent platelet aggregation inhibitory activity. This material was shown to be OI-PGE1 by thin-layer chromatography, gas chromatography and mass spectral analysis. Studies with [3H]-OI-PGE1-amide confirmed the formation of OI-PGE1 in plasma incubations. Amide hydrolytic activity was significantly different between species, the rank order being: rat greater than guine pig greater than monkey = human greater than dog. This relationship corresponded with that determined by measuring the increase in platelet inhibitory activity with time in plasma incubations of OI-PGE1-amide reported above. Present data indicate that (a) OI-PGE1-amide is hydrolyzed to the parent acid by plasma enzymes of several species and (b) hydrolytic activity of plasma varies widely between species.

Adenosine Diphosphate↗
PubMed1979

Glass capillary gas chromatography with electron-capture detection. Separation of prostaglandins.

Glass capillary gas chromatography of the prostaglandins was performed on a system including an all-glass, solventless injector; thermostable methylphenyl-polysiloxane glass capillary columns; and a conventional electron-capture detector fitted with a make-up gas tee. The principal stable metabolites of prostaglandin endoperoxide were separated as perfluorinated derivatives in 35 min. Detection limits equal or exceed those obtained for packed column separations and electron capture detection. Prostaglandin endoperoxide metabolic profiles from mammalian cell cultures were obtained using this system. These profiling studies are not possible with other chromatographic methods because of inferior resolution and sensitivity.

Animals↗
PubMed1979

Regulatory role of cyclic adenosine 3',5'-monophosphate on the platelet cyclooxygenase and platelet function.

Thromboxane A2 plays an important role in arachidonic acid- and prostaglandin H2-induced platelet aggregation. Agents that stimulate platelet adenylate cyclase (prostaglandin I2, prostaglandin I1 and prostaglandin E1) and dibutyryl cyclic AMP inhibit both thromboxane A2 formation and arachidonate-induced aggregation in platelet-rich plasma. Despite complete suppression of aggregation with agents that elevate cyclic AMP, considerable thromboxane A2 is still formed. Prostaglandin H2-induced aggregations which bypass the cyclooxygenase regulatory step are also inhibited by agents that elevate cyclic AMP without any measurable effect on thromboxane A2 production. These data demonstrate that cyclic AMP can inhibit platelet aggregation by a mechanism independent of its ability to suppress the cyclooxygenase enzyme. Parallel experiments with washed platelet preparations suggest that they may be an inadequate model for studying the relationship between the platelet cyclooxygenase and platelet function.

Arachidonic Acids↗
PubMed1979

Prostaglandin D2 formation by malignant melanoma cells correlates inversely with cellular metastatic potential.

B16 malignant melanoma cell lines transform arachidonic acid and its transient metabolite, prostaglandin endoperoxide H2, into prostaglandin D2. The highly metastatic line, B16 F10, forms less prostaglandin D2 compared to the moderately metastatic parent line, B16 F1. Since platelet aggregation may be one factor involved in B16 metastasis and since prostaglandin D2 inhibits platelet aggregation, this prostaglandin could affect the outcome of platelet-tumour interactions, which may contribute ultimately to metastasis. Arachidonic acid metabolism may be another one of the intrinsic biochemical properties of tumor cells that affects their metastasis. Our results suggest that quantitative release of unusual prostaglandins must be considered in this context.

Arachidonic Acids↗
PubMed1978

A comparison of imidazole and 9,11-azoprosta-5,13-dienoic acid. Two selective thromboxane synthetase inhibitors.

Two selective thromboxane A2 synthetase inhibitors, imidazole and 9,11-azoprosta-5,13-dienoic acid (azo analog I) were compared to determine their effects on the quantitative formation of thromboxane B2 and prostaglandin E2 accompanying human platelet aggregation. Azo analog I was at least 200 times more potent, on a molar basis, than imidazole in suppressing thromboxane B2 formation in either platelet-rich plasma or washed platelet suspensions aggregated with arachidonic acid or prostaglandin H2. The inhibitors differed in their effect on the aggregation response itself. Azo analog I selectively suppressed thromboxane A2 formation with an accompanying, parallel, suppression of the platelet aggregation. Imidazole selectively suppressed thromboxane A2 formation, but only suppressed the accompanying aggregation in platelet rich plasma, and not washed platelet suspensions. The results indicate that azo analog I functions by competitive inhibition of prostaglandin H2 on the thromboxane synthetase, and that imidazole, while it suppresses thromboxane A2 formation, may have an associated agonist activity that enhances platelet aggregation. The data presented support this hypothesis, and they emphasize the importance of thromboxane A2 in arachidonate mediated platelet aggregation.

Arachidonic Acids↗
PubMed1978

An antiserum against 9-deoxy-6,9-epoxy-PGF1alpha recognizes and binds PGI2 (prostacyclin).

Antibodies were prepared against 9-deoxy-6,9-epoxy-PGF1alpha, the 5,6-dihydro analog of prostacyclin (PGI2). By using as the hapten, this structurally similar, stable analog, an antibody population was developed which recognized PGI2 and reversed its influence on platelet aggregation. The antibodies also opposed the normal effect of PGI2 on the cAMP and thromboxane B2 levels during aggregation. By anticipating the cross reaction between the analog and PGI2 and by considering it beneficial, the problem of raising antibodies against an unstable compound has been circumvented.

Animals↗
PubMed1978

Prostacyclin biosynthesis in activated, stimulated and normal mouse peritoneal cell populations.

Nonspecific resistance to infectious and neoplastic disease can be enhanced by administration of "immunomodulators". The levels of enhancement can be monitored by following in vitro function of cells of the lympho-reticuloendothelial system. To gain a better understanding of the physiological and biochemical nature of this enhancement, the metabolism of prostaglandin endoperoxide PGH2 was followed in mouse peritoneal cells (PCs). Homogenates of PCs from normal, unstimulated mice yielded primarily prostacyclin (PGI2) when incubated with PGH2. Homogenates of PCs from mice injected with the immunomodulators C. parvum, levamisole HCl, pyran copolymer, or thioglycollate yielded less PGI2. Reductions ranged from 73% for C. parvum to 32% for levamisole. A statistically significant inverse correlation existed between the level of macrophage "activation" and ability of cellular homogenates to produce prostacyclin. The results suggest that prostacyclin may be involved in modulation of nonspecific resistance.

Animals↗
PubMed1978

Hapten mimic elicits antibodies recognizing prostaglandin E2.

Antibodies that recognized the prostaglandin (PG) E structure were elicited from rabbits. 9-Deoxy-9-methylene-PGF2alpha, a stable isosteric mimic of PGE2, was conjugated to two different protein immunogens and the immune response system was duped into producing antibodies with poor recognition for prostaglandins other than the hapten mimic (9-deoxy-9-methylene-PGF2alpha) and its isosteric counterparts (PGE1 and PGE2). With this procedure, crossreaction that would ordinarily arise from the chemical or metabolic instability of an authentic PGE2 immunogen was avoided. Antibodies raised against a keyhole limpet hemocyanin conjugate of 9-deoxy-9-methylene-PGF2alpha had an average intrinsic association constant, Ko = 2.6 X 10(9) liters.mole-1, for PGE2. Crossreaction was low for a number of related prostaglandins, and a sensitive radioimmunoassay procedure with a detection limit of 6 pg was developed.

Animals↗