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Biomedical subjects

A R Morrison

Publications and source records attributed to A R Morrison.

At least 127 records · Page 7Linked to original sources
PubMed1985

Temporal changes in 12-HETE formation in two models of canine myocardial infarction.

Arachidonic acid (AA) metabolism by infarcted canine myocardium was studied and correlated with matched histologic analyses following permanently occluded or reperfused infarction. Histologic analysis of tissues from reperfused infarcts showed a marked acceleration of inflammatory cell invasion and of granulation tissue formation when compared to the occlusive infarct. In the reperfused infarct, polymorphonuclear leukocytes (PMNs) were very prominent at one day after infarction while in the occlusive infarcts the neutrophilic invasion was less intense but more sustained. At one day following reperfused infarction the major arachidonate product, which co-migrated by thin layer chromatography with the mono-hydroxyeicosatetraenoic acids (HETEs), was significantly elevated (254 +/- 49 pmoles/gm wet weight, n = 3) when compared to normal tissue (48 +/- 6 pmoles/gm n = 19). This occurred at a time when the number of PMNs was maximal in the infarcted tissue. Addition of the calcium ionophore A23187 caused a further marked stimulation in HETE production in the one day reperfused infarct but not at the other time points studied. The production of HETE was not significantly different in the infarcted tissue than in the normal tissue at three and seven days following reperfused infarction or at one, three, or seven days after occlusive infarction. The identity of this HETE product was investigated using reverse phase high performance liquid chromatography (RP-HPLC) and gas chromatography-mass spectrometry (GC-MS) and found to be predominantly 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) with a small amount of 15-HETE. Thus the production of 12-HETE parallels the number of neutrophils invading the infarcted area of the heart.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

Incorporation of 5,8,11,14-eicosatetraynoic acid (ETYA) into cell lipids: competition with arachidonic acid for esterification.

5,8,11,14-eicosatetraynoic acid (ETYA), a widely used inhibitor of cyclooxygenase and lipoxygenase, inhibited the incorporation of 14C-arachidonic acid into cell lipids of the murine thymoma EL4 whereas oleic acid had no effect. Inhibition appeared to result from the ability of ETYA to compete with arachidonic acid for esterification enzymes and to be itself incorporated into cell lipids. The positional specificity for ETYA incorporation was similar to that of arachidonic acid. ETYA, but not oleic acid competed with arachidonate for activation by a selective arachidonoyl CoA synthetase in lymphocytes. This may explain in part the apparent specificity of effects seen on incorporation into whole cells. In addition ETYA, unlike other arachidonate analogs tested previously, caused significant inhibition of the nonselective acyl CoA synthetase in lymphocytes. These results are discussed with respect to the use of ETYA to examine the role of intrinsic arachidonic acid metabolism in cellular processes.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1985

The effects of a diet rich in fish oil on human neutrophils: identification of leukotriene B5 as a metabolite.

Diets that are enriched with fish oil have been shown to alter arachidonic acid metabolism via the cyclooxygenase pathway. Recently it has been shown that one of the major component fatty acids of fish oil, eicosapentaenoate (EPA), is a substrate for the leukotriene B (LTB) pathway when added exogenously to human neutrophils in vitro. We fed a diet that contained 8-10gm/day of EPA to four human subjects for three weeks and compared the arachidonate metabolism of their neutrophils to the same functions while the subjects were on their usual diet. The fish oil-supplementation increased neutrophil EPA content from undetectable levels to 7.4 +/- 2.4% (p less than 0.01, expressed as % of total fatty acid), and decreased arachidonate from 15.4 +/- 2.3% to 12.8 +/- 2.3% (p less than 0.05). Leukotriene B5 was identified as a metabolite during the fish oil-diet by its chromatographic profile and mass spectrum. During the experimental diet LTB4, decreased from 160 +/- 37 ng/10(7) neutrophils to 120 +/- 12 (p less than 0.05), and LTB5 increased from 0 to 39 +/- 9 ng/10(7) neutrophils (p less than 0.005). The diet had no effect on neutrophil aggregation or adherence to nylon fibers.

Arachidonic Acid↗
PubMed1985

Arachidonic acid metabolic pathway of the rabbit placenta.

Placenta microsomes prepared from animals late in gestation (29 days) efficiently metabolize arachidonic acid into PGE2, PGF2 alpha, PGD2, TxA2 and little or no prostacyclin. In contrast to the late gestation placenta, the early (17 day) placental microsomes synthesize primarily PGE2. The cytosolic (100,000 X g supernatant) fraction from early or late gestation placentae converted arachidonic acid, with a calcium dependent enzyme, into non-polar metabolites whose synthesis was inhibited by ETYA but not indomethacin. These metabolites were purified by HPLC and GC-MS analysis indicated the presence of 12-hydroxy-, 15-hydroxy-, and 11-hydroxy-eicosatetraenoic acid. The mitochondrial (8,000 X g pellet) produced PGE2; PGF2 alpha; 12-, 11-, 15-HETE; the C-17 fragment HHT; and the unusual cyclooxygenase metabolite 15-keto-PGE2. These biologically active metabolites may play a vital role in the reproductive function of the placenta.

Animals↗
PubMed1985

Bradykinin-induced changes in phosphatidyl inositol turnover in cultured rabbit papillary collecting tubule cells.

Rabbit renal papillary collecting tubule cells were isolated as a homogeneous population and grown in primary culture. These cells were maintained in fully defined medium to inhibit fibroblast overgrowth and to facilitate labeling of endogenous inositol phospholipids with myo-[2-3H]inositol with high specific activity. These cells demonstrated the morphology, cyclic AMP responsiveness, and prostaglandin E2 (PGE2) elaboration, consistent with previous published characterizations. When cells labeled with myo-[2-3H]inositol were stimulated by bradykinin at 10(-7) M, time-dependent and reversible changes in the distribution of inositol polyphosphates were observed. Inositol 1,4,5-triphosphate and inositol 1,4-diphosphate showed time-dependent and dose-dependent increases to maximal levels of 225 and 223% of control, respectively. These data indicate that the elaboration of inositol polyphosphates is a biochemical correlate to bradykinin stimulation and may play a role in PGE2 release in renal papillary collecting tubule cells.

Animals↗
PubMed1985

Inhibition of cytotoxic T lymphocyte-mediated lysis by ETYA: effect independent of arachidonic acid metabolism.

Cytotoxic T lymphocyte (CTL)-mediated lysis of target cells was inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA) and other inhibitors of the lipoxygenase pathway at concentrations that inhibited arachidonic acid metabolism in mixed lymphocyte cultures. Inhibition was reversible and selective for the "lethal hit" stage in the CTL-target interaction. Studies to define CTL-specific arachidonic acid metabolites demonstrated that cloned CTL populations have little or no capacity to metabolize arachidonic acid. Therefore, inhibitor actions appear to be independent of the effects on CTL arachidonic acid metabolism. Alternative explanations for inhibitory effects are discussed.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1984

A novel cyclooxygenase metabolite of arachidonic acid.

The 8000 X g pellet of rabbit placenta transformed arachidonic acid into a number of lipoxygenase and cyclooxygenase products of known structure. A metabolite was also produced which was inhibited by indomethacin and required calcium for its formation. This compound had a UV absorption maximum at 227 nm under acidic or neutral conditions and gave a bathochromic shift to 281 nm under alkaline conditions. Reduction of this metabolite with sodium borohydride produced prostaglandin (PG) F2 alpha (as determined by mass spectrometry), while catalytic hydrogenation increased the molecular weight by four mass units, indicating the presence of two double bonds. Based on the mass spectrum of the derivatized metabolite, the structure proved to be 9,15-dioxo-11-hydroxyprosta-5,13-dienoic acid. This compound is produced by the term placenta and does not appear to be formed from PGE2, PGF2 alpha, or PGD2. The compound is suppressed by GSH and NADPH, but its formation is not increased by NAD or NADP. PGH2 and PGG2 are not converted to 9,15-dioxo-11-hydroxyprosta-5,13-dienoic acid under similar in vitro incubation conditions. This therefore represents conversion of arachidonate to 9,15-dioxo-11-hydroxyprosta-5,13-dienoic acid through a Ca2+-dependent, non-PG dehydrogenase pathway.

Animals↗
PubMed1984

Identification of an unusual cyclooxygenase metabolite of arachidonic acid in rabbit renal medulla.

A renal medulla 100,000g pellet metabolized arachidonic acid, C20:4, to the previously described prostaglandins prostaglandin E2, 6-ketoprostaglandin F1 alpha, thromboxane B2, 12-hydroxyheptadecatrienoic acid, and 11-hydroxyeicosatetraenoic acid. In addition, under conditions of low enzyme to substrate ratios, the renal medulla also produced an unusual metabolite from arachidonic acid. This metabolite was inhibited by indomethacin, and thus suggested that it was a product of the cyclooxygenase. Addition of GSH to the incubation inhibited its formation, while p-hydroxymercuribenzoate enhanced its formation. This compound was identified by HPLC purification, uv absorption, and gas chromatography-mass spectroscopy. The compound was 9,15-dioxo,11-hydroxyprosta-5,13-dienoic acid.

Animals↗
PubMed1984

The Taub case.

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Animal Husbandry↗
PubMed1984

Arachidonic acid metabolic pathways in the rabbit pericardium.

Minced rabbit pericardium actively converts [1-14C]arachidonic acid into the known prostaglandins (6-[1-14C]ketoprostaglandin F1 alpha, [1-14C]prostaglandin E2 and [1-14C]prostaglandin F2 alpha) and into several unidentified metabolites. The major metabolite was separated by C18 reverse-phase high-pressure liquid chromatography (HPLC) and identified by gas chromatography-mass spectrometry (GC-MS) to be 6,15-[1-14C]diketo-13,14-dihydroprostaglandin F1 alpha. The other nonpolar metabolites were 15-[1-14C]hydroxy-5,8,11,13-eicosa-tetraenoic acid (15-HETE), 11-[1-14C]hydroxy-5,8,12,14-eicosatetraenoic acid (11-HETE) and 12-[1-14C]hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE). Arachidonic acid metabolites actively produced by the pericardium could influence the tone of surface blood vessels on the myocardium.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1984

Reversal of rapid eye movement sleep without atonia by chloramphenicol.

Bilateral pontine tegmental lesions produce in cats the phenomenon known as rapid eye movement (REM) sleep without atonia. During episodes of REM sleep without atonia cats are capable of exhibiting such complex behaviors as head-raising, body-righting, standing, and in some cases, walking and attacking. Since release of such behaviors implies disinhibition of specific motor systems, the purpose of this study was to determine whether the administration of chloramphenicol (CAP), which is known to attenuate the firing frequencies of cells that become activated during REM and motor activity, could reverse this phenomenon. Cats with dorsolateral tegmental pontine (DLTP) lesions producing REM without atonia were thoroughly studied in terms of the muscular and behavioral activity they displayed during REM before and after systemic CAP administration. Thiamphenicol (TAP), a CAP analogue that does not reduce neuronal firing frequency during REM sleep, was used as a control drug. The results of these experiments showed that CAP but not TAP induced a return of the atonia during REM sleep. It is suggested that the return of atonia induced by CAP in DLPT lesioned cats is caused by attenuation in the activity of medial reticular neurons which have somatotopical representation. Such cells, which have high levels of activity during REM sleep and motor activation is wakefulness, are normally overwhelmed by the inhibitory mechanism of the atonia of REM. The return of atonia and consequent reduction in complex behavior following CAP administration may be due to withdrawal of the excitatory influence of these neurons.

Animals↗
PubMed1984

Iothalamate stimulates hydroperoxide formation by soybean lipoxygenase.

Sodium iothalamate produced a dose dependent increase in basal oxygen consumption when soybean lipoxygenase was incubated with arachidonic acid in 0.1M borate buffer pH 9.0. The increase in oxygen consumption was associated with an increase in absorbance at 234 nm indicating an increased conjugated diene formation. The stimulation of 02 consumption was demonstrated to be due to an increase in 1500H arachidonic formation. The increase in 1500H arachidonate formation could be blocked by mannitol which is an inhibitor of the lipoxygenase enzyme. N-methyl glucamine (meglumine) which is added to some preparations of iothalamate, was also able to suppress the increase in hydroperoxide formation in a dose dependent fashion.

Chromatography, High Pressure Liquid↗
PubMed1984

Biochemical alterations of membrane lipids associated with renal injury.

Ureteral obstruction and partial renal vasoconstriction are associated with increased prostaglandin biosynthesis and arachidonate release from cellular phospholipids. HgCl2-induced renal injury was associated with changes in respiratory control of mitochondria with loss of acceptor control and with marked morphological changes seen ultrastructurally. The mitochondrial lipids showed losses of 29 and 46%, respectively, of phosphatidylethanolamine and cardiolipin. These biochemical changes may be the markers of the functional and ultrastructural derangements seen in toxic renal injury.

Acute Kidney Injury↗
PubMed1983

Increasing PGO spike density by auditory stimulation increases the duration and decreases the latency of rapid eye movement (REM) sleep.

The purpose of this study was to determine whether ponto-geniculo-occipital (PGO) spikes play a role in triggering or maintaining sleep. During the recording of the sleep cycle of cats, the appearance of the first PGO spike automatically triggered an auditory stimulus through a speaker placed in the cat's recording cage. The effect of this procedure was compared to similar period when no such stimulus was given. The results showed that the auditory stimulus increased PGO spike density during REM sleep. It also produced a spectacular increase in the duration of REM, while decreasing the latency of its appearance from the first PGO spike. It is suggested that the auditory stimulus reinforces the 'PGO system', which in turn may function as a pace-setter for priming and maintaining REM sleep.

Acoustic Stimulation↗
PubMed1983

Products derived from 5,8,11-eicosatrienoic acid by the 5-lipoxygenase-leukotriene pathway.

Analysis of products derived from 5,8,11-eicosatrienoic acid via the 5-lipoxygenase-leukotriene pathway showed that this fatty acid is readily converted to leukotriene (LT)A3. When 10,000 X g supernatant from rat basophilic leukemia cell homogenates was incubated with 30 microM fatty acid, 5,8,11-eicosatrienoic acid produced 6.2 +/- 1.1 nmol of LTA3 and arachidonic acid 15.5 +/- 1.9 nmol of LTA4 (n = 4). However, only insignificant amounts of LTB3 were formed (0.15 +/- 0.04 nmol of LTB3 and 4.2 +/- 0.4 nmol of LTB4, n = 4). These data indicate that the LTA-hydrolase requires not only the three double bonds of the triene but also the double bond at C-14 to efficiently convert LTA to LTB. These findings have significant implications for essential fatty acid deficiency.

8,11,14-Eicosatrienoic Acid↗