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Biomedical subjects

J A Oates

Publications and source records attributed to J A Oates.

At least 55 records · Page 3Linked to original sources
PubMed1989

Mechanistic studies of the dioxygenase and leukotriene synthase activities of the porcine leukocyte 12S-lipoxygenase.

Lipoxygenases react with hydroperoxy fatty acids and catalyze dioxygenase or dehydrase (leukotriene A4 (LTA4) synthase) types of reactions. In the present investigation we studied the mechanism of reaction of the purified porcine leukocyte 12S-lipoxygenase with 15S-hydroperoxyeicosatetraenoic acid (15S-HPETE). Oxygen-18 labeling experiments with GC-MS analysis were used to distinguish dioxygenase and leukotriene synthase activities of the enzyme; 8S,15S-DiHPETE and 14R,15S-DiHPETE were formed by oxygenation, and a series of 8,15- and 14,15-diols were formed via enzymatic synthesis of 14,15-LTA4 and nonenzymatic hydrolysis of the epoxide. 10D-3H- and 10L-3H-labeled substrates were used to study the stereospecificity of the C-10 hydrogen abstraction in the synthesis of these products. Formation of 14,15-DiHPETE and 14,15-LTA4 was associated with stereoselective abstraction of hydrogen from the 10L position of 15S-HPETE. The same type of measurements on the 8S,15S-DiHPETE product indicated a variable (50-250%) retention of the 10L-3H label, and a consistent 90% retention of the 10D-3H. In contrast, the synthesis of 8S,15S-DiHPETE by the soybean lipoxygenase was associated with the expected stereoselective abstraction of the 10D hydrogen. It appears that the porcine leukocyte 12S-lipoxygenase synthesizes 8S,15S-DiHPETE by a different mechanism.

Animals↗
PubMed1989

Allergen-stimulated release of mediators into sheep bronchoalveolar lavage fluid. Effect of cyclooxygenase inhibition.

Products of arachidonic acid have been implicated as potential mediators of allergic airway responses in sheep and in humans. We therefore measured the release of arachidonate metabolites into sheep bronchoalveolar lavage fluid (BALF) after local instillation of Ascaris antigen, using a highly specific and sensitive approach, gas chromatography-negative ion-chemical ionization mass spectrometry. Allergen instillation caused increases in the levels of the potent bronchoconstrictors prostaglandin (PG) D2 and thromboxane (TX) A2 (as reflected by levels of TXB2) and of their enzymatic metabolites, 9 alpha, 11 beta-PGF2 and 11-dehydro-TXB2, respectively. Potential bronchodilators, PGI2 and PGE2, were also formed in increased amounts. Levels of the 5-lipoxygenase products, leukotriene (LT) B4 and C4, were not significantly increased. Pretreatment of sheep with cyclooxygenase inhibitors was associated with a decrease in the release of cyclooxygenase products and a concomitant increase in the allergen-stimulated release of LTB4 and LTC4. Eicosanoids are formed promptly in vivo in sheep after allergen instillation: inhibition of cyclooxygenase results in augmented generation of leukotrienes in the airways of sensitive sheep in response to antigen challenge.

Allergens↗
PubMed1988

Pre-treatment with somatostatin in the anaesthetic management of a patient with carcinoid syndrome.

Carcinoid syndrome produces flushing, bronchoconstriction and gastrointestinal hypermotility secondary to serotonin, histamine, bradykinin and prostaglandin release. A variety of drugs, foods and anaesthetic agents may provoke this syndrome. Under anaesthesia, the flushing produced may be associated with acute hypotension and cardiovascular collapse; this phenomenon is called a carcinoid crisis. Recently, somatostatin analogue has been used successfully to treat intraoperative carcinoid crisis. In this report, we present a 66-year-old lady with carcinoid syndrome who was pre-treated with 50 micrograms somatostatin analogue IV and IM prior to surgical manipulation. The anaesthetic course was relatively uneventful and the patient did well postoperatively.

Aged↗
PubMed1988

Cigarette smoking and hemostatic function.

Epidemiologic studies clearly link cigarette smoking with vasoocclusive cardiovascular disease. Postmortem studies provide evidence of accelerated atherogenesis in asymptomatic smokers. However, the rapid regression of cardiovascular risk within the first year of quitting smoking is difficult to explain solely in terms of vascular disease. Recent evidence indicates that plasma fibrinogen, which has been prospectively associated with the risk of ischemic heart disease, is elevated in smokers. Similarly, results from studies investigating thromboxane metabolite excretion in urine confirm those involving radiolabeled platelet turnover, suggesting that platelets are activated in the circulation of chronic smokers. Altered hemostatic function, either as a direct result of smoking or caused by smoking-induced vascular damage, may account for the more rapidly reversible component of cardiovascular risk observed in chronic smokers.

Cardiovascular Diseases↗
PubMed1988

Hypertension complicating essential thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by marked thrombocytosis with associated hemorrhagic, thrombotic and embolic complications caused by platelet dysfunction. In this report we describe two cases of ET and moderate to severe hypertension associated with renal artery stenosis and renal microvascular lesions. In both cases treatment of the hematologic disorder resulted in reduction of blood pressure and improvement of clinical symptoms.

Adult↗
PubMed1988

Prostaglandin E2 attenuation of sheep lung responses to endotoxin.

Prostaglandin (PG) E2 can inhibit inflammatory responses of neutrophils and lymphocytes, including eicosanoid release. Diffuse lung injury after endotoxemia in sheep is accompanied by sequestration of neutrophils and lymphocytes in the lungs, and eicosanoids mediate some of the pathophysiology of the response. To determine whether exogenous PGE2 could prevent the endotoxin response, we measured pulmonary hemodynamics, gas exchange, and lung lymph responses to infusion of Escherichia coli endotoxin (0.5 micrograms/kg iv over 30 min) in unanesthetized sheep in the presence and absence of PGE2 (0.5 micrograms.kg-1.min-1) infused intravenously for 4 h beginning 0.5 h before endotoxin infusion. We also measured lung lymph concentrations of thromboxane B2 (TxB2) and prostacyclin metabolite, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), by radioimmunoassay and leukotriene B4 (LTB4) by gas chromatography-mass spectrometry. PGE2 decreased endotoxin-induced pulmonary hypertension and hypoxemia and markedly attenuated the lymph flow and lymph protein clearance responses. PGE2 also attenuated endotoxin-induced increases in lung lymph TxB2 and 6-keto-PGF1 alpha and decreased lymph LTB4 flow after endotoxin without decreasing lymph LTB4 concentrations. We conclude that PGE2 infusion attenuates lung dysfunction caused by endotoxemia, possibly by preventing endogenous release of other eicosanoids.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Antagonism of antihypertensive drug therapy by nonsteroidal anti-inflammatory drugs.

Certain nonsteroidal anti-inflammatory drugs antagonize the action of antihypertensive therapy. Indomethacin has been shown to abrogate the antihypertensive effect of beta-adrenergic receptor blockers, diuretics, converting enzyme inhibitors, and several antihypertensive drug combinations, and the accumulated evidence on piroxicam indicates that it also raises arterial pressure in treated patients. In contrast, sulindac and aspirin do not reverse the effects of antihypertensive drugs, and currently available data indicate that they are the safest cyclooxygenase inhibitors for use in hypertensive patients. In the absence of definitive information on the array of other nonsteroidal anti-inflammatory drugs, they should be considered to pose a risk similar to indomethacin until proved otherwise. The magnitude of the elevation in blood pressure varies between patients, ranging from no effect to dangerous hypertensive responses. Generalized inhibition of the cyclooxygenase enzyme has opposing effects on arterial pressure, lowering renin on one hand and causing sodium retention on the other. Some evidence suggests that cyclooxygenase inhibition causes the greater increments in pressure in patients who initially have low plasma renin activity (often the elderly). The potential for cerebral vascular catastrophes attends these drug interactions in which platelet function also is suppressed by cyclooxygenase inhibition.

Aged↗
PubMed1988

Normal SPECT thallium-201 bull's-eye display: gender differences.

The bull's-eye technique synthesizes three-dimensional information from single photon emission computed tomographic 201TI images into two dimensions so that a patient's data can be compared quantitatively against a normal file. To characterize the normal database and to clarify differences between males and females, clinical data and exercise electrocardiography were used to identify 50 males and 50 females with less than 5% probability of coronary artery disease. Results show inhomogeneity of the 201TI distributions at stress and delay: septal to lateral wall count ratios are less than 1.0 in both females and males; anterior to inferior wall count ratios are greater than 1.0 in males but are approximately equal to 1.0 in females. Washout rate is faster in females than males at the same peak exercise heart rate and systolic blood pressure, despite lower exercise time. These important differences suggest that quantitative analysis of single photon emission computed tomographic 201TI images requires gender-matched normal files.

Adult↗
PubMed1987

Lipoxin synthesis by arachidonate 12-lipoxygenase purified from porcine leukocytes.

Arachidonate 12-lipoxygenase purified from porcine leukocytes shows 14R-oxygenase and 14, 15-leukotriene A synthase activities with 15-hydroperoxy-arachidonic acid as substrate. The enzyme transformed 5, 15-dihydroperoxy-arachidonic acid to several compounds with a conjugated tetraene. A major product was identified as 5S, 14R, 15S-trihydroperoxy-6, 10, 12-trans-8-cis-eicosatetraenoic acid, which was reduced to 5S, 14R, 15S-8-cis-lipoxin B. A requirement of molecular oxygen and the results of H2(18)O experiments suggested that formation of the latter compound was attributed mostly to the 14R-oxygenase activity of the enzyme. There were several other minor products identified as lipoxin A and B isomers. They were produced presumably by hydrolysis of 14, 15-epoxy compound formed by the leukotriene A synthase activity of 12-lipoxygenase.

Animals↗
PubMed1987

Eicosanoid biosynthesis in human cardiovascular disease.

Thromboxane A2, the predominant cyclooxygenase product in platelets, is a potent platelet agonist and vasoconstrictor in vitro. Prostacyclin, the major product of vascular endothelium, has opposite effects on platelet function and vascular tone. These properties prompted the hypothesis that a "balance" between these compounds regulated interactions between platelets and the vessel wall in vivo. Although this possibility has been addressed extensively through experiments in vitro, clinical investigations commonly have been confounded by problems with analytic methodology, by selection of inappropriate metabolic targets for analysis, and by artifacts of trial design. The most reliable forms of assessing biosynthesis that are currently available still do not provide definitive information as to the tissue of origin of the compound studied and are directed toward stable but biologically inactive metabolites rather than the evanescent primary compounds themselves. Despite these limitations, both biochemical evidence and clinical trials clearly implicate thromboxane A2 as an important mediator of vascular occlusive disease in humans. The role of prostacyclin is much more conjectural. It does not circulate in concentrations sufficient to exert a systemic effect, but it may play a local homeostatic role in the regulation of platelet-vascular interactions. Whether preservation of the capacity to form prostacyclin coincident with inhibition of thromboxane A2 is of functional importance can be addressed only by clinical trials comparing inhibitors of thromboxane synthesis inhibition that are selective with cyclooxygenase inhibitors that also block the biosynthesis of prostacyclin. The recognition that multiple factors have the potential to regulate both platelet and vascular function at their interface renders the concept of a thromboxane A2-prostacyclin "balance" somewhat unlikely. However, both eicosanoids may interact with other factors to determine the development or persistence of vascular occlusion. Inhibition of the synthesis or function of thromboxane A2 remains the predominant mechanism for achieving interference with platelet function in vivo. Accumulating evidence for the efficacy of aspirin in human syndromes of vascular occlusion suggests that the biologic role of these compounds in humans should be pursued.

Cardiovascular Diseases↗
PubMed1987

Epoxygenase metabolites of arachidonic acid inhibit vasopressin response in toad bladder.

In addition to cyclooxygenase and lipoxygenase pathways, the kidney can also metabolize arachidonic acid by a NADPH-dependent cytochrome P-450 enzyme to epoxyeicosatrienoic acids (EETs); furthermore, 5,6-EET has been shown to alter electrolyte transport across isolated renal tubules. We examined the effects of three EETs (5,6-, 11, 12-, and 14,15-EET) on osmotic water flow across toad urinary bladder. All three EETs reversibly inhibited vasopressin-stimulated osmotic water flow with 5,6- and 11,12-EET being the most potent. The effects appeared to be independent of prostaglandins. EETs inhibited the water flow response to forskolin but not (with the exception of 11,12-EET) the response to adenosine 3',5'-cyclic monophosphate (cAMP) or 8-BrcAMP, consistent with an effect on cAMP generation. For 11,12-EET the question of an additional inhibition at a site beyond or independent of cAMP has to be considered. To determine whether these effects were due to the EETs or to products of their metabolism, we examined the effects of their vicinal diol hydrolysis products, the dihydroxyeicosatrienoic acids. Nonenzymatic conversion of labeled 5,6-EET to its vicinal diol occurred rapidly in the buffer, whereas 11,12-EET was hydrolyzed in a saturable manner only when incubated in the presence of bladder tissue. The dihydroxyeicosatrienoic acids formed inhibited water flow in a manner paralleling that of the EETs. Both 5,6-EET and 11,12-EET (10(-5) M) prevented the increase in intracellular cAMP content observed in control tissues after vasopressin stimulation. Finally, 11,12- and 14,15-dihydroxyeicosatrienoic acid inhibited vasopressin- and forskolin-stimulated adenylate cyclase in the same rank order as their inhibition of water flow.(ABSTRACT TRUNCATED AT 250 WORDS)

8,11,14-Eicosatrienoic Acid↗
PubMed1987

Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes.

Cigarette smoking is associated with increased mortality from cardiovascular disease that declines after cessation. This study extends the evidence regarding the effects of chronic smoking on platelets and the vessel wall in vivo. Excretion of a major urinary thromboxane metabolite, 2,3-dinor-thromboxane B2, is significantly (p less than .01) elevated in apparently healthy chronic smokers (20 cigarettes daily) compared with that in nonsmoking control subjects. This difference in excretion of 2,3-dinor-thromboxane B2 was abolished by the administration of 20 mg aspirin twice daily, a dose shown to selectively inhibit platelet cyclooxygenase. After aspirin, the return of the excretion of 2,3-dinor-thromboxane B2 to pretreatment levels paralleled the recovery of platelet cyclooxygenase. These findings indicate that excessive thromboxane A2 generation in chronic smokers predominantly derives from platelets. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha also is increased during chronic cigarette smoking, as is the case with other diseases associated with accelerated interaction of platelets with the vessel wall. We have found evidence of platelet and vascular dysfunction in vivo in chronic cigarette smokers before the manifestation of overt cardiovascular disease. The results would also be consistent with the hypothesis that in chronic smokers, the platelet defect is largely reflective of smoking-induced vascular injury.

Adult↗