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Biomedical subjects

J A Oates

Publications and source records attributed to J A Oates.

At least 127 records · Page 7Linked to original sources
PubMed1982

Formation of a novel dihydroxy acid from arachidonic acid by lipoxygenase-catalyzed double oxygenation in rat mononuclear cells and human leukocytes.

Elicited rat peritoneal mononuclear cells converted arachidonic acid to a new dihydroxy acid, 5(S), 15(S)-dihydroxy-6,13-trans-8,11-cis-eicosatetraenoic acid (5,15-DiHETE). In this system, the amount of 5,15-DiHETE formed was about 20% that of leukotriene B4. The structure of the compound was determined by ultraviolet and mass spectrometric analysis, and comparison to a reference compound prepared by incubation of synthetic 5(R,S)-hydroxy- or hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5(R,S)-HETE or HPETE) with soybean lipoxygenase (linoleate:oxygen oxidoreductase, EC 1.13.11.12). Cell incubations performed under an atmosphere of 18O2 demonstrated that both hydroxyl groups in the cell product derived from molecular oxygen and that the oxygen atoms were from different oxygen molecules. Steric analysis indicated that each hydroxyl group had the S-configuration. The structural data thus indicate that 5,15-DiHETE is formed by an enzymatic double oxygenation of arachidonic acid catalyzed by both C-5 and C-15 lipoxygenases. Incubations with with [3H 8]5 (S)-HETE and [3H8]15(S)-HETE revealed that both compounds could be converted to the product. When [3H8]5(S), 15(S)-DiHPETE was added to cells, the majority of the substrate was reduced to 5,15-DiHETE. Leukocytes obtained from three human donors with peripheral blood eosinophilia also synthesized 5,15-DiHETE. Formation of the compound occurred in both eosinophils and neutrophils from these donors.

Animals↗
PubMed1982

Arachidonic acid 15-lipoxygenase products from human eosinophils.

A series of six derivatives of arachidonic acid containing a conjugated triene system and hydroxyl groups at C-15 and at C-8 or C-14 (15-series leukotrienes) was isolated from eosinophil-rich human leukocyte preparations. Among classes of leukocytes in these preparations, eosinophils were the dominant source of the 15-series leukotrienes. The most abundant arachidonate metabolite recovered from human eosinophils was 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid. This compound was synthesized by a lipoxygenase enzyme and is a reduction product of the precursor to the 15-series leukotrienes (15(S)-hydroperoxy-5,8,11-cis-13-trans-eicosatetraenoic acid).

Arachidonate Lipoxygenases↗
PubMed1982

Oxygenation of arachidonic acid by hepatic monooxygenases. Isolation and metabolism of four epoxide intermediates.

[3H]Arachidonic (eicosatetraenoic) acid was incubated with rabbit liver microsomes, NADPH, and 1 mM 1,2-epoxy-3,3,3-trichloropropane, an epoxide hydrolase inhibitor, for 15 min at 37 degrees C. The metabolites were separated by reverse phase high performance liquid chromatography and two epoxides, 11(12)oxido-5,8,14-eicosatrienoic acid and 14(15)oxido-5,8,11-eicosatrienoic acid, were identified by gas chromatography-mass spectrometry. Hepatic cytochromes P-450 purified from rabbits and rats treated with phenobarbital metabolized arachidonic acid to these two epoxides, as well as 5(6)oxido-8,11,14-eicosatrienoic acid and 8(9)oxido-5,11,14-eicosatrienoic acid and the corresponding vic-diols as the major products. Cytochromes P-450 purified from rabbits and rats treated with beta-naphthoflavone mainly formed (omega-1)- and omega-hydroxylated arachidonic acids, while the four epoxides and the vic-diols were formed in small amounts. Synthetic [14C]14(15)oxido-, 11(12) oxido-, 8(9)oxido-, and 5(6)oxidoeicosatrienoic acid were enzymatically converted to vic-diols by hepatic and renal cortical microsomal and cytosolic fractions and by purified liver microsomal epoxide hydrolase. Liver microsomes oxygenated the epoxides to many polar products in the presence of NADPH. All eight trihydroxy acids, formed by omega- or (omega-1)-hydroxylation of the four vic-diols, four vic-diol dicarboxylic acids, and other metabolites were identified by gas chromatography-mass spectrometry.

Animals↗
PubMed1982

Selection of an antiarrhythmic drug for a sudden-death-prevention trial.

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Acecainide↗
PubMed1982

Evidence for pulmonary release of 5-hydroxyeicosatetraenoic acid (5-hete) during endotoxemia in unanesthetized sheep.

Leukocyte trapping in the pulmonary circulation may be an important component of the lung vascular injury response to endotoxin, but mediators of the pulmonary leukostasis and increased lung vascular permeability are unknown. The leukocyte 5-lipoxygenation pathway of arachidonic acid metabolism yields highly biologically active products including leukotrienes C4 and D4 (formerly slow reacting substance of anaphylaxis) and the potent chemotaxin, leukotriene B4. A major product of 5-lipoxygenation is 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), for which a sensitive, stable isotope dilution assay employing combined gas chromatography-mass spectrometry is available. This assay was used to test the hypothesis that 5-lipoxygenation products might participate in pulmonary vascular responses to endotoxin. We measured 5-HETE concentrations in lung lymph at three intervals during endotoxemia in unanesthetized sheep. Concentrations of 5-HETE in lung lymph exceeded those in aortic blood plasma. Lymph 5-HETE concentrations increased from 1.7 +/- 0.3 (mean +/- SEM, N = 7) ng/ml during baseline to peak values of 6.1 +/- 1.8 ng/ml (p less than 0.05) during the 2 1/2 hours after endotoxemia and preceeding the steady state increased lung vascular permeability response. During the increased permeability steady state from 240 to 270 minutes after endotoxin, lymph 5-HETE concentrations (1.4 +/- 0.3 ng/ml) and lymph 5-HETE flow (i.e., 5-HETE concentration x lung lymph flow rate) returned to baseline values. Although these observations are consistent with the hypothesis that 5-lipoxygenation products participate in the pulmonary vascular injury response to endotoxin, lymph 5-HETE concentrations did not correlate with any of the other experimental measurements. It may be only coincidence that the increase in lymph 5-HETE concentrations appeared contemporaneous with the onset of lung vascular injury.

Animals↗
PubMed1982

Antiarrhythmic effects of the quaternary propranolol analog that does not induce beta-adrenergic blockade.

Pranolium chloride (dimethylpropranolol chloride) is a nonbeta blocking quaternary ammonium that has structural similarities to propranolol and bretylium that exert antiarrhythmic effects in animals. In initial studies, eight patients with chronic ventricular arrhythmias were given gradually increasing intravenous doses of pranolium (up to 3 mg/kg) obtaining plasma concentrations up to 7 micrograms/ml without change in pulse, blood pressure, or arrhythmia frequency. We therefore evaluated the response to pranolium in seven similar patients at doses up to 10 mg/kg as an infusion of 100 microgram/kg/min over 40 to 100 min. At plasma concentrations of 4.7 to 12.2 micrograms/ml, there was suppressing of ventricular ectopic depolarization (greater than 90%) in three subjects and in two others there was partial suppression (49% and 82%). Arrhythmia frequency was unchanged in two. At plasma concentrations of 4.1 to 17.2 micrograms/ml four subjects developed nausea (two of these also vomited) and to experienced perioral numbness. There was no change in sinus heart rate, supine or standing blood pressure, venous reflex response (adrenergic reflex venoconstriction), or ECG intervals in any subject. Pranolium appeared to have antiarrhythmic efficacy in five of seven subjects, without evidence of beta-adrenergic blockade or interference with sympathetic neuron function known to occur with its congeners, propranolol and bretylium. There is a narrow margin between pranolium efficacy and toxicity. It may, however, be a prototype for antiarrhythmic drugs that do not exert undesirable effects on the adrenergic nervous system.

Adult↗
PubMed1982

Evidence that alpha-methylepinephrine is an antihypertensive metabolite of alpha-methyldopa.

Several medullary cardiovascular relay nuclei contain high concentrations of epinephrine and phenylethanolamine-N-methyl transferase (PNMT), the enzyme which catalyzes the conversion of norepinephrine to epinephrine. Since alpha-methylnorepinephrine, a metabolite of alpha-methyldopa, has been shown to be a substrate for adrenal PNMT, we postulated that alpha-methylnorepinephrine would also be a substrate for central PNMT, resulting in the synthesis of alpha-methylepinephrine. Therefore, alpha-methylepinephrine could be an active metabolite of alpha-methyldopa. We have investigated this hypothesis. 1) The centrally-active PNMT inhibitor SKF-64139 attenuated the hypotensive response to alpha-methyldopa in spontaneously hypertensive rats at doses that had little effect on the hypotensive response to clonidine. 2) In radioligand binding studies, alpha-methylepinephrine was as potent as norepinephrine in competing for alpha 2-receptors, more potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for beta-receptors, and less potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for alpha 1-receptors. 3) Intracerebroventricular administration of methylepinephrine (1-40 micrograms) to Sprague-Dawley rats elicited profound hypotension and bradycardia. alpha-Methylepinephrine was more potent than epinephrine in lowering blood pressure. We conclude that alpha-methylepinephrine is a centrally active depressor agent and could therefore be an active metabolite of alpha-methyldopa.

Animals↗
PubMed1982

Effects of indomethacin on beta adrenoreceptor-stimulated renin release in the dog.

The hypothesis that prostaglandins participate in beta adrenoreceptor-stimulated renin release was tested by examining the effects of prostaglandin synthesis inhibition on renal nerve stimulation (0.5-5.0 Hz)-induced renin release. In phentolamine (5 micrograms/kg/min, intrarenal artery)-treated dogs (n = 6), renal nerve stimulation produced a frequency-related increase in renal renin secretion rate, without altering renal blood flow. In phentolamine plus propranolol (0.3 mg/kg i.v. bolus + 5 micrograms/kg/min infusion)-treated dogs (n = 6), renal nerve stimulation-induced renin release was inhibited by 86% (P less than .03), 75% (P less than .03) and 73% (P less than .02) at 1, 2 and 5 Hz, respectively. In contrast to propranolol, blockade of prostaglandin synthesis with indomethacin (8 mg/kg i.v. bolus) failed to alter the renin secretory response to renal nerve stimulation in phentolamine-treated animals. These results indicate that, in a situation of intrarenal alpha adrenoreceptor blockade, renal nerve stimulation induces renin secretion by a beta adrenoreceptor mechanism that is independent of prostaglandin biosynthesis.

Animals↗
PubMed1982

Surgical experience with retrogastric and retropancreatic pheochromocytomas.

From 1972 to 1981 at Vanderbilt University Hospital there were seven patients with midline retrogastric or retropancreatic pheochromocytomas. Each of these tumors arose between the aorta and the inferior vena cava. This report details the difficulties in localization before and at operation in the smaller tumors in these sites. Our experience suggests that small midline pheochromocytomas in these sites may be readily missed by computerized tomographic scan, aortography, or surgical search at laparotomy unless subtraction arteriograms are used and the Kocher maneuver is employed at operation routinely.

Adolescent↗
PubMed1982

Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE.

Anti-IgE-dependent activation of rat and human mast cells resulted in the preferential generation of the cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin I2 (PGI2) in the rat and PGD2 in the human. The average net generation of PGD2, determined by gas chromatography-mass spectrometry, was 13.1 ng/10(6) purified rat mast cells and 39.5 ng/10(6) dispersed, enriched human mast cells. After IgE-dependent activation, there was a linear relationship between the net quantities of PGD2 generated and of histamine secreted from dispersed human pulmonary cells when the number of mast cells was varied but the total number of cells was held constant, indicating that it is the number of mast cells participating in IgE-dependent activation, rather than total mast cell number, that determines PGD2 generation. A linear relationship was also shown between PGD2 generation, determined by radioimmunoassay, and the release of the granule marker beta-hexosaminidase from purified rat mast cells on the dose-response portion of the plot of their response to anti-IgE challenge. With higher concentrations of anti-IgE, PGD2 generation from rat mast cells plateaued, whereas net percent beta-hexosaminidase release increased further. In kinetic studies of rat mast cells activated with anti-IgE, the onset (1 to 2 min) and time of maximum generation (5 to 10 min) for PGD2 were delayed relative to the onset (15 to 30 sec) and completion (1 to 2 min) of beta-hexosaminidase release. Thus, the extracellular appearance of PGD2 during IgE-dependent mast cell activation represents a response additional to the secretion of granule-associated mediators.

Animals↗
PubMed1982

Assessment of the extent to exogenous prostaglandin I2 is converted to 6-keto-prostaglandin E1 in human subjects.

6-Keto-prostaglandin (PG) E1 has been suggested as a possible active metabolite of PGI2. The objective of this study was to evaluate whether 6-keto-PGE1 might mediate the biological responses of exogenous PGI2 in man. Toward this end, a novel gas chromatographic-mass spectrometric assay for 6-keto-PGE1, was developed. Selective ion monitor traces from human plasma detected levels that were at the lower limit of sensitivity for this assay and positive mass spectral identification was not possible. An infusion of PGI2 (8 ng/kg/min) which caused systemic hemodynamic changes did not alter plasma levels of 6-keto-PGE1. We conclude that exogenous PGI2 is not converted to an appreciable extent to 6-keto-PGE1 in man and, therefore, 6-keto-PGE1 biosynthesis is unlikely to be responsible for the biological effects of infused PGI2.

Adult↗
PubMed1982

Differential competition by L-alpha-methyldopa metabolites for adrenergic receptors in rat forebrain.

The capacity of a series of intraneuronal metabolites of L-alpha-methyldopa to compete for alpha-1 ([3H]prazosin, alpha-2([3H]clonidine and beta ([3H]dihydroalprenolol) receptor binding in rat forebrain was studied. Each metabolite studied had a unique order of activity at each receptor. These data show that (-)-erythro-alpha-methylnorepinephrine and (-)-erythro-alpha-methylepinephrine compete with high affinity for alpha-2 receptors, thereby supporting the suggestion that alpha-2 receptors mediate hypotensive effects of L-alpha-methyldopa . Furthermore, these metabolites of L-alpha-methyldopa competed with high potency for beta-1 receptors in forebrain and (-)-erythro-alpha-methylepinephrine was more potent than (-)-epinephrine, (-)-norepinephrine and (-)-erythro-alpha-methylnorepinephrine in competing for beta-2 receptors on human lymphocytes. These data suggest that beta receptor stimulation may be important in determining the net effects of L-alpha-methyldopa. L-alpha-Methyldopa metabolites were much less potent than (-)-epinephrine and (-)-norepinephrine in competition for alpha-1 receptors. (+/-)-alpha-Methyldopamine was less potent than other l-alpha-methyldopa metabolites at all three receptors, suggesting that it is unlikely to be an important hypotensive metabolite of L-alpha-methyldopa.

Animals↗