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Biomedical subjects

W J Elliott

Publications and source records attributed to W J Elliott.

At least 73 records · Page 4Linked to original sources

Equivalent antihypertensive effects of combination therapy using diuretic + calcium antagonist compared with diuretic + ACE inhibitor.

To test the hypothesis that the combination of a calcium antagonist and diuretic is less effective in lowering BP than the combination of ACE inhibitor plus diuretic, we compared two groups of patients. The first was a group of 157 consecutive patients (32% male, 90% black, aged 57 +/- 1 years) in whom the only change in therapy was the addition or deletion of either a calcium antagonist or diuretic. Each patient served as his/her own control, with a follow-up time of 41 +/- 4 days. The BP responses of this group were compared with those of another group of 170 consecutive patients (33% male, 85% black, aged 55 +/- 1 years), who had had the addition or deletion of an ACE inhibitor or diuretic some 32 +/- 2 days previously. As there were no statistically significant differences either between drugs within the classes or between the addition or deletion of a drug, the BP results were pooled. Combination therapy with calcium antagonist + diuretic was associated with a 13.4 +/- 1.7/5.4 +/- 0.9 mmHg drop in supine BP; the ACE inhibitor + diuretic combination lowered supine BP by 12.3 +/- 1.6/8.0 +/- 0.9 mmHg compared with monotherapy (all P less than 0.001 by paired t-test). The effects on standing BP were similar: calcium antagonist + diuretic, 13.2 +/- 1.9/5.6 +/- 0.9 mmHg; and ACE inhibitor + diuretic, 12.3 +/- 1.5/7.0 +/- 0.9 mmHg (all P less than 0.001). There were no significant differences in BP responses between the calcium antagonist + diuretic and ACE inhibitor + diuretic combinations. These data indicate that, regardless of the order of addition or subtraction, the combination of calcium antagonist + diuretic was more effective in lowering BP than either agent used alone, and that the combination of calcium antagonist + diuretic was as effective as the ACE inhibitor + diuretic combination.

Angiotensin-Converting Enzyme Inhibitors↗

Improved safety of glucagon testing for pheochromocytoma by prior alpha-receptor blockade. A controlled trial in a patient with a mixed ganglioneuroma/pheochromocytoma.

The glucagon stimulation test has been superseded in recent years by the clonidine suppression test because it can provoke dangerous increases in blood pressure in patients with pheochromocytomas. We describe the first patient in whom a pheochromocytoma was diagnosed by a glucagon test, after which the blood pressure (but not the plasma catecholamine) response to a second injection of glucagon was blocked by pretreatment with phenoxybenzamine. After the tumor (which contained both pheochromocytoma and ganglioneuroma tissue) was removed, a third glucagon test result was negative. This experience suggests that patients with normal plasma catecholamine levels who are suspected of harboring a pheochromocytoma may be accurately diagnosed, but potentially dangerous increases in blood pressure may be minimized, by performing the glucagon test after alpha-adrenergic blockade.

Adrenal Gland Neoplasms↗

Reduced specificity of the clonidine suppression test in patients with normal plasma catecholamine levels.

Although originally devised to discriminate between patients with pheochromocytoma and those with elevated plasma catecholamine levels for other reasons, the clonidine suppression test has recently been used in patients with normal resting catecholamine levels. Upon review of 49 patients evaluated for pheochromocytoma, 26 had elevated plasma norepinephrine levels and underwent clonidine suppression testing. Only one of 13 patients with sustained elevated norepinephrine levels before clonidine administration had a false-positive clonidine test result, in contrast to five of 13 patients whose pre-clonidine norepinephrine levels had decreased into the normal range. This difference was statistically significant (by chi-square) at p less than 0.05. Clonidine suppression testing for pheochromocytoma should be performed only in patients with elevated catecholamine levels, because it carries a higher false-positive rate in patients with normal resting norepinephrine levels; a more accurate diagnosis may be made in such patients using glucagon stimulation tests.

Adrenal Gland Neoplasms↗

Evaluation of the Suntech Accutracker. A novel noninvasive ambulatory blood pressure monitor.

The "Accutracker," a novel ambulatory blood pressure monitor based on auscultation triggered by the electrocardiographic R wave, was evaluated by comparing its blood pressure readings with those obtained by direct auscultation. Simultaneous measurements were made (in 24 volunteers, by 4 trained observers) using a Y connector so that the Accutracker and a mercury sphygmomanometer were in parallel. Average blood pressure by direct auscultation (215 readings) was 129.1 +/- 12.0/77.8 +/- 14.4, and by Accutracker was 130.9 +/- 13.0/75.9 +/- 14.5 mm Hg (P less than 0.01). The Accutracker overestimated systolic blood pressure by 1.7 +/- 5.8 and underestimated diastolic blood pressure by 1.9 +/- 7.6 mm Hg. The average difference between pairs of readings was 5.0 mm Hg for systolic and 5.5 mm Hg for diastolic pressure. These data indicate that the concordance of blood pressure readings recorded by Accutracker and direct auscultation is sufficient to justify its use in noninvasive ambulatory blood pressure monitoring.

Auscultation↗

Comparison of the effects of dopamine and fenoldopam, a selective dopamine-1 agonist, on parathyroid hormone release in man.

Dopamine has been reported to transiently increase parathyroid hormone (PTH) secretion in man; however, the mechanism is unclear. To test the hypothesis that selective dopamine-1 receptor (DA1) stimulation increases PTH secretion, we compared the effects of fenoldopam, a novel selective DA1 receptor agonist, as well as dopamine on serum PTH secretion and total serum calcium concentration in seven normal human subjects. Dopamine was infused at 1 and 3 micrograms/kg/min, each for 10 minutes, and 5 micrograms/kg/min for 25 min. Fenoldopam was infused at 0.1 and 0.3 micrograms/kg/min, each for 10 min. and thereafter at 0.5 micrograms/kg/min for 25 min. The infusions were given at least 1 week apart. Blood samples for PTH, calcium and dopamine or fenoldopam concentrations were drawn prior to and at the 25th minute of each drug infusion. PTH concentrations increased in all subjects at the 25th minute of dopamine but not fenoldopam infusion. Serum calcium was not significantly affected. The plasma concentrations of both dopamine (83.6 +/- 7.1 ng/ml) and fenoldopam (13.0 +/- 3.4 ng/ml) were in the range known to cause equivalent DA1 receptor stimulation. Since dopamine but not fenoldopam increased PTH secretion in man, we conclude that selective DA1 receptor stimulation alone does not increase PTH release and the effects of dopamine must be mediated through some other mechanism.

Adolescent↗

Calcium-dependent oxidation of 5,8,11-icosatrienoic acid by the cyclooxygenase enzyme system.

Mead (5,8,11-icosatrienoic) acid was found to be metabolized by the cyclooxygenase enzyme system of ram seminal vesicle microsomes in a calcium-dependent manner. Although the enzyme converted Mead acid to products more slowly and less completely than the isomeric 8,11,14-icosatrienoic acid, both oxidations were inhibitable by indomethacin. Experiments using purified cyclooxygenase confirmed the participation of this enzyme system in the calcium-dependent oxidation. The products of the oxidation were separated by high performance liquid chromatography and analyzed by ultraviolet and gas chromatography-mass spectrometry. The spectra obtained were consistent with the products having the structures 13-hydroxy-5,8,11-icosatrienoate (the major product), 11-hydroxy-5,8,12-icosatrienoate, 9-hydroxy-5,7,11-icosatrienoate, and two isomeric 8,11-dihydroxy-5,9,12-icosatrienoates. No prostaglandin-like, cyclized products could be identified. This report is only the second to illustrate a calcium-dependent oxidation of a polyunsaturated fatty acid by a cyclooxygenase enzyme system and further extends the metabolic potential of Mead acid.

8,11,14-Eicosatrienoic Acid↗

Essential fatty acid deficiency: a new look at an old problem.

Essential fatty acid (EFA) deficiency is a useful tool to study the role of arachidonate and its metabolites in various physiologic and pathologic states. Recent studies have clarified the effects of EFA deficiency on membrane arachidonate and its metabolites, and have demonstrated that 20:3(n-9) (which accumulates in EFA deficiency) can be metabolized to a variety of eicosanoids. EFA deficiency has been shown to exert an anti-inflammatory effect. The mechanism of this effect may in part be mediated through a decrease in leukocyte leukotriene formation. In contrast, studies using the novel fatty acid, columbinic acid, have shown that the epidermal dysfunction seen in EFA deficiency may be a function of linoleate and its lipoxygenase metabolites rather than of arachidonate and the prostaglandins. Finally, it has recently been shown that EFA deficiency potentiates the effects of volatile anesthetics. EFA deficiency may thus provide a useful tool to investigate the molecular mechanism of these drugs.

Anesthetics↗

Manipulation of rat brain fatty acid composition alters volatile anesthetic potency.

The molecular mechanism of volatile anesthetic action remains unknown. Attempts to elucidate this mechanism have been complicated by the absence of models in which changes in neuronal cellular properties can be correlated with changes in whole animal anesthetic effect. In this study we describe a model where diet-induced alterations in rat brain fatty acid composition are correlated with alterations in volatile anesthetic potency. Rats maintained on a fat-free diet showed significant depletion of arachidonic acid (20:4 omega 6; 5,8,11,14-eicosatetraenoic acid) and docosahexaenoic acid (22:6 omega 3; 4,7,10,13,16,19,-docosahexaenoic acid) in brain, and a corresponding increase in Mead acid (20: 3 omega 9; 5,8,11-eicosatrienoic acid). These fat-deprived rats were significantly more sensitive to all volatile anesthetics tested than were age-controlled rats on a normal diet. Parenteral supplementation of the fat-deprived animals with linolenic acid (18: 3 omega 3, 9,12,15-octadecatrienoic acid) completely reconstituted the docosahexaenoic acid content of brain without affecting anesthetic sensitivity. In contrast, supplementation of the fat-deprived rats with linoleic acid (18: omega 6; 9,12-octadecadienoic acid) caused a dramatic decrease in anesthetic sensitivity, but only a small change in whole brain arachidonate content. Further analysis revealed that linoleate supplementation of fat-deprived animals resulted in a preferential normalization of the arachidonate content of brain phosphatidylinositol as compared with other brain phosphoglycerides. These results demonstrate for the first time a correlation between changes in membrane composition and anesthetic effect, and indicate that the precise fatty acid composition (perhaps in specific phospholipids) of brain is important in the mechanism of volatile anesthetic action.

Anesthetics↗

A unique cardiac cytosolic acyltransferase with preferential selectivity for fatty acids that form cyclooxygenase/lipoxygenase metabolites and reverse essential fatty acid deficiency.

The rabbit heart contains a cytosolic enzyme which selectively incorporates polyunsaturated fatty acids into phosphatidylcholine. This unique acyltransferase is selective for fatty acids, thus far tested, that are substrates for cyclooxygenase or lipoxygenase (i.e., arachidonic, eicosapentaenoic, linoleic and dihomo-gamma-linoleic acids) or which reverse the symptoms of essential fatty acid deficiency (columbinic acid). On the other hand, palmitic, oleic, 5,8,11-eicosatrienoic (n-9, Mead acid), and docosatetraenoic acid (n-6, adrenic acid) were not incorporated in phospholipids by the cytosolic acyltransferase. No such fatty acid selectivity was exhibited by the cytosolic acyl-CoA synthetase or by the acyltransferase activities present in cardiac microsomes and mitochondria.

Acyltransferases↗

Physiologic effects of columbinic acid and its metabolites on rat skin.

Columbinic acid and its cyclooxygenase and lipoxygenase metabolites were applied topically to the skin of essential fatty acid-deficient rats and their transepidermal water loss was measured. Despite the ability of the major lipoxygenase metabolite to reverse the scaly dermatitis, neither metabolite of columbinate was able to normalize the epidermal water loss, but the parent acid lowered the measurements in a dose-dependent fashion. These results indicate that some essential fatty acids have important functions as such, and not merely as precursors for other, biologically active, oxygenated metabolites.

Animals↗

The metabolic transformations of columbinic acid and the effect of topical application of the major metabolites on rat skin.

The metabolism of columbinic acid by various fatty acid oxidizing enzyme systems was studied. A cyclooxygenase product, 9-hydroxy-(5E,10E,12Z)-octadecatrienoic acid, was formed nearly quantitatively by ram seminal vesicle microsomes and in small amounts by washed human platelets. The major lipoxygenase product from washed human platelets, soybean lipoxygenase, and neonatal rat epidermal homogenate was 13-hydroxy-(5E,9Z,11E)-octadecatrienoic acid, although lesser quantities of other isomers differing in the double bond configurations were also identified by ultraviolet spectrophotometry and gas chromatography-mass spectroscopy. Topical application of the major lipoxygenase product to paws of essential fatty acid-deficient rats resulted in nearly as complete resolution of the scaly dermatitis as did the application of columbinic acid itself; the cyclooxygenase product was not at all effective.

3-Hydroxyacyl CoA Dehydrogenases↗

Arachidonic acid metabolism by rabbit fetal membranes of various gestational ages.

The ability of rabbit fetal membranes to convert arachidonic acid to both lipoxygenase and cyclooxygenase products was studied by separation and identification of products derived from incubations of 1-14C-arachidonate with subcellular fractions obtained by differential centrifugation of tissue homogenates. Both amnion and splanchnopleure (the chorion-equivalent of the rabbit) produced a mixture of 11-, 12-, and 15-hydroxyeicosatetraenoic acids when stimulated by calcium ions; these products were produced in greater quantity in middle pregnancy (20-22d) than later (28-30d). Cyclooxygenase products included PGD2, PGE2, TxB2 and PGF2 alpha, all of which were made more actively in late pregnancy than the middle in both amnion (which was more active) and chorion-equivalent. These data suggest that arachidonate metabolism by rabbit fetal membranes in middle pregnancy is directed primarily toward production of monohydroxy fatty acids, but that as pregnancy nears term, the PG-producing enzymes are induced, preparing the uterine smooth muscle for parturition.

Amnion↗

Ear lobe crease and coronary artery disease. 1,000 patients and review of the literature.

One thousand unselected patients admitted to large urban medical centers were examined for the presence of a diagonal ear lobe crease and evaluated for the presence of coronary artery disease. A high degree of correlation between the two was seen, using both clinical and angiographic criteria for the diagnosis of coronary artery disease. The association between the ear lobe crease and coronary artery disease was independent of patient age. Prospective analysis of single risk factors in 112 consecutive patients subjected to coronary cineangiography revealed that demonstrable coronary artery disease was correlated only with the ear lobe crease and with previous acute myocardial infarction (although less strongly with the latter). These conclusions are consistent with those of the world's literature, which also finds a strong correlation between coronary artery disease and the ear lobe crease, with the exception of Oriental patients, native American Indian patients, and children with Beckwith's syndrome.

Adolescent↗

Systematic discovery and evaluation of complement inhibitors.

Methods are presented for an orderly search of a chemical file for complement inhibitors. Compounds are initially examined for intrinsic activity against dilute human components in vitro, using hemolytic assays to detect inhibitors of fluid phase C1, of late components lysis of EAC142, and of CVF-induced passive lysis of AET-treated human erythrocytes. Active compounds are then examined for activity against undiluted serum in vitro. Compounds passing this test are examined for activity in vivo against serum complement and complement-dependent lesions, viz. Forssman vasculitis, the reverse passive Arthus phenomenon, and Forssman shock. Methods are given for quantitation of these lesions.

Animals↗