A study of receptors activated by analogues of prostaglandin H2 [proceedings].
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Animals↗
Biomedical subjects
D E Wilson
Publications and source records attributed to D E Wilson.
Hyperlipidemia in renal failure: studies of plasma lipoproteins, hepatic triglyceride production, and tissue lipoprotein lipase in a chronically uremic rat moedl.
To determine whether hypertriglyceridemia in chronic renal failure resulted from altered production and/or removal, Sprague-Dawley rats in which chronic uremia had been induced by five-sixths nephrectomy were studied. In this model, basal plasma TG levels were higher than in controls (uremic 141 +/- 52 mg/100 ml; control 83 +/- 25; mean +/- SD; p less than 0.001) at 1 month after nephrectomy and remained significantly elevated throughout the 10-week duration of study. In the uremic animals hepatic TGSR's (Triton) were not increased (uremic 0.56 +/- 0.11 mg/min; control 0.63 +/- 0.13) and AcCoAc, the rate-limiting enzyme in hepatic lipogenesis, was significantly reduced (control 24.5 +/- 3.8 nM/min/mg protein; uremic 18.2 +/- 1.1; p less than 0.005). The TG removal system--heparin-elutable LPL activities--was similar in control and uremic animals in heart, diaphragm, and adipose tissue. However, serum from both acute and chronically uremic rats lowered adipose LPL activity (P less than 0.01). These observations suggest that in uremia (1) TG production is not increased and (2) the clearance of TG-rich lipoprotein from the circulation is reduced because of a functional impairment in LPL.
Acetyl-CoA Carboxylase↗
Prostaglandin therapy for peptic ulcer disease.
The demonstration of inhibition of acid secretion in man or cytoprotection in animals is not proof of efficacy in clinical disease. Indeed, there has been continued debate up to now as to whether any of our previous standard therapies for peptic ulcer disease did more than alleviate symptoms. The use of the fiberoptic endoscope to locate and measure ulcers precisely and evaluate the progress of ulcer healing may finally allow us to assess the efficacy of new therapy. Several endoscopically controlled studies abroad have found PG analogs to be effective in both gastric and duodenal ulcer disease. Clearly, well-controlled, large clinical trials are needed to assess the efficacy of these compounds when compared to placebo and other modes of therapy. A close watch must be kept to detect the possible development of toxicity or other unwanted effects. We are still at an early stage in the development of the specific PG molecule that will affect only the stomach and duodenum in a favorable way, while having no effect on other tissues. When we come close enough to this goal, a PG may be the drug of choice for peptic ulcer disease in man.
Animals↗
Tissue lipoprotein lipase in the hyperthyroid rat. Effect of growth and aging.
The hydrolysis of lipoprotein triglycerides is catalyzed by lipoprotein lipase (LPL), an enzyme found in many tissues. We have examined tissue LPL activity (LPLA) in rats with experimentally-induced hyperthyroidism. In younger, lighter rats, hyperthyroidism was accompanied by a decrease in LPL in adipose tissue whereas heart and diaphragm muscle LPL activities were increased. These changes are consistent with the hypothesis that the hypercatabolism and increased beta-adrenergic activity of hyperthyroidism result in characteristic changes in tissue LPLA. In older, heavier hyperthyroid animals, however, adipose tissue LPLA was increased and heart and diaphragmatic LPLA were similar to control activities. Propranolol feeding abolished the thyroxine-induced increase in adipose tissue LPLA. In euthyroid animals of similar size the response of muscle LPLA to short-term starvation was also attenuated. These changes in tissue LPLA may provide a mechanism for shunting triglyceride fatty acids away from adipose tissue for utilization by muscle in the hyperthyroid state. During growth and aging, these adaptations are modified.
Adipose Tissue↗
Bat mortality: pesticide poisoning and migratory stress.
Organochlorine residues in the fat of young Mexican free-tailed bats, Tadarida brasiliensis, reached the brain and caused symptoms of poisoning after the fat mobilization that takes place during migratory flight was simulated. These chemical body burdens were obtained naturally under free-living conditions at the maternity roost. The data obtained support the hypothesis that pesticides have contributed to recent declines in populations of this bat.
Adipose Tissue↗
Estrogen treatment and gonadal function in the regulation of lipoprotein lipase.
Lipoprotein lipase (LPL) activity was measured in adipose tissue, heart and diaphragm in Sprague--Dawley rats after estrogen therapy or orchiectomy. Enzyme activity was measured by incubation of tissue fragments with a triolein emulsion in the presence of serum and heparin. In confirmation of other work, depression of adipose tissue LPL followed estradiol treatment in pharmacologic or near-physiologic doses. Cardiac and diaphragmatic muscle LPL were increased. Estrogen-treated male animals showed growth retardation. However, they gained weight steadily and did not show significant differences in serum insulin, glucose of D-beta-hydroxybutyrate. The effects of estradiol in male animals were reversed by sequential fasting and re-feeding. At times during growth and aging in normal female rats, adipose tissue activity was decreased while cardiac and skeletal muscle activities were increased relative to males of the same age or body weight. Castration of male rats failed to reproduce the effect of estrogens on tissue lipoprotein lipase. These in vitro data suggest that exogenous estrogens may shift the flux of triglyceride fatty acids from storage in the adipose organ toward incorporation by muscle. These, and other data, raise the possibility that physiological estrogen secretion exerts a tonic influence over the synthesis and ultimate destination of triglyceride fatty acids.
Adipose Tissue↗
Uric acid catabolism in the woolly monkey.
The degradation and excretion of 2-14C-uric acid were examined in three adult woolly monkeys (Lagothrix lagothrichia) to determine the basis for the relatively high serum and urinary uric acid concentrations previously reported in this species. Like man and the great apes which lack uricase, but in distinction to most other mammals, these animals converted very little urate to allantoin. Uric acid turnover, as has been reported for other New World monkeys, was several times that of normal man. Renal urate excretion as well as disposition by extrarenal mechanisms may protect Lagothrix vrom hyperuricemia. The capacity to convert urate to allantoin appears to have been lost late in the evolution of New World monkeys. The woolly monkey deserves further study as a primate model for investigations of enzyme replacement strategies.
Animals↗
Heparin metabolism and heparin-release lipase activity during long-term estrogen-progestin treatment.
Short-term oral contraceptive therapy has been reported to decrease postheparin lipolytic activity (PHLA). Resistance to heparin has been held responsible for this effect. To test several alternative explanations, we studied both PHLA and heparin concentrations in nine control women and nine women receiving long-term estrogen-progestin therapy after they were given heparin intravenously (10 units/kg). There were no significant differences in the concentration of heparin, its rate of disappearance, or calculated space of distribution between control and treated groups. PHLA was depressed (p less than 0.05) by approximately 50% during long-term estrongen-progestin therapy. PHLA disappearance was similar in both groups. Thus, reduced PHLA in women receiving long-term oral contraceptive therapy cannot be related to altered heparin metabolism or to accelerated enzyme disappearance from plasma. Long-term estrogen-progestin administration may decrease the heparin-facilitated release of individual triglyceride hydrolase activities or enhance the affinity of enzyme binding to tissues.
Contraceptives, Oral↗
Adenylate kinases in man: evidence for a third locus.
The tissue distribution of the adenylate kinase isozymes in man has been examined using various substrates. The isozymes attributable to the AK1 and AK2 loci were identified, and an additional set of isozymes probably attributable to a third locus was also found. This locus has been provisionally designated AK3. The AK3 isozymes show activity with either GTP + AMP or ITP + AMP but do not show activity with ATP + AMP. They also differ from the AK1 and AK2 isozymes in electrophoretic mobility and from the AK1 isozymes in being resistant to silver inhibition. They are similar in molecular size to the AK1 isozymes whereas the AK2 isozymes are apparently larger. The AK3 isozymes evidently correspond to the enzyme nucleosidetriphosphate-adenylate kinase (2.7.4.10). Somatic cell hybrid studies indicate that the AK3 locus is not syntenic with that of AK2 (chromosome 1). The AK3 locus is however, probably syntenic with the AK1 locus, on chromosome 9. Genetically determined variation of AK3 has not been seen in a survey of about 80 individuals.
Adenosine Monophosphate↗
Evidence for the assignment of the loci AK1, AK3 and ACONs to chromosome 9 in man.
The segregation of human enzymes and chromosomes has been studied in more than 30 independent primary human-rodent somatic cell hybrids and a series of 64 subclones. The results strongly suggest that the locus determining AK1, 'red cell' adenylate kinase, is on chromosome 9 in man, and hence that the locus for the ABO blood groups and that for the Nail-patella syndrome may also be assigned to this chromosome. Evidence is presented indicating that another adenylate kinase, nucleoside triphosphate adenylate kinase, and also the soluble form of aconitase, are probably syntenic with AK1, and that the mitochondrial form of aconitase is probably not syntenic with these loci.
Aconitate Hydratase↗
Adenylate kinase and aconitase in human-rodent somatic cell hybrids.
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Aconitate Hydratase↗
Inhibition of stimulated gastric secretion by an orally administered prostaglandin capsule. A study in normal men.
The effect of ingestion of a gelatin capsule containing 127 mug of 16,16-dimethyl prostaglandin E2 (DM-prostaglandin E2) or a liquid containing 127 mug of DM-prostaglandin E2 on stimulated gastric secretion in man was studied. DM-prostaglandin E2 significantly reduced the volume, acid concentration, and total acid output of gastric secretion. Secretory inhibition during the 3 h after treatment with the capsule was 37% (volume), 39% (acid concentration), and 60% (acid output). The DM-prostaglandin E2 capsule was nearly as effective as equivalent amount of DM-prostaglandin E2 in solution. Prostaglandin analogues, because of their oral effectiveness and duration of action, may have therapeutic value in peptic ulcer disease.
Administration, Oral↗
Mechanism(s) of hyperlipidemia in chronic uremia.
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Adipose Tissue↗
Adenylate kinase and aconitase in human-rodent somatic cell hybrids.
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Aconitate Hydratase↗
Prostaglandin E in cholera toxin-induced intestinal secretion. Lack of an intermediary role.
Prostaglandin E1 (PGE1) and cholera enterotoxin stimulate small-intestine mucosal adenylate cyclase and intestinal secretion of water and electrolytes. The previous suggestion that PGE may mediate cholera-toxin effects was explored in these studies. Closed rabbit jejunal loops were injected in vivo with cholera toxin and compared to similar loops in the same animal injected with buffer. Loop mucosal homogenates and intestinal secretions were analyzed by radioimmunoassay for cAMP and PGE concentrations. Cholera toxin produced significant increases in mucosal and intestinal fluid cAMP; however, there were no significant increases in PGE in the toxin-treated loops when compared to the control loops. In addition, there was no correlation between cAMP and PGE in the same samples. These studies indicate that cholera toxin stimulates intestinal cAMP anc secretion independent of PGE synthesis and provide evidence against a specific role for PGE in mediating cholera-toxin effects.
Animals↗
Multiple myeloma, cryoglobulinemia and xanthomatosis. Distinct clinical and biochemical syndromes in two patients.
Studies were carried out in two patients with multiple myeloma (immunoglobulin G, [IgG], K light chain), cryoglobulinemia and xanthomatosis with clinical features and lipid transport abnormalities which were quite different. One patient had nodular xanthomatosis and lipemia with delayed triglyceride and apolipoprotein removal. In vivo heparin resistance was present and heparin-paraprotein interaction was shown in vitro. The lipoprotein removal defect may have been due to impaired uptake of the "remnants" of glyceride-rich lipoproteins. Abnormalities were found both in primary platelet aggregation and in the platelet release reaction. The second patient had diffuse plane xanthomatosis with normal lipids. An orange cryoprecipitate contained IgG, beta- and prebeta lipoproteins, albumin, carotenoids and about half of the serumcholesterol. Triglyceride turnover was normal. These observations show that M-proteins may interfere with lipid transport by at least two mechanisms and illustrate the clinical diversity of xanthomatous myeloma.
Adult↗
Effects of indomethacin on intestinal secretion, prostaglandin E and cyclic AMP: evidence against a role for prostaglandins in cholera toxin-induced secretion.
The effects of indomethacin on intestine mucosal cAMP, intestinal fluid secretion, and mucosal and fluid PGE were studied in rabbits in vivo following challenge with cholera toxin. Indomethacin had no effect on cholera toxin-induced fluid secretion or cAMP accumulation. Inhibition of PGE synthesis was achieved by the administration of two but not one injection of indomethacin. These studies provide evidence against a role for PGE in mediating cholera toxin-induced secretion and point out the need to measure prostaglandin levels when using prostaglandin synthetase inhibitors in vivo.
Animals↗
Sub-unit structure of soluble and mitochondrial malic enzyme: demonstration of human mitochondrial enzyme in human-mouse hybrids.
1. Malic enzyme has been examined by starch-gel electrophoresis in human cultured fibroblasts and in 60 brain samples. The polymorphism of MEM has been confirmed and the electrophoretic pattern suggests that this enzyme, like MES, is a tetramer. 2. The appearance of the soluble and mitochondrial malic enzymes in mouse and Chinese hamster is described, and the identity of the enzymes in man, mouse and hamster has been established from a study of interspecific somatic cell hybrids. In man and in hamster MES migrates anodal to MEM, whereas in the mouse MES is relatively less anodal than MEM. 3. Segregation of human enzymes in human--mouse and human--hamster somatic cell hybrids confirms the synteny of MES and PGM3. Data from human--mouse hybrids suggest that MEM is probably not syntenic with MES is probably not syntenic with MES in man, nor is it syntenic with GPI.
Animals↗