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Biomedical subjects

G Constantopoulos

Publications and source records attributed to G Constantopoulos.

At least 37 records · Page 2Linked to original sources
PubMed1983

A canine model of human alpha-L-iduronidase deficiency.

A disease discovered in three Plott Hound littermates was found to be associated with a profound and specific deficiency of alpha-L-iduronidase (mucopolysaccharide alpha-L-iduronohydrolase; EC 3.2.1.76) in fibroblasts and leukocytes. The pedigree was consistent with autosomal recessive inheritance. A markedly increased amount of dermatan sulfate and heparan sulfate was excreted in urine. Fibroblasts cultured from the skin of the affected dogs accumulated excessive 35S-labeled mucopolysaccharide; this accumulation could be decreased to a normal level by exogenous human high-uptake alpha-L-iduronidase (Hurler corrective factor) as well as by secretions of normal human or canine fibroblasts. The correction was inhibited by mannose 6-phosphate. Maturation of alpha-L-iduronidase in normal canine fibroblasts followed the pathway previously observed in human fibroblasts; no cross-reactive material was observed in the cells or in secretions from the fibroblasts of the affected dogs. The canine disorder thus resembles mucopolysaccharidosis I in all biochemical parameters tested; the clinical appearance of the animals is closest to Hurler-Scheie syndrome, a form of alpha-L-iduronidase deficiency of intermediate severity. The animal model should prove valuable for therapeutic experiments.

Animals↗
PubMed1983

Effect of a potassium-deficient diet on arterial blood pressure, plasma and tissue cations, and tissue norepinephrine in the hypertensive dog.

Chronic potassium deficiency in one-kidney one-clip hypertensive dogs significantly reduces blood pressure and plasma potassium, with a simultaneous increase in plasma renin activity. Tissue potassium concentration was decreased and tissue sodium concentration was increased in striated muscle and adrenal glands, which may suggest that the sodium-potassium pump was inhibited. In myocardium the sodium concentration was higher but the potassium concentration was not significantly lower than in control hypertensive dogs on normal diets. Arterial cation concentrations in the potassium-deficient group were not significantly different from those in the control group. Tissue norepinephrine concentration was higher in arteries from potassium-deficient animals, significantly so in the mesenteric and femoral arteries. The conclusion is that potassium deficiency may decrease blood pressure in the one-kidney one-clip hypertensive dogs by impairing the release of norepinephrine.

Animals↗
PubMed1982

Organomegaly and histopathology in an animal model of mucopolysaccharidosis induced by suramin.

The trypanocidal drug suramin causes glycosaminoglycan and sphingolipid accumulation in the rat, thus simulating a mucopolysaccharidosis (Constantopoulos et al. 1980). In this paper we report on the extent and nature of the morphological changes that occur in the liver, kidneys, spleen, heart, lung and brain as a result of short or long term suramin administration. The first group of rats received a single intravenous injection of suramin (500 mg/kg) and was sacrificed 3-9 days after the injection. The second group received low doses of suramin (50-90 mg/kg) at 2-3 weekly intervals over 3 months. Samples of the above mentioned organs were processed for light and electronmicroscopy and the remainder of the tissue weighed and assayed for total protein, DNA and RNA content. In both groups of rats, suramin caused an abnormal enlargement of the spleen, kidney, lung and liver, splenomegaly being the most pronounced. The total protein, and DNA content did not alter in the treated rats, however, the RNA content of the spleen increased 100%, 9 days after injection and there was a small but consistent increase in RNA content of the liver, kidney and lung. Significant pathological changes were observed in these organs and also in the brain and heart. The changes were similar in many respects to the pathology seen in the lysosomal storage disorder, mucopolysaccharidosis and further support the proposition that the suramin treated rat might be a useful experimental animal model of the disease. Several mechanisms by which suramin might produce organomegaly in the rat are discussed.

Animals↗
PubMed1981

Effect of suramin on the activities of degradative enzymes of sphingolipids in rats.

Three to nine days after administration of suramin, 500 mg/kg intravenously in rats, a small amount of the drug (about 0.25 micromoles/g tissue) was retained by the liver and spleen, and a larger amount (about 1.2 micromoles/g tissue) was retained by the kidneys. The activities of the sphingolipid hydrolases beta-hexosaminidase and GM3-sialidase were strongly inhibited by suramin in vitro. The activity of beta-hexosaminidase was inhibited 70% by 10(-5M) and 85% by 10(-4M) suramin, and the activity of GM3-sialidase was inhibited 80% by 10(-4M) suramin. The activities of sphingomyelinase and beta-galactosidase were also inhibited by suramin but at higher concentrations of the drug. Suramin, in vitro is a weak inhibitor of glucocerebrosidase, galactocerebrosidase, alpha-galactosidase and arylsulfatase A (less than 50% inhibition at 10(-3M) concentration of the drug). The inhibition of beta-hexosaminidase by suramin was non-competitive. Inhibition of beta-hexosaminidase and GM3-sialidase may explain the accumulation of GM2 and GM3 gangliosides in the brains of rats treated intracerebrally with suramin (Constantopoulos et al, 1980).

Animals↗
PubMed1980

Pathologic findings in mucopolysaccharidosis type IIIB (Sanfilippo's sydnrome B).

The pathologic changes in a rare case of mucopolysaccharidosis (MPS) type IIIB or Sanfilippo's syndrome B (absence of alpha-N-acetylglucosaminidase) are presented, along with the biochemical findings. Comparisons were made with other reported cases of MPS III subtypes and related storage disorders in terms of clinical, light microscopic, electron microscopic, and chemical findings, and a correlation of the ultrastructural changes made with the severe neurological dysfunction noted in this disorder. At present, MPS III subtypes cannot be separated from one another by morphological means because the same expression and distribution of lesions may be encountered among differing subtypes.

Adolescent↗
PubMed1980

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Intracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration suramin, 500 mg/kg, to 2-month-old rats causes a 5- to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excertion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 micrograms of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside GM2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, beta-glucuronidase, and hyaluronidase in the liver of the suramin-treated mature rats were consistently decreased, whereas those of alpha-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 microM or higher. The activity of beta-glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncompetitive. The suramin-treated rat may be a useful experimental animal model of mucopolysaccharidosis.

Age Factors↗
PubMed1977

Mucopolysaccharidosis type I, II, IIIA and V. Pathological and biochemical abnormalities in the neural and mesenchymal elements of the brain.

Histochemical and electron microscopic studies of the brains inclusive of the leptomeninges containing large blood vessels from 7 patients with mucopolysaccharidosis (MPS) I, II, IIIA and V showed marked increase in mesenchymal elements and the generalized presence of characteristic lesions around cerebral veins and arteries. The periadventitial space was greatly distended and filled with viscous fluid and numerous mononuclear cells containing large cytoplasmic vacuoles; these cells stained positively for glycosaminoglycans (GAG). In contrast, the neurons showed only a slight increase of GAG over the normal controls but contained an excessive amount of glycolipid-like material. The amount of GAG in the leptomeninges, inclusive of the large blood vessels, was 10.8, 6.5, 4.5 and 2.2 times greater in patients with MPS I, II, V and IIIA respectively, than the mean of unaffected controls. Dermatan sulfate (DS) accounted for most of the GAG increase in MPS I, II and V [mixed excretors of DS and heparan sulfate (HS)], and HS for the GAG increase in MPS IIIA (HS excretor). With the exception of the patient with MPS IIIA, whose GAG content and composition were the same in both the neural and mesenchymal elements, in all the other MPS types the mesenchymal elements contained more GAG, with a preponderance of DS. We conclude that the mesenchymal elements contribute substantially to the increased content of GAG in the brain and its coverings, mostly in the form of dermatan sulfate.

Adult↗
PubMed1977

Content and composition of urinary glycosaminoglycans in the patients with myoclonus epilepsy with and without Lafora bodies.

Content, composition and molecular weight distribution of the urinary glycosaminoglycans (GAG) were determined in five patients with progressive myoclonus epilepsy (PME). In one patient (Family B) this syndrome was associated with cerebral Lafora bodies and in four siblings of Family A, no Lafora bodies were present in brain biopsy. Only one of the five patients had a moderate increase of urinary GAG excretion as expressed by 24-h output or creatinine. The heparan sulfate component of the GAG was moderately increased in two other patients. The molecular weight distribution of the urinary GAG was normal. The results do not support the contention that urinary GAG excretion is abnormal in PME. Among nine lysosomal enzymes in leucocytes, only the activity of alpha-mannosidase was increased 3-fold in the four siblings.

Adolescent↗
PubMed1977

Effects of reserpine on water, cation, and norepinephrine contents of cardiovascular tissues of normotensive dogs.

Six adult male mongrel dogs were treated orally with reserpine (0.03 mg/kg) for 6 weeks, after which time the arterial tissue content of water, cations (sodium, potassium, magnesium, and calcium), and norepinephrine was determined and compared with those of six untreated dogs. Reserpine administration resulted in sustained decreases in the mean arterial blood pressure and heart rate, and the arterial tissues of the treated dogs contained less potassium, calcium, and magnesium, the last-named being affected most, but the sodium remained the same. Arterial norepinephrine content was significantly decreased. There was a slight but significant increase in plasma magnesium, without any noticeable changes in other plasma cations. The reduction in the arterial magnesium by reserpine may help to regulate vascular tone and (or) vascular reactivity.

Animals↗