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Biomedical subjects

L A Kelly

Publications and source records attributed to L A Kelly.

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

Role of acyl CoA:cholesterol acyltransferase in cholesterol absorption and its inhibition by 57-118 in the rabbit.

Esterification of cholesterol in rabbit small intestine mucosal microsomes by acyl CoA:cholesterol acyltransferase (ACAT, Ec 2.3.1.26) and mucosal cytosol by cholesterol esterase (EC 3.1.1.13) was studied. Compound 57-118. N-(1-oxo-9-octadecenyl)-DL-tryptophan(Z)ethyl ester, an inhibitor of cholesterol absorption, was found to inhibit in vitro ACAT in mucosal microsomes at concentrations of 2-20 nmol/0.5 ml incubation mixture, but had no effect on cholesterol esterase in the cytosol at similar concentrations. A kinetic analysis using a Lineweaver-Burk plot indicates that 57-118 acts as a competitive inhibitor of ACAT. An ex vivo study in the rabbit where 57-118 was given by gavage at a dose of 200 mg/kg also showed inhibition of ACAT but not of cholesterol esterase. High performance liquid chromatography determination of 57-118 in various subcellular fractions demonstrated the presence of this substance after oral administration in concentrations in mucosal microsomes equivalent to those required to show inhibition of ACAT in vitro. These data support the work of Norum et al. (1979, Eur. J. Clin. Invest. 9: 55-62) indicating mucosal ACAT plays a significant role in cholesterol absorption.

Acyltransferases↗
PubMed1980

Effects of two glucose absorption inhibitors: phenformin and 43-522 on hepatic gluconeogenesis.

The glucose absorption inhibitors, Phenformin and 3-phenylpropylaminoguanide HCl (SaH 43-522) have different effects on hepatic gluconeogenesis. Unlike phenformin, 43--522 in vivo does not inhibit hepatic gluconeogenesis; inhibition occurred only when 43--522 was added directly to a liver perfusion system. This suggests that when 43--522 is administered in vivo it is metabolized to an agent that does not inhibit hepatic gluconeogenesis whereas phenformin is not metabolized, and does inhibit gluconeogenesis. This is an advantage of 43--522 since it thereby specifically inhibits intestinal glucose absorption without a potential hypoglycaemic effect due to the suppression of gluconeogenesis.

Alanine↗
PubMed1979

Effects of delta 1-tetrahydrocannabinol on cyclic AMP in cultured human diploid fibroblasts.

(-)-trans-delta 1-Tetrahydrocannabinol (delta 1-THC) antagonized the cyclic AMP responses of WI-38 fibroblasts to both prostaglandin E1 (PGE1) and catecholamines. Both cellular cyclic AMP accumulation and cyclic AMP escape to the incubation medium were reduced, but the reduction of escape was much more dramatic at all concentrations of the drug. Conversely, long term incubations of cells with delta 1-THC alone resulted in substantial accumulations of cyclic AMP in the incubation medium. This effect was potentiated by the phosphodiesterase inhibitor 1-methyl, 3-isobutylxanthine and appeared to result from weak agonist activity of the cannabinoid as determined by a) stimulation of radioactivity incorporated into cyclic AMP using 3H-adenine prelabelled cells, and b) a rapid and pronounced increase in the activity ratio of cellular protein kinase. The antagonistic effect of delta 1-THC on the cellular response to PGE1 was greater in preconfluent cells than in confluent monolayers. Further, the increased sensitivity of preconfluent cultures to delta 1-THC was associated with the appearance of cytoplasmic vacuoles in the perinuclear region of the cells. Cannabidiol acted similar to delta 1-Thc in affecting cyclic AMP metabolis whereas cannabinol and cannabicyclol showed mixed effects on the various parameters studied.

1-Methyl-3-isobutylxanthine↗
PubMed1978

The escape of cyclic AMP from human diploid fibroblasts: general properties.

A variety of human diploid fibroblasts released large amounts of cAMP to the medium in a time-dependent fashion concomitant with stimulation of the cells by agonists of the adenylate cyclase. In WI-38 cells increased medium cAMP levels were detectable as quickly as increased cellular levels. Escape was not secondary to serum deprivation nor cell injury. It occurred in defined media, and was pH and temperature dependent. Elevated rates of escape were maintained for up to 24 hours after stimulation. A variety of PDE inhibitors reduced the rate of escape. A rough proportionality existed between the potencies of the compounds as potentiators of PGE1 increased cellular cAMP levels on the one hand and as inhibitors of escape on the other. In the case of IBMX, the inhibition of escape was transient, the most pronounced effect being during the first 5 minutes of incubation. In addition, a variety of compounds without significant acute effects on cellular cAMP levels inhibited escape.

1-Methyl-3-isobutylxanthine↗
PubMed1977

Distortion of cyclic AMP responses to catecholamine due to destruction of the hormone.

The acute actions of low and moderate concentrations of catecholamines on cyclic AMP metabolism in SV40-transformed human lung fibroblasts (VA13) were seriously distorted by non-enzymatic destruction of the agonist. Catecholamine destruction, as measured directly with an isotopic method, was slowed by a variety of anti-oxidants and chelating agents. A combination of two anti-oxidants, ascorbate and thiourea, was very effective in protecting isoproterenol in the cell culture system. That is, there was a 10-fold increase in the sensitivity of VA13 to isoproterenol and the duration of action of the catecholamine was greatly prolonged. However, the anti-oxidants did not alter the responses of the cells to prostaglandins. We conclude that any quantitative studies of cyclic AMP responses to catecholamines must address the question of agonist destruction if meaningful results are to be expected. The use of anti-oxidants, especially the combination of ascorbate and thiourea, would appear to be advisable, particularly in situations where the catecholamine concentrations are less than supramaximal.

Antioxidants↗
PubMed1977

Inhibition of glucose absorption by 3-phenylpropylaminoguanidine-HCl (SaH 43-522) in laboratory animals.

The present studies were undertaken to define the effects of 3-phenylpropylaminoguanidine-HCl (SaH 43-522 or 43-522) on glucose active transport in the gastrointestinal tract. A comparison with phenformin (DBI) was made in certain studies. SaH 43-522 is 2 to 3 times more potent than DBI with regard to its inhibitory effect on glucose active transport in the gastrointestinal tract of rats. The activity lasts for 5 hr after oral administration. SaH 43-522 also inhibits intestinal glucose absorption in the hamster, guinea-pig, dog, and monkey in either in vitro or in vivo systems. SaH 43-522 differs from DBI in that when glucose active transport is studied in vitro by adding drug into the incubation fluid, DBI is active only when the drug is present in the incubation fluids on both the mucosal and serosal sides, whereas SaH 43-522 is active in inhibiting intestinal glucose active transport when the drug is present in mucosal fluid only.

Animals↗
PubMed1975

Studies on cyclic AMP metabolism in human epidermoid carcinoma (HEp-2) cells.

Cultured human epidermoid carcinoma (HEp-2) cells were found to contain a highly responsive, catecholamine-sensitive adenyl cyclase activity in cellfree preparations. By contrast, cyclic AMP levels in intact HEp-2 cells were at best only marginally increased by catecholamines under a variety of conditions. The lack of an intact cell response could not be accounted for by escape of cyclic AMP to the medium, excessive phosphodiesterase activity, inactivation of the catecholamine, or by unusual kinetics of the system. However, in the presence of 1-methyl,3-iso-butylxanthine (MIX), a potent phosphodiesterase inhibitor, a moderate catecholamine response was observed in the intact cells. A significant elevation of cyclic AMP levels in the presence of MIX was observed at 0.3 muM epinephrine, and maximal levels occurred at 10 muM. Norepinephrine was much less effective than either epinephrine or isopropylnorepinephrine at 10 muM concentrations. In addition, intact cells slowly but steadily released cyclic AMP into the incubation medium over the course of 60-min incubations in the presence of MIX and epinephrine; maximum intracellular levels were reached by 5 min.

Adenosine↗
PubMed1975

The effects of 5-hydroxy-5(4'-chlorophenyl)-2, 3-dihydro-5H-imidazo (2, 1-a) isoindole (mazindol, SaH 42-548) on the metabolism of brain norepinephrine.

Mazindol, 5-hydroxy-5-(4'-chlorophenyl)-i, 3-dihydro-5H-imidazo-(2, 1-a) isoindole, has demonstrated anorexic activity and other pharmacological responses which suggest alterations in brain norepinephrine metabolism. Studies of the effects of mazindol on neuronal uptake and/or release of norepinephrine showed that mazindol, when given before cerebral intraventricular injection of 3-H-norepinephrine by a mechanism that increases 3-H-normetanephrine synthesis via catechol-O-methyl-transferase and provided no significant effect on deamination of the catecholamine. Studies designed to measure norepinephrine release showed that mazindol (in contrast to d-amphetamine) did not cause release of 3-H-norepinephrine from neuronal stores. Furthermore, mazindol did not inhibit norepinephrine synthesis, whereas d-amphetamine did. The effect of d-amphetamine on norepinephrine release and synthesis may be more important than effects on uptake of this catecholamine. In contrast, mazindol appears to produce its primary effect on norepinephrine metabolism by inhibition of neuronal uptake mechanism.

Animals↗