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Biomedical subjects

R E Larson

Publications and source records attributed to R E Larson.

At least 73 records · Page 4Linked to original sources
PubMed1982

Interaction of insulin and prostacyclin production in the rat.

The effects of hyperinsulinemia on production of prostacyclin (PGI2), a potent inhibitor of platelet aggregation, was studied in vitro in the rat. Aortic rings following 1-h preincubation at 37 degrees C and 1 h at 4 degrees C were incubated with and without purified porcine insulin in Krebs' glucose at 37 degrees C for 5 min and immediately percent inhibition of platelet aggregation was determined. PGI2 production in ng/mg aorta was estimated from a curve using PGI2 standard. The mean PGI2 production was significantly decreased in those rings incubated with insulin in concentration of 2500, 500, and 250 microunits/ml. Likewise, incubation of rings at 22 degrees C for 30 min resulted in at least ten times less PGI2 with insulin. Since PGI2 appears to exert its antiaggregatory effect through cyclic AMP, theophylline was added to the incubation medium resulting in potentiation of inhibition of aggregation which was decreased to control levels when insulin was also added to the medium. Pancreatic slices yielded no significant change in insulin obtained when incubated with and without 5 ng of PGI2 in 2 ml of 2.8 mM glucose, but in a high glucose medium (28 mM) the PGI2-treated slices yielded significantly less insulin. Since PGI2 may play a role in the formation of atherosclerotic plaques, these results suggest a possible deleterious effect of elevated insulin levels in type II and in insulin-treated type I diabetics with regard to macrovascular disease. Suppression of insulin production in presence of PGI2 in high glucose medium resembles the action of other prostaglandins and suggests it may inhibit insulin secretion after a glucose load.

Animals↗
PubMed1982

Responsiveness of Carmustine (BCNU) treated mice to induction and inhibition of mixed function oxygenases.

The responsiveness of BCNU treated mice to phenobarbital (Pb) induction of hepatic microsomal mixed function oxygenase (MFO) activity was studied. BCNU (30 mg/kg ip) produced significant (P less than 0.05) decreases in cytochrome P-450, total ethylmorphine metabolism (TEM) and ethylmorphine N-demethylase (EMN) by 21 days after treatment. The specific activities of TEM and EMN were decreased more than was P-450 content. Benzpyrene hydroxylase (BPH) was increased and 7-ethoxycoumarin 0-deethylase (ECD) was unaffected at this time. Pb induction beginning on day 17 after BCNU treatment resulted in a greater inductive response in the BCNU treated mice than in controls. The specific activities of all MFO enzymes studied were more markedly affected than were the raw activities suggesting activation. However, the responsiveness of the MFOs to the actions of inhibitory was not markedly influenced by BCNU pretreatment.

Animals↗
PubMed1981

Effects of adrenocorticotropin and cycloheximide on adrenal diglyceride kinase.

We studied the effects of adrenocorticotropin (ACTH) and cycloheximide on adrenal enzymes involved in phosphatidate synthesis. Treatment of rats in vivo with ACTH induced a rapid increase in phosphatide synthesis from diglyceride and ATP in adrenal homogenates, and cycloheximide treatment prevented this increase if given before ACTH and rapidly reversed the increase if given after ACTH. The stimulatory effect of ACTH appeared to be largely due to an increase in diglyceride substrate, as kinase activity was not altered. The inhibitory effect of cycloheximide, on the other hand, appeared to be due to a decrease in diglyceride kinase activity. Neither ACTH nor cycloheximide treatment had any effect on the activity of glycerol-3'-phosphate acyltransferase or phosphatidate phosphatase. Our findings suggest that (a) ACTH increases the flow of phospholipid (and their levels) throughout the entire circular pathway, i.e., phosphatidate leads to CDP-diacylglycerol leads to inositides leads to diglycerides leads to phosphatidate, and (b) a labile protein may serve to allow entry into a recycling of diglyceride in this pathway. In addition, since cycloheximide blocked carbachol-induced increases in pancreatic and salivary glandular phosphatidate synthesis resulting from phosphatidylinositol hydrolysis and consequent diglyceride generation, the putative labile protein may have widespread importance.

Adrenal Glands↗
PubMed1981

Effects of dibutyryl cyclic AMP and theophylline on rat pancreatic phospholipids in vitro. Ca2+-sensitive decrease in phosphatidylinositol and cycloheximide-sensitive increase in phosphatidic acid.

We evaluated the effects of dibutyryl cyclic AMP and theophylline on rat pancreatic phospholipid metabolism in vitro. Dibutyryl cyclic AMP decreased mean phosphatidylinositol concentration by 30%, increased phosphatidic acid and phosphatidylglycerol concentrations by 90 and 25%, respectively, and increased [32P]phosphate incorporation into phosphatidic acid and phosphatidylinositol several-fold. Theophylline provoked similar changes in phosphatidic acid and phosphatidylinositol concentrations, and both stimulatory agents enhanced amylase and insulin secretion. Effects of dibutyryl cyclic AMP on amylase secretion and phospholipid levels were dependent on Ca2+. Cycloheximide blocked induced increases in phosphatidic acid, but did not diminish phosphatidylinositol breakdown or amylase secretion. Contrary to previous postulations, the present findings suggest: (a) cyclic AMP provokes large-scale phosphatidylinositol breakdown in the pancreas; (b) this phosphatidylinositol breakdown is dependent on Ca2+; and (c) phosphatidylinositol breakdown may contribute to exocytosis. In addition, it appears that a labile protein is required for synthesis of phosphatidic acid from 1,2-diacylglycerol and ATP.

Animals↗
PubMed1981

Early effect of glucose and oxygen deprivation on the spontaneous acetylcholine release from the myenteric plexus of the guinea pig ileum.

The early effects of glucose and oxygen deprivation on the spontaneous acetylcholine output from the myenteric plexus - longitudinal muscle preparation of the guinea pig ileum were studied using an incubation chamber that permitted rapid sample collection in 2-min intervals. Glucose deprivation or hypoxia resulted in a gradual decline in rate of spontaneous acetylcholine collection in 2-min intervals. Glucose deprivation or hypoxia resulted in a gradual decline in rate of spontaneous acetylcholine output. However, glucose deprivation plus hypoxia caused an acceleration in acetylcholine output within 10-15 min, which attained a rate seven times greater than observed under normal conditions. Recovery of low resting rates was obtained by reintroduction of oxygen and glucose into the bath medium. Neither morphine (2.7 x 10(-5) M) nor tetrodotoxin (1.6 x 10(-6) M) prevented the increase in acetylcholine output induced by energy deprivation. The substitution of Ca2+ by Mg2+, in the presence of EGTA, greatly reduced the acetylcholine output induced by energy deprivation. However, a small transitory output of acetylcholine was observed under these conditions which was resistant to tetrodotoxin and ot affected by depolarizing amounts of K+. The transitory output was repeatable by reintroduction of glucose and oxygen to the Ca2+-free medium with subsequent return to conditions of hypoxia and glucose deprivation. These results suggest that energy deprivation initially stimulates normal acetylcholine secretion by (a) increasing Ca2+ influx across the plasma membrane and (b) mobilizing an intracellular Ca2+ poll. This implies that processes involved in maintenance of normal low transmitter release are more sensitive to energy lack than the neurosecretion process itself.

Acetylcholine↗
PubMed1981

A23187 inhibits adrenal protein synthesis and the effects of adrenocorticotropin (ACTH) on steroidogenesis and phospholipid metabolism in rat adrenal cells in vitro: further evidence implicating phospholipids in the steroidogenic action of ACTH.

We examined the effects of ACTH and the Ca++ ionophore, A23187, on steroidogenesis and phospholipid metabolism during incubation of dispersed rat adrenal cells. Increasing doses of ACTH elicited nearly parallel increases in corticosterone production and adrenal inositide (mono- and di-) concentrations. As reported previously by other investigators in Y1 cells, A23187 inhibited ACTH- and cAMP-stimulated, but not basal or pregnenolone-stimulated, corticosterone production. A23187 also inhibited ACTH-induced increases in phosphatidic acid, phosphatidylinositol, and diphosphoinositide, and this was attended by inhibition of [3H]leucine incorporation into protein. These findings support our previous contentions that: 1) a labile protein is required for ACTH-induced increases in adrenal phospholipids in the phosphatidate-polyphosphoinositide-polyglycerophospholipid pathway; and 2) these phospholipids are involved in the steroidogenic action of ACTH.

Adrenal Cortex Hormones↗
PubMed1981

Kinetic aspects of cycloheximide-induced reversal of adrenocorticotropin effects on steroidogenesis and phospholipid metabolism in rat adrenal sections in vitro.

We examined the rate of cycloheximide-induced reversal of ACTH effects on steroidogenesis and phospholipid metabolism in adrenal sections in vitro. In the absence of cycloheximide, ACTH treatment elicited sustained increases in steroidogenesis (approximately 3- to 5-fold) and adrenal concentrations (approximately 2-fold) of phosphatidic acid, phosphatidylinositol, and polyphosphoinositides. These increases in phospholipids were not dependent on steroidogenesis, since they were also apparent in aminoglutethimide-blocked adrenal sections. The addition of cycloheximide 30 min after ACTH treatment reversed the stimulatory effects of ACTH on steroidogenesis and phospholipids, and the rates of decay for both processes were identical, viz 28 min. This relatively slow turnover in adrenal sections in vitro contrasts with a much more rapid turnover observed previously in vivo and presently in dispersed adrenal cells in vitro; thus, it appears that an artefact of the in vitro adrenal section system stabilizes the putative labile protein. More importantly, the identical rates of decay for steroidogenesis and phospholipids suggest that the same labile protein is required for both phospholipid metabolism and steroidogenesis. These findings are in keeping with our postulate that the labile protein is required for phospholipid metabolism, which, in turn, is required for steroidogenesis.

Adrenal Glands↗
PubMed1981

Adrenocorticotropin and adenosine 3',5'-monophosphate stimulate de novo synthesis of adrenal phosphatidic acid by a cycloheximide-sensitive, CA++-dependent mechanism.

We tested further our postulate that enhanced de novo synthesis of phosphatidic acid is responsible for ACTH- and cAMP-induced increases in adrenal phospholipids in the phosphatidate polyphosphoinositide pathway. During incubation of adrenal sections or cells in vitro, ACTH and cAMP increased the concentrations of and incorporation of [3H]glycerol and [14C]palmitate into phosphatidylcholine and phosphatidylethanolamine, two major phospholipids which are derived from phosphatidic acid, but are extrinsic to the inositide pathway. Thus, it is unlikely that ACTH and cAMP increase inositide phospholipids at the expense of other phospholipids. Similar to previously reported effects on phosphatidic acid and inositide phospholipids, cycloheximide blocked the effects of ACTH and cAMP on phosphatidylcholine and phosphatidylethanolamine. In addition, Ca++ was required for these effects, as well as for cAMP-induced increases in phosphatidic acid, inositide phospholipids, and steroidogenesis. Our findings strongly suggest that ACTH, via cAMP, stimulates de novo phosphatidate synthesis by a cycloheximide-sensitive, Ca++-dependent process, and this stimulation causes a rapid generalized increase in adrenal phospholipids. Moreover, the increased incorporation of labeled glycerol and palmitate into phospholipids suggests that ACTH and cAMP may stimulate the glycerol-3'-PO4 acyltransferase reaction. This stimulatory effect may play a central role in the steroidogenic and trophic actions of ACTH and cAMP.

Adrenal Glands↗
PubMed1981

Insulin and its secretagogues activate Ca2+-dependent phosphatidylinositol breakdown and amylase secretion in rat pancreas in vitro.

We studied the effects of insulin and insulin secretagogues on pancreatic phospholipids and the release of amylase from pancreatic fragments incubated in vitro. Insulin provoked rapid, dose-related increases in amylase release, and these were accompanied by decreases in phosphatidylinositol and increases in phosphatidic acid. Glucose and other insulin secretagogues elicited similar changes in amylase release and pancreatic phospholipids; epinephrine blocked these effects of glucose, presumably via inhibition of glucose-induced insulin secretion. Effects of insulin and glucose on phospholipids and amylase release were dependent on Ca2+ in the incubation medium. These findings suggest that, in the pancreas, insulin enhances Ca2+-dependent phosphatidylinositol breakdown, which in turn influences amylase secretion. The effects of insulin on phospholipids may also explain certain other actions of insulin.

Amylases↗
PubMed1981

The effect of hypothermia on biochemical and morphological aspects of carbon tetrachloride hepatotoxicity.

The temporal relationships among selected correlates of hepatocellular damage were investigated in cordotomized, hypothermic rats intoxicated with carbon tetrachloride (CCl4). Rats were spinally transected between C6 and C7 and allowed to become hypothermic. CCl4 (1.25 ml/kg ip) was administered as a 1:1 solution in corn oil. Plasma alanine aminotransferase (ALT) activity and bilirubin concentrations, hepatic malondialdehyde (MDA) formation, glucose-6-phosphatase (G6Pase) activity, and microsomal diene conjugations, as well as morphological changes were monitored over a 48 h time course. Diene conjugation, ALT and morphologic changes were all delayed and attenuated in CCl4 treated transected rats. The depression of hepatic G6Pase after CCl4 treatment was of the same magnitude in both transected and nontransected rats and was delayed only slightly in the cordotomized animals. Elevation of plasma bilirubin was delayed in transected rats, but the magnitude of the response was greater than that seen in nontransected rats. Parallel increases in MDA occurred in both CCl4 and corn oil treated transected rats over the 48 h period. These results demonstrate that spinal cord transection had differential influences upon the developing hepatotoxic effects of CCl4.

Alanine Transaminase↗
PubMed1980

Effects of Ca2+ ionophore A23187 and Ca2+ deficiency on pancreatic phospholipids and amylase release in vitro.

The Ca2+ ionophore A23187 elicits a transient increase in pancreatic amylase release in vitro, and this is accompanied by a transient decrease in phosphatidyl inositol concentration. Effects of ionophore A23187 and carbachol on amylase release and phosphatidylinisitol breakdown are dependent on medium Ca2+. These results suggest that major secretagogue-induced, pancreatic phospholipid changes follow, rather than precede, changes in Ca2+ in the pancreas.

Amylases↗