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Biomedical subjects

C R Morgan

Publications and source records attributed to C R Morgan.

At least 19 recordsLinked to original sources
PubMed1992

Digoxin and digoxin derivative induced arrhythmias: in vitro binding and in vivo abolition of arrhythmias by digoxin immune Fab (DIGIBAND).

OBJECTIVE: The aim was to compare the binding characteristics of a highly purified digoxin specific antigen binding fragment (digoxin immune Fab: DIGIBIND) with digoxin and with two commonly used derivatives of digoxin, beta methyl digoxin and beta acetyl digoxin, and to assess its ability to abolish the arrhythmogenic effects of these digitalis glycosides. METHODS: The binding characteristics of DIGIBIND with digoxin, beta methyl digoxin, and beta acetyl digoxin were assessed in vitro by measuring their ability to inhibit the binding of DIGIBIND to 3H-digoxin. From these studies the affinities of the interactions between DIGIBIND and these glycosides, and the binding capacity of DIGIBIND for each of these glycosides, could be measured. The ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin, beta methyl digoxin, and beta acetyl digoxin was assessed using an in vivo anaesthetised guinea pig model (n = 36, weight 300-400 g), in which these glycosides were infused intravenously (50 micrograms.kg-1 x min-1) until the onset of ventricular arrhythmias, at which point the total amount of glycoside given was calculated. A single bolus dose of either vehicle or DIGIBIND was then given intravenously, and the time to restoration of normal cardiac rhythm noted. After the administration of DIGIBIND, a second infusion of the same glycoside was given to reinitiate the ventricular arrhythmias. The time to onset of the arrhythmias was noted, and the additional amount of glycoside given calculated. RESULTS: In vitro studies showed the binding of DIGIBIND to 3H-digoxin to be inhibited by digoxin and by the two derivatives. The affinities of these interactions with DIGIBIND were significantly different, that for digoxin being some twofold greater than that for beta methyl digoxin and beta acetyl digoxin. The ED50 concentrations were 14.1 (95% CI 12.2, 15.2), 29.2(26.1, 32.7), and 36.2(33.0, 39.8) nM, respectively. However, there were no significant differences between these glycosides in their binding capacities. The in vivo studies showed that intravenous infusion of digoxin, beta methyl digoxin, or beta acetyl digoxin induced similar ventricular arrhythmias. The onset of the arrhythmias was clearly discernible, and required a significantly lower dose of digoxin compared with that of beta methyl digoxin and beta acetyl digoxin. These doses were 667(SEM 55), 868(33), and 854(40) nmol.kg-1, respectively. Termination of the infusion had no effect on the arrhythmias, and in those animals which received a bolus intravenous injection of saline there was no return to normal cardiac rhythm. By contrast, in animals which received a bolus intravenous injection of DIGIBIND, there was complete abolition of the arrhythmias within 4-6 min. Although the dose of DIGIBIND given to abolish digoxin induced arrhythmias was approximately 25% less than that given to abolish beta methyl digoxin and beta acetyl digoxin induced arrhythmias (p < 0.05), the time to restoration of normal cardiac rhythm after DIGIBIND was not significantly different for digoxin compared with beta methyl digoxin and beta acetyl digoxin, at 4.6(0.9), 4.9(0.8), and 5.7(0.8) min, respectively. To reinitiate the arrhythmias in those animals which had received DIGIBIND, a dose of glycoside was required which was not significantly different from that given prior to the DIGIBIND. This observation therefore confirmed the stoichiometric relationship between DIGIBIND and each of the glycosides in respect of the neutralising action of DIGIBIND in abolishing the arrhythmogenic effects of these agents. CONCLUSIONS: Although there is some small difference in the affinities of the binding interactions, there is no difference in the binding capacities of DIGIBIND for digoxin, beta methyl digoxin, or beta acetyl digoxin in vitro. These binding interactions are manifest as the ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin and the two derivatives in vivo.

Acetyldigoxins↗
PubMed1988

Influence of developmental auditory deprivation on neuronal ultrastructure in the mouse anteroventral cochlear nucleus.

Developmental auditory deprivation caused mouse anteroventral cochlear nucleus neurons to have significantly fewer auditory nerve terminals and more non-auditory nerve terminals. This suggested that stimulation regulated the developmental arborization of auditory nerve terminals and competition for synaptic space. Intracellularly, mitochondria were smaller and darker in the deprived neurons and appeared less active metabolically. Interference with these neuronal processes may underlie the impaired development seen in auditory deprivation.

Afferent Pathways↗
PubMed1988

In vitro pharmacodynamics of 1-beta-D-arabinofuranosylcytosine: synergy of antitumor activity with cis-diamminedichloroplatinum(II).

1-beta-D-Arabinofuranosylcytosine (ara-C) was tested at a concentration of 10 micrograms/ml in the human tumor colony-forming assay against 55 human tumors of various histological types. Using the criterion for sensitivity of at least 70% inhibition of colony formation, 12 tumors (22%) were sensitive to ara-C. ara-C was most active against lung tumors (3 of 8 tumors were sensitive), and melanomas (6 of 8 sensitive). However, ara-C was not active against breast cancer (0 of 7) or colon cancer (0 of 3), and only 1 of 13 ovarian cancers was sensitive to ara-C. The activity of ara-C against melanoma and other solid tumors was confirmed using a thymidine incorporation assay. The time (t) and concentration (C) dependency of the cytotoxicity of ara-C and other chemotherapeutic agents was determined. Most agents such as Adriamycin, cis-diamminedichloroplatinum(II) (cis-platinum), and bleomycin were found to follow the C x t rule. That is, as the drug concentration was doubled, an equivalent amount of cell kill was achieved in half the time. However, the activity of ara-C was more concentration dependent than time dependent. ara-C was more effective when cells were exposed to high concentrations for short time periods. Synergy of activity between ara-C and cis-platinum was demonstrated in the breast 231 and melanoma M19 cell lines. No synergy of interaction between these two drugs was observed in the colon HT29 and lung P3 cell lines. When fresh biopsy specimens were tested with the combination, there was evidence of a synergistic interaction in 9 of 36 (25%). Maximum cytotoxicity was obtained when cells were exposed to ara-C 2 h before the addition of cis-platinum. The addition of cis-platinum before ara-C decreased the synergism.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Stimulation-dependent development of neuronal cytoplasm in mouse cochlear nucleus.

The extent of neuronal development in the mouse ventral cochlear nucleus was examined in normal and developmentally auditory deprived mice. Mice were unilaterally deprived on postnatal day three by external auditory meatus removal and sacrificed with controls on day 45, which is after the developmental period. Light microscopic morphometry of neuronal nucleus and cytoplasm areas demonstrated that the normal spherical and globular cells were larger in their low frequency regions than in their high frequency regions. This size difference occurred mainly in the cytoplasm. Developmental deprivation reduced neuronal cytoplasm areas similarly in the high and low frequency regions of both neuronal types, but had no effect on the size of the neuronal nucleus. It was interpreted that cytoplasmic metabolic events are dependent on developmental levels of stimulation and high and low frequency regions normally are differentially stimulated. Furthermore, these stimulation-dependent cytoplasmic events are impaired by developmental hypostimulation, which retards neuronal metabolism and growth. No changes were observed in the cochlear nucleus contralateral to the deprived side, suggesting that compensatory changes, such as hypertrophy, did not occur.

Aging↗
PubMed1985

Age- and diabetes-related changes in tissue glucose uptake and estradiol accumulation in the C57BL/KsJ mouse.

The effect of the diabetes (db/db) mutation on the age-related changes in glucose uptake and estradiol incorporation in peripheral tissues were investigated in C57BL/KsJ mice between 2 and 16 wk of age. Glucose uptake in the uterus, ovaries, pancreas, lung, liver, heart, kidney, and spleen were markedly increased in diabetic mice after the development of the hyperglycemic condition, as compared with control mice. The age-related increase in glucose uptake observed in control mice was enhanced in hyperglycemic (i.e., greater than or equal to 4 wk of age) animals. In contrast, the diabetes mutation caused a decreased estradiol uptake by the uteri, ovaries, and mesometrial fat pads at 16 wk, while having little effect in nontarget tissues of diabetic mutants. These data indicate that the diabetes mutation enhances glucose uptake, especially in estradiol target tissues (i.e., uterus, ovary), at the same time that estradiol incorporation is depressed. These results suggest that an alteration in glucose utilization by steroid-sensitive reproductive tract tissue may underlie the impaired reproductive ability in these animals. Other peripheral tissues did not demonstrate any remarkable changes in estradiol uptake, but the enhanced carbohydrate metabolism observed may relate to the subsequent age- and diabetes-related changes in tissue structure and function in these animals.

Aging↗
PubMed1984

Glucose utilization by the mouse brain: influence of age and diabetes.

The effects of diabetes on the age-related changes in glucose utilization by various brain regions were examined in genetically diabetic (db/db) and normal (+/?) C57BL/KsJ mice following a 10 muCi injection of [3H]2-deoxyglucose (2-DOG). Brains were collected from 2 to 16-week-old mice at 30 min postinjection with 2-DOG, and the brain regions isolated by microdissection. Glucose utilization was expressed as mumol/mg/30 min for each brain region from match-paired control +/? and db/db mice. No differences in utilization were seen in brain regions from control and db/db mice at 2 weeks of age. In contrast, the diabetic condition effectively depressed the age-related increase in glucose metabolism associated with maturation in control mice between 4 and 16 weeks of age. Of particular interest was the observation that the pituitary gland of the db/db mice did not demonstrate a maturation-associated increase in glucose utilization typical of +/? mice. By 16 weeks of age, all of the brain regions of db/db mice exhibited a depressed glucose utilization rate as compared with +/? mice. These studies demonstrate that the diabetic condition impairs the normal age-related increase in CNS glucose utilization in the mouse, and suggests that decreased glucose utilization may be causally related to diabetes-associated, CNS and peripheral neuropathy.

Age Factors↗
PubMed1984

Glucose affects in vitro maturation of fetal rat islets.

Fetal pancreatic islets (21.5 days old) were cultured in RPMI 1640 containing either 2.8 or 11.1 mM glucose for 7 days. After the 7-day culture period, islets cultured in 2.8 mM glucose demonstrated a minimal first phase of insulin secretion in response to acute glucose stimulation, whereas islets cultured in 11.1 mM glucose demonstrated a biphasic insulin secretory pattern. Islets cultured in 11.1 mM glucose initiated insulin secretion at 4.4 +/- 0.1 mM glucose and plateaued at 11.6 mM glucose when exposed to a linear gradient. In addition, culture in 11.1 mM glucose increased DNA content (P less than 0.01) and [3H]thymidine incorporation (P less than 0.05) in fetal islets. However, ultrastructural morphometric analysis indicated that the actual number of beta-cells within islets cultured in either 2.8 or 11.1 mM glucose did not increase. The insulin contents of islets cultured in 2.8 and 11.1 mM glucose were 0.46 +/- 0.06 and 1.14 +/- 0.10 mU/islet, respectively. During subsequent glucose stimulation, islets cultured in 2.8 and 11.1 mM glucose released 3% and 5.6% of their total insulin content, respectively. Ultrastructural morphometric analysis indicated that 11.1 mM glucose stimulated an increase in the volume of individual beta-cells, i.e. hypertrophy. The hypertrophy of beta-cells within islets cultured in 11.1 mM glucose resulted in a concomitant increase in islet volume. Finally, the hypertrophy of beta-cells within islets cultured in 11.1 mM glucose was a result of increased volumes of mitochondria, secretory granules, and, to the greatest extent, endoplasmic reticulum. These findings indicate that glucose is a potent factor in the maturation of cultured fetal rat islets.

Animals↗
PubMed1984

Effects of alloxan-induced diabetes on corpus luteum function in the pseudopregnant rat.

The effects of alloxan-induced diabetes mellitus on rat ovarian structure and function were examined throughout pseudopregnancy (PSP). Animals received either saline (C) or alloxan (40 mg/kg) treatment on the day of proestrus (PA) preceding PSP or on day 1 (D-1A) of PSP (day 0 = ovulation). Serum samples were analyzed by radioimmunoassay for progesterone (P) and 17-beta-estradiol (E) levels and compared with the corresponding changes in ovarian and uterine weights in C, PA, and D-1A rats. In addition, the effects of daily treatment with 6 IU ovine insulin (AI) on serum P levels were assessed in D-1A-treated rats and compared with controls. Alloxan treatment effectively elevated blood glucose levels (P less than or equal to 0.01) in PA and D-1A groups as compared with controls or AI rats. Alloxan treatment reduced both ovarian and uterine weights of PA and D-1A groups as compared with C and AI rats. Serum P levels were significantly reduced in PA (P less than or equal to 0.01) and D-1A (P less than or equal to 0.05-0.01) rats as compared with control rats throughout PSP. Daily insulin treatment reversed the suppressive effects of D-1A treatment on serum P levels, but did not restore luteal function to control levels. Neither C nor D-1A groups exhibited any marked differences in serum E levels throughout PSP. The results of these studies indicate that the administration of alloxan before the onset of PSP effectively inhibits luteal function, whereas D-1A treatment induces early luteolysis as compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effects of growth hormone on the in vitro maturation of fetal islets.

To study the effects of growth hormone (GH) on the in vitro maturation of fetal islets, the fetal islets were cultured for 7 days in RPMI 1640 containing 10% fetal bovine serum and 11.1 mM glucose with or without GH. Culture with 1 microgram/ml of bovine GH increased the DNA content of the islets and [3H]thymidine incorporation into DNA confirming results of other investigators. In addition, however, the insulin secretory dynamics and ultrastructural morphometrics were investigated. It was found that GH-treated islets demonstrated increased insulin release during acute glucose stimulation when expressed as microunits per islet per minute. However, when insulin release during acute glucose stimulation was expressed as microunits per microgram of DNA per minute to compensate for the increased DNA content of GH-treated islets, no change in insulin release was observed compared to control islets. When GH-treated islets were perifused with a linear glucose gradient, the insulin secretory response was suppressed as indicated by changes in the threshold level, plateau level, and half-maximal response. Ultrastructural morphometric data showed that the average beta-cell volume in control and GH-treated islets was the same, eliminating the possibility that beta-cell hypertrophy occurred. Similarly, the nuclear volumes of the beta cells in control and GH-treated islets remained unchanged. This finding coupled with the observed increased DNA content and [3H]thymidine incorporation suggests that GH functions by increasing cell multiplication within the islets and not by inducing polyploidy. Finally, the volumes of cytoplasmic organelles in control and GH-treated islets were the same indicating that cytodifferentiation did not occur.

Animals↗
PubMed1983

Multiple effects of growth hormone on insulin release from isolated pancreatic islets.

The direct effects of growth hormone (GH) on the endocrine pancreas were studied in isolated islets of rats. To study GH-induced insulin release, islets were incubated in RPMI 1640 medium containing 1 or 10 micrograms/ml of bovine GH for 120 minutes. Islets incubated in the absence of GH served as controls. During the incubation, GH significantly increased the insulin concentration in the medium. To study the effect of GH on subsequent glucose-induced insulin release, islets were preincubated with GH; then the islets were transferred to perifusion chambers and after a 30-minute stabilization period with 2.8 mM glucose, the islets were stimulated by addition of 16.7 mM glucose for 60 minutes. These perifusions were performed in the absence of GH. Glucose-induced insulin release from control and GH-pretreated islets peaked at five minutes during the first phase (0-8 minutes) and plateaued at 25 minutes during the second phase (9-60 minutes). Preincubation with GH (1 microgram/ml) did not change baseline or first phase release, but significantly suppressed the second phase of insulin release. When islets were preincubated with 10 micrograms/ml of GH, both phases of glucose-induced insulin release were suppressed; the total amount of insulin released by GH-pretreated islets was suppressed by 36.6% during the subsequent glucose stimulation period. These data indicate that GH stimulates insulin release by itself (GH-induced insulin release) but inhibits subsequent glucose-induced insulin release in a dose-dependent manner.

Animals↗
PubMed1979

Ultrastructural heterogeneity of the mesocoxal muscles of Periplaneta americana.

Ultrastructural studies have been performed upon the posterior coxal depressor muscle (136) and a coxal branch of the main depressor group (135d') from the mesocoxa of the cockroach, Periplaneta americana. The quantitative stereometric analyses performed have shown the latter muscle to consist of a dorsal band of fibers having 25.% mitochondria and 13.6% sarcoplasmic reticulum (SR) and T-tubules (TTS), and a ventral group of fibers with only 4.4% mitochondria and 26.6% SR/TTS. The volume fractions characteristic of the ventral fibers of muscle 135d' are also typical of muscle 136.

Animals↗
PubMed1979

Enzyme histochemistry of the mesocoxal muscles of Periplaneta americana.

Histochemical techniques have been employed to characterize enzymatic activity in the mesocoxal muscles of the cockroach, Periplaneta americana. Through our studies of the enzymes myosin-ATPase, NADH reductase, succinic dehydrogenase (SDH), and lactic dehydrogenase (LDH), we were able to classify fibers within these muscles according to criteria established for muscle fibers of vertebrates. Many of the mesocoxal muscles possess two different and distinct populations of fibers, whereas the remaining muscles are homogeneous with respect to their constituent fibers. The data presented here indicate biochemical heterogeneity for muscles of differing structural and functional features and possible neurotrophic influences upon oxidative enzymes and myosin-ATPase isozymes.

Adenosine Triphosphatases↗
PubMed1970

Template activity of liver chromatin increased by in vivo administration of insulin.

The hypothesis that insulin may serve as a derepressor of genetic information in the liver of diabetic rats has been tested by comparing the template activity for RNA synthesis of chromatin from liver of insulin-treated diabetic rats to that of chromatin from liver of insulin-deficient diabetic rats. The template activity of the chromatins of insulin-treated diabetic rats is found to be 28 per cent greater than that of chromatin from liver of diabetic rats not treated with insulin. Time course studies show that the template activity of liver chromatin of rats injected with a single dose of insulin reaches a peak at two hours, which is some hours before the appearance of a typical insulin-induced liver enzyme, glucokinase. We conclude that insulin derepresses genetic material of the diabetic liver genome that is repressed in the absence of insulin.

Animals↗