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J D Geiger

Publications and source records attributed to J D Geiger.

122 records · Page 7Linked to original sources
PubMed1985

Characterization of nitrobenzylthioinosine binding to nucleoside transport sites selective for adenosine in rat brain.

Nucleoside transport sites in rat brain membrane preparations were labeled with [3H]nitrobenzylthioinosine ([3H] NBI), a potent inhibitor of nucleoside transport systems. The membranes contained a single class of very high affinity binding sites with KD and Bmax values of 0.06 nM and 147 fmol/mg of protein, respectively. The displacement of [3H]NBI binding by various nucleosides, adenosine receptor agonists and antagonists, and known nucleoside transport inhibitors was examined. The Ki values (micromolar concentration) of [3H]NBI displacement by the nucleosides tested were: adenosine, 3.0; inosine, 160; thymidine, 240; uridine, 390; guanosine, 460; and cytidine, 1000. These nucleosides displayed parallel displacement curves indicating their interaction with a common site labeled by [3H]NBI. The nucleobases, hypoxanthine and adenine, exhibited Ki values of 220 and 3640 microM, respectively. Adenosine receptor agonists exhibited moderate affinities for the [3H]NBI site, whereas the adenosine receptor antagonists, caffeine, theophylline, and enprofylline, were ineffective displacers. The Ki values for cyclohexyladenosine, (+)- and (-)-phenylisopropyladenosine, 2-chloroadenosine, and adenosine 5'-ethylcarboxamide were 0.8, 0.9, 2.6, 12, and 54 microM, respectively. These affinities and the rank order of potencies indicate that [3H]NBI does not label any known class of adenosine receptors (i.e., A1, A2, and P). The Ki values of other nucleoside transport inhibitors were: nitrobenzylthioguanosine, 0.05 nM; dipyridamole, 16 nM; papaverine, 3 microM; and 2'-deoxyadenosine, 22 microM. These results indicate that [3H]NBI binds to a nucleoside transporter in brain which specifically recognizes adenosine as its preferred endogenous substrate. This ligand may aid in the identification of CNS neural systems that selectively accumulate adenosine and thereby control "adenosinergic" function.

Adenosine↗
PubMed1984

Ontogenesis of adenosine receptors in the central nervous system of the rat.

The ontogeny of adenosine receptors was studied in rat brain and spinal cord using the specific ligand [3H]cyclohexyladenosine [( 3H]CHA). The [3H]CHA affinity constant (Kd) and the maximum receptor binding capacity (Bmax) were analyzed at all ages and in all CNS regions studied. Throughout development the Kd of [3H]CHA binding remained relatively stable and for cortex, cerebellum, subcortex, midbrain, brainstem and spinal cord ranged from 2.2 +/- 0.2 to 5.5 +/- 0.6 nM (mean +/- S.E.M.). In contrast, the Bmax values from 1- and 90-day animals increased by as little as 2-fold in subcortical regions and by as much as 9- and 16-fold in cortex and cerebellum, respectively. The highest density of binding sites was observed in subcortical structures and the lowest in brainstem and midbrain. In cortex, a steady increase in receptor number began at day 1 and stopped at the adult level by 21 days. In cerebellum, maximum receptor proliferation began at about 14 days and continued to adulthood. Other CNS regions showed intermediate rates of receptor development. These differences may reflect both the pattern of postnatal neurogenesis in the rat CNS and the maturation of those neural elements containing adenosine receptors.

Adenosine↗
PubMed1984

Heterogeneous distribution of adenosine transport sites labelled by [3H]nitrobenzylthioinosine in rat brain: an autoradiographic and membrane binding study.

A highly heterogeneous distribution of [3H]nitrobenzylthioinosine [( 3H]NBI) binding sites was observed using both autoradiographic and membrane binding methodology. Of the 24 brain regions examined in the radio-ligand binding studies, the highest levels of [3H]NBI sites were found in the thalamus, followed by midbrain, superior colliculus, olfactory cortex and hypothalamus. The thalamus contained over 5 times more sites than cerebellum which exhibited the lowest [3H]NBI binding levels. The results obtained from autoradiographic analysis agreed well with quantitative measurements and revealed that subnuclei of thalamus and hypothalamus as well as specific layers of the superior colliculus contained particularly high concentrations of [3H]NBI sites. When the [3H]NBI autoradiograms were compared with the distribution of adenosine deaminase in brain it was found that brain regions richest in neural elements immunoreactive for adenosine deaminase contained the greatest numbers of [3H]NBI sites. In contrast, a poor correlation was found between the distribution of [3H]NBI binding and adenosine receptors labelled with [3H]cyclohexyladenosine. The co-localization of [3H]NBI binding and adenosine deaminase in brain indicates the existence of neural systems having a high capacity to take up and metabolize adenosine.

Adenosine↗
PubMed1984

Receptor-binding changes in copper-deficient rats.

Male weanling Sprague-Dawley rats were fed a copper-deficient diet for 40 days. Copper-deficient rats weighed significantly (p less than 0.001) less (175 +/- 7 g) than copper-supplemented rats (230 +/- 6 g). Hematocrits were also significantly (p less than 0.001) decreased in deficient as compared to control animals from 43 +/- 0.6 to 30 +/- 2.7%. The binding of 3H-QNB to striatal and cerebellar membrane muscarinic receptors from control and deficient rats increased from 594 +/- 25 to 704 +/- 31 (p less than 0.02) and from 19 +/- 2 to 28 +/- 3 (p less than 0.01) pmol/g protein, respectively. Similarly, 3H-muscimol binding to GABA receptors (cerebellum) also increased from 39 +/- 5 to 58 +/- 3 (p less than 0.02) pmol/g protein. 3H-diazepam binding to benzodiazepine receptors in deficient versus control animal frontal cortex membranes decreased from 92 +/- 8 to 75 +/- 5 (p less than 0.02) pmol/g protein, respectively. These results may help explain CNS manifestations of copper deficiency.

Animals↗
PubMed1984

Characterization and localization of adenosine receptors in rat spinal cord.

Adenosine A1 receptors were characterized in membranes from rat dorsal and ventral spinal cord using [3H] cyclohexyladenosine [( 3H]CHA) and compared with those in brain. For determination of anatomical loci of adenosine A1 receptors in the dorsal and ventral spinal cord, various lesions were employed, including kainic acid injections directly into the lumbar dorsal spinal cord, spinal cord hemitransections, dorsal rhizotomies, and neonatal capsaicin treatment. In control animals a single high affinity binding component was observed in dorsal and ventral spinal cord with KD values of 2.3 and 2.6 nM and Bmax values of 170 and 123 fmol/mg of protein, respectively. In comparison, [3H]CHA binding to whole brain membranes exhibited KD and Bmax values of 2.3 nM and 301 fmol/mg of protein, respectively. The IC50 values for CHA, (-)-phenylisopropyl adenosine, adenosine-5'-ethylcarboxamide, 2-chloroadenosine, (+)-phenylisopropyl adenosine, and theophylline to displace [3H]CHA were 3.6, 2.3, 15, 17, 21, and 30,500 nM for dorsal horn and 5.1, 2.7, 9.8, 24, 25, and 21,000 nM for ventral horn. The potencies of the various ligands are similar to those found for brain tissue. Injection of kainic acid directly into the dorsal spinal cord significantly reduced specific [3H]CHA binding by 33% in this tissue when compared to values from saline-injected control animals. This decrease was accompanied histologically by the depletion of intrinsic neuronal cell bodies and extensive gliosis at the injection site. Terminals of descending or primary afferent systems appear not to contain [3H]CHA-binding sites since lesions which interrupt these systems failed to alter the levels of [3H]CHA receptors in denervated spinal cord tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1983

Effects of helium-oxygen and hyperbaric helium-oxygen environment on drug-metabolizing enzyme activity in rat liver.

The effects of room-air normoxic (22 degrees C +/- 1 degree C), 1.2-ATA He-O2 (400 mmHg PO2, 29.0 degree C +/- 1 degree C), and 21-ATA He-O2 (400 mmHg PO2, 32.5 degrees C +/- 1 degree C) environments were investigated on the activity of drug-metabolizing enzyme systems in rat liver, as monitored by O-dealkylation and N-dealkylation reactions. Continuous exposure of rats to both He-O2 environments for 12 days significantly increased the in vitro activity of drug-metabolizing enzymes in liver preparations. The increase in the in vitro O-dealkylation of p-nitroanisole based on product formed X mg protein-1 X 20 min-1 was 32.2% (P less than 0.05) between normoxic animals and those exposed to 1.2 ATA He-O2, and 24.4% (P less than 0.01) in animals exposed to between 1.2 and 21 ATA He-O2. A significant increase of 48.8% (P less than 0.001) was noted between normoxic animals and those exposed to 21 ATA He-O2. Similar differences were noted if the data were expressed on the basis of 200 mg liver wet wt. The N-dealkylation of morphine based on product formed X mg protein-1 X 20 min-1 was significantly increased between animals kept at normoxic and at 1.2-ATA He-O2 conditions (17.6%, P less than 0.05) and between animals kept at normoxic and at 21 ATA He-O2 conditions (28.2%, P less than 0.05). No significant differences for N-dealkylation of morphine were noted between animal groups at 1.2 and those at 21 ATA He-O2 nor between any animal groups for N-dealkylation of cocaine.

Animals↗
PubMed1982

Digoxin-quinidine interaction in unanesthetized guinea pigs.

The clinically relevant interaction between quinidine (3 mg/kg) and digoxin (0.6 mg/kg plus 20 microCi 3H-digoxin) was investigated using unanesthetized and unrestrained guinea pigs for in vivo pharmacokinetic and tissue disposition studies. Quinidine caused a significant elevation of plasma levels of digoxin as early as 5 min after injection, and the increase persisted for at least 8 h. A significant decrease in the volume of distribution for digoxin from 3.6 to 2.7 liters/kg (20%) was observed in quinidine-treated animals. No change was noted in the dominant elimination half-life of digoxin in quinidine-treated animals. The decreased volume of distribution appeared to be due to displacement of digoxin from tissue stores by quinidine as evidenced by decreased tissue to plasma ratios for kidney (41%), intestine (41%), fat (33%), lung (31%), left ventricle (27%), liver (24%), left atrium (22%), right ventricle (21%), right atrium (18%), pancreas (12%), and bladder (-4%) samples.

Animals↗
PubMed1979

Superficial temporal to middle cerebral artery anastomosis. Clinical outcome in patients with ischemia of infarction in internal carotid artery distribution.

The clinical outcome of our first 40 patients (six with transient ischemic attacks, 22 with mild ischemic infarctions, and 12 with moderate ischemic infarctions) treated with a superficial temporal artery-middle cerebral artery anastomosis was analyzed. All cerebral ischemias or infarctions occurred in the internal carotid artery distribution. An independent neurologist observer recorded the patients preoperative and postoperative medical and neurological histories and objective neurological findings. There was no operative mortality. During the period of observation (up to 36 months), four patients died of probable myocardial infarction. No patient suffered from recurrent cerebral infarction. Three patients experienced a single ischemic event postoperatively. Neurological deficits were either unchanged (21 patients) or improved (19 patients). Postoperative angiograms showed patency in 97% of the anastomoses.

Adult↗
PubMed1977

Selective induction of liver drug-metabolizing enzymes in rats exposed to a 21 ATA He-O2 environment.

The effects of prolonged exposure to a hyperbaric environment (21 ATA He-O2, 200 +/- 300 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the activity of rat liver drug-metabolizing enzyme systems, as monitored by O-dealkylation and N-dealkylation reactions. Continuous exposure of different groups of rats to a hyperbaric environment for 8, 22, 39, 57, or 84 d significantly increased the in vitro activity of drug-metabolizing enzymes in liver preparations obtained from rats subjected to prolonged exposures. The increase in the in vitro O-dealkylation of p-nitroanisole was selective; and the percent increases were 27, 146, 58, 40, 49, and 44 in liver preparations obtained from rats exposed continuously for 8, 22, 39, 57, 72, or 84 d, respectively. On the other hand, no statistically significant increase was observed in the in vitro activity of rat liver drug-metabolizing enzyme preparations during N-dealkylation of morphine and cocaine.

Animals↗
PubMed1976

Effects of a hyperbaric environment on respiratory and monoamine oxidase activities.

The effects of a prolonged hyperbaric environment (21 ATA He-O2, 200 +/- 30 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the respiratory activity of rat liver homogenates and the activity of monoamine oxidase in isolated rat-liver preparations. Exposure to a hyperbaric environment for 84 days caused selective in vitro inhibition of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, D-isocitrate, and alpha-ketoglutarate by rat-liver homogenates. The addition of NAD to the reaction mixture decreased the degree of such an inhibition. No effects on the in vitro activity of liver monoamine oxidase and its inhibition by pheniprazine were observed during exposure of animals to a prolonged high-pressure environment.

Animals↗
PubMedDate not supplied

Administered peptides inhibit the degradation of endogenous peptides. The dilemma of distinguishing direct from indirect effects.

Virtually all peptides are biologically active following central administration as a consequence of both direct and indirect cellular actions. Direct effects are mainly interactions with specific membrane receptors but may include unions with other components of the receptor/effector complex. Significant indirect biological effects of exogenous peptides, including apparent secretagogue effects on endogenous peptides largely overlooked in practice, result from extensive competition with endogenous peptides for degradative enzymes (peptidases). A consequence of this competition is enhancement of tonic or intermittent activity of endogenous peptides. The pharmacological profile of any peptide reflects or includes, therefore, the spectrum of endogenous peptides that is protected from peptidase action. It is likely that certain pharmacologically active peptides, including a large number of di-, tri- and oligo-peptides, elicit responses mainly or exclusively by competing for peptidases. Therefore, reliable estimates of the relative contributions of direct and indirect actions of exogenous peptides may be difficult, if not impossible, to obtain.

Analgesia↗
PubMedDate not supplied

Autoradiographic analysis of [3H]Ryanodine binding sites in rat brain: regional distribution and the effects of lesions on sites in the hippocampus.

Quantitative and qualitative autoradiographic methods together with lesion approaches were used to determine the distribution of [3H]ryanodine binding sites in rat brain and the neuronal localization of these sites in the hippocampus. In normal animals, levels of [3H]ryanodine binding sites ranged from a low of about 1 fmol/mg tissue in subcortical structures to a high of 12-18 fmol/mg tissue in subregions of the hippocampus and the olfactory bulb. Relatively high densities of sites (5-9 fmol/mg tissue) were also seen in the olfactory tubercle, most areas of the cerebral cortex, accumbens nucleus, striatum, lateral septal nuclei, pontine nucleus, superior colliculus and granule cell layer of the cerebellum. Specific binding was undetectable in white matter. In experimental animals, intracerebral injections of kainic acid caused neuronal degeneration and a near total depletion of [3H]ryanodine binding sites in the dentate gyrus and in fields CA1, CA2 and CA3 of the hippocampus. Injections of kainic acid that left dentate granule cells largely intact while destroying all neurons in field CA3 had no effect on binding sites in the dentate gyrus. However, these lesions substantially reduced the density of binding in field CA3, leaving a narrow band of sites outlining the position of the degenerated CA3 pyramidal cells. Mechanical knife-cut lesions that severed the granule cell mossy fiber input to field CA3 reduced the density of binding sites in the CA3 region. The results indicate that [3H]ryanodine binding sites in brain are heterogeneously distributed and suggest that a proportion of these sites in the hippocampus may be contained in mossy fiber terminals where a presumptive calcium channel/ryanodine receptor complex may be involved in the regulation of calcium mobilization and/or neurotransmitter release.

Animals↗
PubMedDate not supplied

Use of cholecystokinin to prevent the development of parenteral nutrition-associated cholestasis.

BACKGROUND: Neonates are at high risk for the development of parenteral nutrition-associated cholestasis when receiving a prolonged course of total parenteral nutrition (TPN). Although this cholestasis is of unknown etiology, it may result from a lack of gastrointestinal hormone formation, including cholecystokinin, which normally occurs after enteral feedings. METHODS: Two groups of neonates were studied. The treatment group consisted of 21 consecutive, prospectively enlisted neonates receiving TPN for > 14 days. The nontreatment group consisted of 21 infants from the 2 years preceding the study who were matched to the treatment group by gestational age, diagnosis, and duration of TPN. The major outcome determinant was direct bilirubin. Cholestasis was defined as a direct bilirubin > 2.0 mg/dL and was considered severe if the direct bilirubin was > 5.0 mg/dL after other causes were ruled out. RESULTS: The mean direct bilirubin levels in the nontreated group progressively rose over time, whereas the mean direct bilirubin the treated group remained level. The incidence of infants with a direct bilirubin > 2.0 mg/dL was 24% and 43% in the CCK+ and CCK- groups, respectively, and was not significant (p = .14). The percentage of infants with a direct bilirubin > 5.0 mg/dL was 9.5% and 38% in the treatment and nontreatment groups, respectively, and was significant, p = .015. CONCLUSIONS: Levels of direct bilirubin were lower in the treated compared with the nontreated group. These findings suggest that cholecystokinin prophylaxis in high-risk neonates may help prevent the development of parenteral nutrition-associated cholestasis.

Bilirubin↗