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Biomedical subjects

E Richelson

Publications and source records attributed to E Richelson.

At least 145 records · Page 8Linked to original sources
PubMed1985

Lithium ions inhibit function of low- but not high-affinity muscarinic receptors of murine neuroblastoma cells (clone N1E-115).

Murine neuroblastoma cells (clone N1E-115) possess both high- and low-affinity muscarinic receptors. The low-affinity muscarinic receptor, when stimulated, initiates the formation of cyclic GMP by activating the enzyme guanylate cyclase; whereas stimulation of the high-affinity receptor inhibits prostaglanding E1-mediated cyclic AMP formation by inhibiting the enzyme adenylate cyclase. We have reported that lithium ion (Li+) inhibits cyclic GMP formation mediated by the muscarinic receptor agonist, carbachol, in a concentration-dependent manner and that neither ammonium nor sodium ions have such an effect. We extended this study to show that Li+ was an apparently noncompetitive inhibitor of the low-affinity muscarinic receptor with an IC50(+/- SEM) = 13.6 +/- 0.8 mM. In addition, Li+ with a similar IC50 inhibited the cyclic GMP response in intact cells to sodium azide, which is thought to stimulate guanylate cyclase directly. Moreover, though Li+ was found to have a slight inhibitory effect on prostaglandin E1-stimulated cyclic AMP formation (15% inhibition at 10 mM), it had no effect on the function of the high-affinity muscarinic receptor in intact murine neuroblastoma cells.

Alprostadil↗
PubMed1985

Antipsychotic agents: a clinical update.

Antipsychotic agents have many indications and are frequently used. All physicians, regardless of their subspecialty, will most likely treat patients who receive these drugs. This article is designed to help nonpsychiatric physicians use antipsychotics appropriately. The indications, recommended dosages, side effects, and drug interactions of antipsychotic medications are reviewed. Receptor binding data are used to help predict the side-effect profile of these agents. Knowledge of these side effects and of the patient's medical condition helps the physician select a drug that the patient can tolerate. Management of overdose situations is discussed.

Adolescent↗
PubMed1985

Glucocorticoids potentiate the prostaglandin E1-mediated cyclic AMP formation by a cultured murine neuroblastoma clone.

The effect of steroid hormones on the prostaglandin E1 (PGE1)-mediated cyclic AMP formation by murine neuroblastoma clone N1E-115 was studied. Dexamethasone at submicromolar concentrations and corticosterone at micromolar concentrations (steroids with glucocorticoid activity) were able to modify the PGE1-mediated response whereas testosterone, progesterone, and estradiol each at 10 microM had no effect. Glucocorticoids added to the culture medium of N1E-115 cells produced an increase in the maximal response to PGE1 only after long-term (greater than or equal to 4 h) incubation with the hormone. Inhibitors of protein and RNA synthesis blocked this effect of glucocorticoids. Basal activity of adenylate cyclase in treated cells was twofold higher than that in control cells, and this enzyme seemed to be the primary target for the hormone action, since the activity of 3':5'-cyclic AMP phosphodiesterase and the binding of [3H]PGE1 to its receptors were not altered by glucocorticoid treatment. Our results indicate that glucocorticoids modulate receptor-mediated responses in cells of neural origin through a mechanism that involves induction of protein synthesis.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Influence of delta-opioid receptors on production of labeled methionine5-enkephalin in murine neuroblastoma cells.

Synthesis of methionine5-enkephalin by intact cells of murine neuroblastoma clone N1E-115 has been demonstrated both immunocytochemically and biochemically. In addition, N1E-115 cells possess homogeneous enkephalin (delta) receptors which inhibit prostaglandin E1-induced intracellular cyclic AMP formation. An assay was developed for measuring de novo synthesis of methionine5-enkephalin by pulsing cells in culture with radioactive methionine and isolating this pentapeptide to radiochemical purity by a procedure that included immunoaffinity chromatography specific for oxidized methionine5-enkephalin. This assay indicated that production of radiolabeled-methionine5-enkephalin was increased upon lengthy exposure of intact N1E-115 cells in the late logarithmic phase of growth to a nonproteolyzable analog of methionine5-enkephalin. This increase in synthesis of intracellular methionine5-enkephalin relative to control cells was prevented by prior incubation of the clone with naloxone, indicating that the response was mediated by the delta receptor.

Animals↗
PubMed1985

Pharmacology of neuroleptics in use in the United States.

The currently available data on the pharmacology of antipsychotic drugs, particularly on the neurotransmitter receptor blockade by this class of drugs, provide the clinician with practical and valuable information for choosing medication for the psychotic patient. Neuroleptics vary widely in their affinities for various receptors, and these differences help to explain the variations in their propensities to cause certain adverse effects in patients. By choosing a drug with low affinity for certain receptors, the clinician can minimize some of the adverse effects of neuroleptics.

Antipsychotic Agents↗
PubMed1985

Muscarinic responses and binding in a murine neuroblastoma clone (N1E-115). Mediation of separate responses by high affinity and low affinity agonist-receptor conformations.

Murine neuroblastoma cells (clone N1E-115) possess muscarinic receptors that mediate multiple responses, including the elevation of cyclic GMP levels and the inhibition of receptor-mediated increases in cyclic AMP. Evidence is presented showing that two muscarinic agonist-receptor conformations in N1E-115 cells each separately mediate a cyclic nucleotide response. Pirenzepine inhibited the [3H]cyclic GMP response to carbachol with a KD value of approximately 6 nM, whereas it inhibited the ability of carbachol to reduce prostaglandin E1-mediated elevations in [3H]cyclic AMP levels with a KD value of 93 nM, thus differentiating between two classes of receptors involved in these responses. Ten muscarinic agonists were studied for their ability to mediate the two cyclic nucleotide responses. Six were as effective as acetylcholine in the reduction of [3H]cyclic AMP levels, but only two were as effective as acetylcholine in elevating [3H]cyclic GMP levels. Four agonists (arecoline, pilocarpine, oxotremorine, and McN-A343) were ineffective in increasing [3H]cyclic GMP levels. These four agonists and bethanecol, which could increase [3H]cyclic GMP levels only 18% as well as acetylcholine, behaved as competitive antagonists in this response to carbachol. These partial agonists, in contrast to carbachol, bound to only one class of muscarinic sites in N1E-115 cells with equilibrium dissociation constants determined by competition binding assays which agreed well with their respective EC50 values for their effect on [3H]cyclic AMP levels. The equilibrium dissociation constants for the partial agonists determined by their inhibition of carbachol in the [3H] cyclic GMP response also agreed well with their respective EC50 values for mediating the [3H]cyclic AMP response. Thus, the partial agonists bound to the same receptors at which carbachol mediated [3H]cyclic GMP formation, but with KD values about the same as their respective EC50 values for inhibition of prostaglandin E1-mediated [3H]cyclic AMP increases. The full agonists acetylcholine and methacholine, like carbachol, bound to two sites in N1E-115 cells. For the six agonists able to stimulate both responses at least to some degree, the ratio of their potencies at each response correlated with their respective efficacies at each response but with much more dependence in the [3H]cyclic GMP response.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.

Inhibitor constants (Ki's) for blocking uptake of [3H]norepinephrine, [3H]serotonin, and [3H]dopamine into synaptosomal preparations of rat brain were determined for 25 antidepressants and putative antidepressants, some neuroleptics, stimulants, antihistamines and other monoamines. With Ki's we could directly and definitively compare the relative potencies of a drug at the three processes. Eighteen or 72% of the antidepressants (including tertiary amine tricyclics) were more potent at blocking uptake of norepinephrine than at blocking uptake of serotonin. Considering all three biogenic amines, 17 antidepressants were selective for blocking [3H]norepinephrine uptake, one (bupropion) was selective although weak for blocking [3H]dopamine uptake, and the remainder were selective for blocking [3H]serotonin uptake. The neuroleptics chlorpromazine and promazine were relatively potent at blocking uptake of [3H]norepinephrine and some tricyclic antidepressants (notably, trimipramine and butriptyline) were very weak at blocking any biogenic amine uptake.

Animals↗
PubMed1984

Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro.

Using radioligand binding techniques, we determined the equilibrium dissociation constants (KD's) for a series of neuroleptics at the dopamine (D-2), muscarinic, histamine H1, alpha 1- and alpha 2-adrenergic receptors of normal human brain tissue obtained at autopsy. Seventeen different compounds were studied at the D-2 receptor and 15 compounds at the remaining receptors. At the D-2 receptor of caudate nucleus, spiperone was the most potent compound (KD = 0.16 nM); clozapine the least potent (KD = 180 nM). The KD's for six compounds at the D-2 receptor of nucleus accumbens were not significantly different from their respective KD's in the caudate nucleus. The most potent and least potent compounds at the other receptors were clozapine and molindone at the muscarinic receptor, mesoridazine and molindone at the H1 receptor, spiperone and molindone at the alpha 1-receptor, and clozapine and haloperidol at the alpha 2-receptor, respectively.

Adolescent↗
PubMed1984

Activation of cyclic nucleotide formation in murine neuroblastoma N1E-115 cells by modified human thrombins.

The activity of alpha-thrombin and chemically modified derivatives of this enzyme in stimulating cGMP formation in murine neuroblastoma clone N1E-115 cells is reported. The rank order potency of the compounds falls into three classes: 1) alpha-thrombin is the most potent and effective; 2) the catalytically active enzymes gamma-thrombin, trypsin, and nitro-alpha-thrombin are approximately 50-fold less potent than alpha-thrombin; and 3) active site blocked derivatives of alpha-thrombin are 100 to 1000-fold less potent than alpha-thrombin. Native alpha-thrombin consistently produces the most effective response, usually 1.5 to 3-fold greater than any of the other compounds tested. Preincubation of cells with quinacrine, an inhibitor of phospholipase A2, or with the lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid or nordihydroguaiaretic acid prior to thrombin challenge resulted in a concentration-dependent attenuation of the response. Indomethacin was without effect in modifying the response. These results suggest that thrombin stimulation of neuroblastoma cells involves the release of arachidonic acid and its metabolism by lipoxygenase. These results clearly demonstrate the activity of alpha-thrombin in stimulating a receptor-mediated response in cultured nerve cells. The results are discussed in relation to the interaction of endogenous alpha-thrombin with nerve cells following invasive trauma and to the possible presence of endogenous proteinases with a neurotransmitter-like function.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1984

Histamine H1 receptors in human brain labelled with [3H]doxepin.

Doxepin, a tricyclic antidepressant, is one of the most potent histamine H1 antagonists. Therefore, the binding of [3H]doxepin to human brain membranes was examined. Scatchard analysis revealed two distinct binding sites. The high-affinity binding site with a dissociation constant (KD +/- S.E.M.) of 3.1 +/- 0.3 X 10(-10) M was pharmacologically identified as histamine H1 receptors. Dissociation curves at low concentrations of [3H]doxepin were biphasic, suggesting several possibilities about the interaction between [3H]doxepin and histamine H1 receptors. Tetracyclic antidepressants, mianserin and maprotiline, were very potent, with KDs of 3.6 +/- 0.7 X 10(-10) M and 7.9 +/- 0.5 X 10(-10) M, respectively. Mequitazine, a new antihistamine with a weak sedative effect, had a KD of 5.8 +/- 0.8 X 10(-9), making it ten times as potent as the classic antihistamine diphenhydramine. The highest binding of [3H]doxepin to histamine H1 receptors was found in cerebral neocortex and the limbic system. The distribution of histamine H1 receptors in human central nervous system did not correlate with the previously reported distributions in rat brain and guinea pig brain determined by [3H]doxepin binding.

Adult↗
PubMed1984

Sodium-dependent lithium ion efflux from murine neuroblastoma and rat glioma cells: a minor pathway for efflux of lithium ions.

Lithium ion efflux by murine neuroblastoma (clone N1E-115) and rat glioma (clone C6) cells was studied to determine the presence of a phloretin-sensitive sodium-lithium countertransport pathway which has been found in human erythrocytes. Although this pathway could be identified in these cultured cells, unlike that in red blood cells, it was a very minor (less than 20%) component of the overall efflux of lithium ions from these cells of nervous tissue origin.

Animals↗
PubMed1984

Antidepressants: a clinical update for medical practitioners.

Knowledge of the pharmacologic actions of antidepressants enables the physician to develop an appropriate rationale for the use of these medications in the medical setting. The appropriate choice of drug and adequate dose, duration, maintenance, termination, therapy, and alternatives should be considered.

Antidepressive Agents↗
PubMed1984

Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase.

Evidence is presented that has led us to abandon the hypothesis that receptor-mediated cyclic GMP formation in cultured nerve cells occurs via the influx of extracellular calcium ions and an increase in the cytosolic free calcium ion concentration. While the cyclic GMP response is absolutely dependent on the presence of Ca2+, there is no increase in free intracellular Ca2+ subsequent to agonist stimulation. Instead, we have found that muscarinic or histamine H1 receptor stimulation elicits the release of arachidonic acid through a quinacrine-sensitive mechanism, possibly phospholipase A2. Inhibition of the release or metabolism of arachidonate by the lipoxygenase pathway prevents receptor-mediated cyclic GMP formation. We hypothesize that neurotransmitter receptors that mediate cyclic GMP synthesis function by releasing arachidonic acid and that an oxidative metabolite of arachidonic acid then stimulates soluble guanylate cyclase.

Animals↗
PubMed1984

Kinetic effects of terbium ions on muscarinic acetylcholine receptors of murine neuroblastoma cells.

Preincubation of murine neuroblastoma cells (clone N1E-115) with terbium chloride resulted in a significant potentiation of carbachol-mediated increase in cyclic GMP formation. This effect was accompanied by a shift of the peak response from 30 s to 120 s and a 6-fold decrease in carbachol concentration producing half-maximal responses, in addition to a significant increase in the Hill coefficient. Terbium ions also caused a significant decrease in the affinity and an increase in the maximum binding of [3H]quinuclidinyl benzilate to muscarinic receptors, the change in affinity being mainly due to a decrease in the association rate. Preincubation of cells with 1 mM carbachol for 4 h (the desensitized state of the muscarinic receptor) resulted in a decrease in the ability of terbium to alter [3H]quinuclidinyl benzilate binding. The effects of terbium reported here might be due to its affecting muscarinic receptor-effector coupling, which is considered to be lost upon receptor desensitization.

Animals↗
PubMed1984

Bradykinin receptor-mediated cyclic GMP formation in a nerve cell population (murine neuroblastoma clone N1E-115).

A clone of murine neuroblastoma (N1E-115) was shown to have functional receptors for the nonapeptide bradykinin. These receptors mediated a large, rapid (about 1 min to peak) and calcium-dependent increase in cyclic GMP. The median effective concentration (EC50) averaged 1.4 nM. In addition, this event was inhibited by quinacrine, 5,8,11,14-eicosatetraynoic acid, and nordi-hydroguaiaretic acid, suggesting involvement of phospholipase A2 with subsequent formation of lipoxygenase metabolities of arachidonic acid. [3H]Bradykinin binding to intact cells, investigated under conditions nearly identical to those used in the cyclic GMP assay, yielded binding sites with KDS of 0.83 pM, 1.0 nM, and 4.9 nM with respective Bmax values of 12, 160, and 250 fmol/10(6) cells. Apparently, the cyclic GMP response was associated with the binding site in which the KD = 1.0 nM. Peptide analogs of bradykinin stimulated cyclic GMP with EC50S nearly identical to their respective KDS determined in binding assays with [3H]bradykinin, thus providing evidence for receptor specificity of this response. This finding of a biochemical response of bradykinin promises to make N1E-115 cells a convenient model system for study of neuronal bradykinin receptors.

5,8,11,14-Eicosatetraynoic Acid↗