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Biomedical subjects

E C Cooper

Publications and source records attributed to E C Cooper.

36 records · Page 2Linked to original sources
PubMed1989

Aerosolized pentamidine. Approved for HIV-infected individuals at high risk for Pneumocystis carinii pneumonia.

Aerosolized pentamidine isethionate (NebuPent, LyphoMed Inc, Rosemont, Ill) was recently approved by the US Food and Drug Administration for use in prophylaxis against Pneumocystis carinii pneumonia in individuals infected with the human immunodeficiency virus who are at high risk for this infection. The recommended dose is 300 mg of aerosolized pentamidine isethionate administered every 4 weeks via the Respirgard II nebulizer (Marquest Medical Products Inc, Englewood, Colo). The drug is indicated for individuals infected with the human immunodeficiency virus who have a history of P carinii pneumonia or individuals with a CD4 (T4) lymphocyte count less than or equal to 0.2 x 10(9)/L with no history of P carinii pneumonia. We present information about the drug and its use, including safety information and use of the nebulizer.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Reconstituted voltage-sensitive sodium channels from eel electroplax: activation of permeability by quaternary lidocaine, N-bromoacetamide, and N-bromosuccinimide.

We have investigated the ion permeability properties of sodium channels purified from eel electroplax and reconstituted into liposomes. Under the influence of a depolarizing diffusion potential, these channels appear capable of occasional spontaneous openings. Fluxes which result from these openings are sodium selective and blocked (from opposite sides of the membrane) by tetrodotoxin (TTX) and moderate concentrations of the lidocaine analogue QX-314. Low concentrations of QX-314 paradoxically enhance this channel-mediated flux. N-bromoacetamide (NBA) and N-bromosuccinimide (NBS), reagents which remove inactivation gating in physiological preparations, transiently stimulate the sodium permeability of inside-out facing channels to high levels. The rise and subsequent fall of permeability appear to result from consecutive covalent modifications of the protein. Titration of the protein with the more reactive NBS can be used to produce stable, chronically active forms of the protein. Low concentrations of QX-314 produce a net facilitation of channel activation by NBA, while higher concentrations produce block of conductance. This suggests that rates of modifications by NBA which lead to the activation of permeability are influenced by conformational changes induced by QX-314 binding.

Acetamides↗
PubMed1989

Purified, modified eel sodium channels are active in planar bilayers in the absence of activating neurotoxins.

A recent study showed that limited trypsin treatment of liposomes containing purified Electrophorus electricus sodium channels activates a sodium radiotracer flux. We now report that similarly treated sodium channels show voltage-gated, tetrodotoxin-sensitive and highly sodium-selective single-channel currents when incorporated into planar lipid membranes. The trypsinized channels opened repeatedly in bursts of several seconds duration, as would be expected for channels whose fast inactivation process had been removed. Furthermore, they have a higher conductance, different voltage-dependence of gating, and a remarkably higher selectivity (PNa/PK = 41) than sodium channels bound by batrachotoxin or other activating neurotoxins; these properties of the trypsinized channels are probably closer to those of channels in intact electrocytes.

Animals↗
PubMed1988

Varicella-zoster virus-specific HLA-restricted cytotoxicity of normal immune adult lymphocytes after in vitro stimulation.

Varicella-zoster virus (VZV)-specific cytotoxic T cell responses were studied in 35 presumably immune and two nonimmune adult donors and in two patients with herpes zoster. Peripheral blood lymphocytes (PBLs) were stimulated for five or 12 days with autologous, irradiated, VZV-infected PBLs. Cytotoxicity was measured in a chromium-release assay. Target cells were usually cryopreserved, phytohemagglutinin-stimulated PBLs, either infected with VZV or uninfected. In testing the presumably immune adults, VZV-specific cytotoxicity was observed in 32 (91%) of 35 cases after five days and in 19 (90%) of 21 cases after 12 d of stimulation. Lysis of HLA-matched target cells was significantly greater than that of mismatched, VZV-infected target cells after both intervals. Responses were similar when PBLs from two patients with acute zoster were tested after in vitro stimulation and in one of those two tested without in vitro stimulation.

Antibodies, Viral↗
PubMed1987

Reconstituted voltage-sensitive sodium channel from Electrophorus electricus: chemical modifications that alter regulation of ion permeability.

At equilibrium, voltage-sensitive sodium channels normally are closed at all potentials. They open transiently in response to changes in membrane voltage or chronically under the influence of certain neurotoxins. Covalent modifications that result in chronic opening may help identify molecular domains involved in conductance regulation. Here, the purified sodium channel from electric eel electroplax, reconstituted in artificial liposomes, has been used to screen for such modifications. When the liposomes were treated with the alkaloid neurotoxin batrachotoxin, sodium-selective ion fluxes were produced, with permeability ratios PNa greater than PTl greater than PK greater than PRb greater than PCs. When the liposomes were treated with either of two oxidizing reagents (N-bromoacetamide or N-bromosuccinimide), or with Pronase or trypsin, ion-selective fluxes also were stimulated. These were blocked by tetrodotoxin and the anesthetic QX-314 in a manner suggesting that only modification of the cytoplasmic protein surface resulted in stimulation. Limited exposure to trypsin resulted in strong flux activation, with the concomitant appearance of peptide fragments with masses of approximately equal to 130, 70, and 38 kDa and fragments with masses of 45 and 24 kDa appearing later. We propose that characterization of these fragments may allow identification of channel domains important for inactivation gating.

Acetamides↗
PubMed1985

Stimulation of calcium uptake in PC12 cells by the dihydropyridine agonist BAY K 8644.

Methyl 1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (BAY K 8644), an analog of dihydropyridine calcium channel antagonists, stimulated 45Ca uptake into PC12 pheochromocytoma cells. Half-maximal stimulation occurred at 80 nM BAY K 8644. Enhancement of uptake was inhibited by cationic and organic calcium channel blockers, but not by tetrodotoxin, which is consistent with an effect on voltage-dependent calcium channels. Stimulation of 45Ca uptake by BAY K 8644 occurred only at elevated concentrations of extracellular K+, suggesting that BAY K 8644 may interact with calcium channels in the open (activated) state.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Reversible dihydropyridine isothiocyanate binding to brain calcium channels.

Voltage-dependent calcium channels from ileal smooth muscle can be affinity-labeled with a [3H]dihydropyridine isothiocyanate radioligand. We examined the binding of this agent to brain membranes, to compare the properties of calcium channel drug binding sites in brain with those previously described in ileum. In brain, the [3H]dihydropyridine isothiocyanate labels sites that correspond in number and pharmacologic characteristics to binding sites for the classic calcium entry blocker, [3H]nitrendipine. However, in contrast to the covalent nature of dihydropyridine isothiocyanate binding in ileum, brain calcium channels are labeled reversibly. This difference in binding properties may reflect structural variations in voltage-dependent calcium channels in different tissues.

Animals↗
PubMed1984

Calcium entry activators: distinct sites of dihydropyridine and aminopyridine action.

The dihydropyridine compound BAY K 8644, a putative calcium entry activator, inhibits binding of the dihydropyridine calcium entry blocker, [3H]nitrendipine, to rat skeletal muscle membranes. In contrast, aminopyridine compounds also believed to stimulate calcium flux do not interact with [3H]nitrendipine binding sites in skeletal muscle or brain. These findings suggest that calcium entry activators, like calcium entry blockers, affect voltage-dependent calcium channels by diverse mechanisms.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Calcium channel 'agonist' BAY K 8644 inhibits calcium antagonist binding to brain and PC12 cell membranes.

BAY K 8644, a drug that elicits calcium-dependent muscle contraction, inhibits binding of the voltage-dependent calcium channel antagonist [3H]nitrendipine to brain and PC12 pheochromocytoma cell membranes. This effect is due to high-affinity (Ki = 4.5 nM) competitive inhibition at the binding site for dihydropyridine calcium antagonists. Allosteric sites that mediate calcium channel blockade by non-dihydropyridine calcium antagonists are not similarly affected. Our findings indicate that BAY K 8644 is active at central, as well as peripheral, calcium channels and are compatible with a multi-state model of the voltage-dependent calcium channel in which antagonist drugs promote a closed state of the channel, while BAY K 8644 promotes an open state.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Phenytoin interacts with calcium channels in brain membranes.

Phenytoin at concentrations of between 30 and 300 microM inhibited binding of the calcium antagonist [3H] nitrendipine to voltage-dependent calcium channels in brain membranes. Other anticonvulsants (phenobarbital, carbamazepine, valproic acid, and clonazepam) failed to inhibit binding or did so only at concentrations much higher than occur clinically. Calcium channel blockade may be important in the clinical actions of phenytoin, including certain of the adverse effects of the drug.

Animals↗
PubMed1984

Ethanol and the gamma-aminobutyric acid-benzodiazepine receptor complex.

Ethanol appears to enhance gamma-aminobutyric acid (GABA)-mediated synaptic transmission. Using radioligand binding techniques, we investigated the possibility that the GABA-benzodiazepine receptor complex is the site responsible for this effect. Ethanol at concentrations up to 100 mM failed to alter binding of [3H]flunitrazepam (FNZ), [3H]Ro 15-1788, or [3H]methyl-beta-carboline-3-carboxylate (MBCC) to benzodiazepine receptors, or of [3H]muscimol to GABA receptors in rat brain membranes. Scatchard analyses of the binding of these radioligands at 4 degrees C and 37 degrees C revealed no significant effects of 100 mM ethanol on receptor affinity or number. A variety of drugs as well as chloride ion increased binding of [3H]FNZ and/or [3H]muscimol, but these influences were not modified by ethanol. These findings indicate that ethanol probably potentiates GABAergic neurotransmission at a signal transduction site beyond the GABA-benzodiazepine receptor complex.

Animals↗
PubMedDate not supplied

Effect of ethanol on [3H]nitrendipine binding to calcium channels in brain membranes.

We examined the effect of ethanol on [3H]nitrendipine binding to rat brain membranes, to investigate the possibility that voltage-dependent calcium channels are involved in synaptic actions of ethanol. Ethanol inhibited specific [3H]nitrendipine binding with Ki = 460 mM, by decreasing binding affinity without altering the maximal number of sites labeled. At a lower concentration (100 mM), ethanol had no effect on inhibition of binding by verapamil or diltiazem. The high concentrations of ethanol required to produce alterations in [3H]nitrendipine binding suggest that ethanol and classical calcium channel antagonists influence calcium-mediated synaptic processes by separate mechanisms.

Animals↗