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W W Douglas

Publications and source records attributed to W W Douglas.

At least 19 recordsLinked to original sources
PubMed1992

Effectiveness of GABAB antagonists in inhibiting baclofen-induced reductions in cytosolic free Ca concentration in isolated melanotrophs of rat.

1. The purpose of the present experiments was to assess the activities of GABAB receptor antagonists in mammalian isolated melanotrophs. 2. Cytosolic free Ca concentration ([Ca2+]i) in rat melanotrophs in primary culture was monitored with the fluorescent probe, fura-2. 3. (-)-Baclofen lowered [Ca2+]i in a concentration-dependent manner with an EC50 of 0.96 microM. The reduction in [Ca2+]i produced by (-)-baclofen at a maximally effective concentration (100 microM) was similar to that produced by the classic transmitter inhibitory to melanotroph secretion, dopamine, at a corresponding concentration (100 nM), or by perifusion with a nominally Ca-free solution. 4. The GABAB receptor antagonists, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), 2-hydroxy saclofen, phaclofen and 4-amino-3-(5-methoxybenzo[b]furan-2-yl) butanoic acid (9H), had inhibitory effects on the reduction in [Ca2+]i produced by (-)-baclofen (3 microM). Of the antagonists tested, CGP 35348 was the most potent with an IC50 of 60 microM, compared to 120 to 400 microM for the others. CGP 35348 acted competitively. 5. CGP 35348 alone had no effect on basal [Ca2+]i, or on the changes in [Ca2+]i produced by dopamine (10 nM) or the specific GABAA receptor agonist, muscimol (10 microM). 6. The evidence indicates that of the antagonists tested, CGP 35348 offers the greatest promise for pharmacological analysis of the functional significance of the GABAB receptors in melanotrophs.

Animals↗
PubMed1992

Calcium channels in rat melanotrophs are permeable to manganese, cobalt, cadmium, and lanthanum, but not to nickel: evidence provided by fluorescence changes in fura-2-loaded cells.

Cobalt (Co), nickel (Ni), manganese (Mn), cadmium (Cd), and lanthanum (La) are commonly used as calcium (Ca) channel blockers, but some of them, besides reducing Ca entry, also traverse Ca channels and can exert effects intracellularly that confound interpretation of functional responses. Because of this and our need to use Ca channel blockers in an ongoing analysis of Ca channel activity in the regulation of the cytosolic free Ca concentration ([Ca2+]i) and secretion in melanotrophs, we assessed whether the cations mentioned enter these cells. This was done by incorporating the fluorescence for changes that would signal the presence of the cations in the cytosol. In cell-free solution, where the probe and cations can interact freely, Mn, Co, and Ni all quench fluorescence, whereas Cd and La act in a Ca-like manner. When tested on fura-2-loaded melanotrophs in basal (unstimulated) conditions, Mn, Co, and Cd each yielded corresponding signals, thereby showing that they had penetrated the cells. By contrast, Ni caused no quenching of fluorescence even in melanotrophs exposed to 100 mM K+ to recruit additional Ca channels. Ni, therefore, did not penetrate the cells. However, as expected, Ni quenched fluorescence when given artificial access to the cytoplasm by ionomycin. Ni blocked spontaneous entry of Mn, Co, and Cd. It also lowered [Ca2+]i in unstimulated melanotrophs, consistent with blockade of spontaneous Ca entry. Like Ni, La lowered basal [Ca2+]i in unstimulated melanotrophs without penetrating the cells; however, unlike Ni, it penetrated when the melanotrophs were exposed to high potassium. We conclude that Ni is the most specific of the Ca channel blockers tested and that results obtained with Mn, Co, Cd, and La must be interpreted with reserve.

Animals↗
PubMed1992

Upper lobe pulmonary parenchymal calcification in a patient with AIDS and Pneumocystis carinii pneumonia receiving aerosolized pentamidine.

In patients with AIDS-related Pneumocystis carinii infection occurring during aerosolized pentamidine prophylaxis, roentgenographic findings may be atypical. Pulmonary parenchymal calcification due to P carinii is rare. In this case, extensive upper lobe pulmonary parenchymal, splenic, and nodal calcifications occurred after two years of monthly treatments with aerosolized pentamidine.

Acquired Immunodeficiency Syndrome↗
PubMed1992

High-resolution CT of the lungs: findings in various pulmonary diseases.

High-resolution CT (HRCT) is a technique that optimizes the spatial resolution of conventional scanners. HRCT shows exquisite detail of both normal and diseased lung. The findings seen with HRCT of the lung correlate well with the microscopic and gross pathologic findings. In this review, we describe the technical features of HRCT and discuss the HRCT findings in various lung diseases.

Humans↗
PubMed1991

Studies on pituitary melanotrophs reveal the novel GABAB antagonist CGP 35-348 to be the first such compound effective on endocrine cells.

One obstacle to understanding the action and physiological significance of the responsiveness of various endocrine cells to gamma-aminobutyric acid (GABA) has been that previously available substances, all active as GABAB antagonists in the nervous system, are ineffective on endocrine cells. The introduction of a potent new member of this class, CGP 35-348, of very different chemical structure, encouraged us to examine its effect on endocrine cells. For this purpose, we studied melanotroph secretion from pituitary neurointermediate lobes. We found that CGP 35-348, in contrast to previously available members of this class, suppressed completely, in rat and toad, secretory responses to baclofen, the classic GABAB agonist. Analysis, in toad, showed CGP 35-348 did not affect responses to GABAA agonists (muscimol; isoguvacine), dopamine, or neuropeptide Y. When tested against GABA, the physiological ligand present in the innervation of melanotrophs (along with dopamine and neuropeptide Y), CGP 35-348 completely suppressed the secretory response, which, in toad, is purely inhibitory and unaffected by bicuculline, the specific GABAA antagonist. In addition, CGP 35-348 unmasked a stimulant effect that bicuculline blocked. In CGP 35-348, we thus have a new tool with which to analyse responses to GABA and their physiological involvement in endocrine cells.

Animals↗
PubMed1991

Why are several inhibitory transmitters present in the innervation of pituitary melanotrophs? Actions and interactions of dopamine, GABA and neuropeptide Y on secretion from neurointermediate lobes of Xenopus laevis.

The aim of the present experiments was to determine whether some rationale for the presence of the several inhibitory neurotransmitters in the innervation to the toad melanotroph might be found in differences in their individual effects or in possible cooperative interactions affecting secretion. Measurements of peptide release from isolated, perifused neurointermediate lobes of the toad Xenopus laevis showed that each of the three identified inhibitory transmitters, dopamine, GABA and NPY, was able to inhibit secretion profoundly and no less effectively than omission of Ca. Moreover, the inhibitory effects were rather similar in onset, duration and recovery. Furthermore, there was no evidence of any cooperative interactions when the transmitters were given in various combinations. And finally, the inhibitory response to each of the transmitters was abolished by pretreatment with pertussis toxin. While not excluding differential postsynaptic effects on other parameters of melanotroph function, the similarities observed have encouraged alternative speculations on the significance of the apparent redundancy of inhibitory transmitters.

Animals↗
PubMed1990

Dopamine (D2) or gamma-aminobutyric acid (GABAB) receptor activation hyperpolarizes rat melanotrophs and pertussis toxin blocks these responses and the accompanying fall in [Ca2+]i.

The effects, on membrane potential, of dopamine (DA) and gamma-aminobutyric acid (GABA), transmitters present in the secreto-inhibitor innervation to the melanotrophs, were monitored in primary cultures of rat melanotrophs with bis-oxonol. DA and GABA, acting through D2 and GABAB receptors, hyperpolarized the melanotrophs. Hyperpolarization was not suppressed by tetrodotoxin but was prevented by pertussis toxin and may thus be due to a G protein mediated mechanism. Pertussis toxin also blocked the effects mediated by the two receptors to reduce intracellular free Ca2+ ([Ca2+]i).

Animals↗
PubMed1990

Cytosolic Ca2+ in melanotrophs: pharmacological insights into regulatory influences of electrical activity and ion channels.

The concentration of intracellular free Ca2+ ([Ca2+]i) was measured in melanotrophs, the characteristic endocrine cells of the pars intermedia of the rat pituitary gland, using the fluorescent Ca indicator fura-2. The resting [Ca2+]i was 211 +/- 8 nM and was little affected by tetrodotoxin (TTX; 5 or 10 microM), which inhibits the spontaneous action potentials that occur in these cells. Removal of extracellular Ca2+ (by chelation with EGTA) or addition of the Ca channel blocker nimodipine (1 microM) produced a rapid fall in [Ca2+]i, which occurred whether TTX was present or not. Excess K+ (60 mM), veratridine (10 or 100 microM) and BAY K 8644 (1 microM) each caused a rapid rise in [Ca2+]i, which was blocked or truncated by EGTA or nimodipine. TTX blocked or truncated the increases in [Ca2+]i induced by veratridine, but not those induced by either excess K+ or BAY K 8644. The results show that manipulations that increase or decrease hormone output increase or decrease [Ca2+]i. Furthermore, the resting [Ca2+]i appears to depend importantly on Ca influx, since it is rapidly and markedly reduced by removal of extracellular Ca2+ or addition of a Ca channel blocker.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Effects of BAY K 8644 on Ca-channel currents and electrical activity in mouse melanotrophs.

The effects of BAY K 8644 on both evoked and spontaneous electrical activity were studied in mouse melanotrophs. The action potential in these cells consisted of both a Na and a Ca component. BAY K 8644 greatly increased the duration of the evoked action potential apparently by enhancing the Ca component since this prolongation remained when the Na component was blocked by tetrodotoxin but was diminished by the Ca-channel antagonists Co2+ or nimodipine. In addition to its effects on the evoked action potential, BAY K 8644 sometimes caused action potentials of long duration to occur in otherwise quiescent melanotrophs, even in the presence of tetrodotoxin. These action potentials appeared to be triggered by small, depolarizing prepotentials. Voltage-clamp experiments suggested the existence of 3 types of Ca-channel currents in these cells: one low-threshold current and two high-threshold currents, one of which rapidly inactivated and another which did not. BAY K 8644 caused a shift in the I-V relation for Ca-channel current to more negative values and reduced or abolished the hump in the initial part of the I-V curve produced by the low-threshold current suggesting that BAY K 8644 selectively affects high-threshold Ca current. The action of BAY K 8644 to initiate trains of long-lasting Ca spikes and thereby increase Ca influx, might explain its secretagogue effect on the unstimulated melanotroph.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Silo-filler's disease.

Between 1955 and 1987, 17 patients were examined at the Mayo Clinic shortly after exposure to silo gas. All exposures had occurred in conventional top-unloading silos. Acute lung injury occurred in 11 patients, 1 of whom died; early diffuse alveolar damage with hyaline membranes and hemorrhagic pulmonary edema and acute edema of the airways were found at autopsy. In one patient, hypoxemia and transient obstruction of the airways developed, but no pulmonary infiltrates were noted. One patient had symptoms for 5 weeks and diffuse confluent pulmonary infiltrates; many years later, chronic obstructive pulmonary disease developed (he had, however, been a heavy smoker before exposure). Bronchiolitis obliterans was not observed in the other patients, probably because of less severe exposure or early corticosteroid therapy. Prophylactic corticosteroid therapy is advised for workers who have been exposed to silo gas. The management of patients with established acute lung injury is reviewed. Previously unreported patterns of exposure to silo gas in conventional silos are described, and recommendations for avoiding exposure are suggested.

Acute Disease↗
PubMed1987

Role of bronchoalveolar lavage in the assessment of opportunistic pulmonary infections: utility and complications.

We prospectively evaluated the diagnostic role of bronchoalveolar lavage in the assessment of opportunistic pulmonary infections and the incidence of associated complications in 100 immunocompromised patients during a 9-month period. Bronchoalveolar lavage was useful in detecting the presence of Pneumocystis carinii, viruses, fungi, bacteria, and mycobacteria in the lower respiratory tract. P. carinii was diagnosed by bronchoalveolar lavage in 17 patients and by open-lung biopsy in 1. Other organisms detected by lavage, lung biopsy, or both included viruses (eight patients), fungi (four patients), bacteria (six patients), and mycobacteria (three patients). Of the 100 patients studied, 33 had infectious agents detected in the lung; in 6 of these patients, more than one organism was present. Bronchoalveolar lavage detected the infectious organisms in 30 of the patients, in many of whom an open-lung biopsy was likely avoided because of the lavage studies. Although no major complications of bronchoalveolar lavage were noted in this critically ill population, five patients did require short-term mechanical ventilation after bronchoscopy. When correctly used, bronchoalveolar lavage is a safe and useful procedure for the assessment of immunocompromised subjects with suspected opportunistic pulmonary infections.

Bacterial Infections↗
PubMed1986

Electrical stimulation of neurointermediate lobes of mice elicits calcium-dependent output of melanocyte-stimulating hormone.

Current pulses applied to isolated neurointermediate lobes of mice increased output of melanocyte-stimulating hormone. This response was dependent on extracellular calcium over a wide range of stimulus intensities and thus appears to be a true secretory response from the melanotrophs. Since substantial responses persisted in the presence of tetrodotoxin, much of the effect seems to be independent of Na spiking.

Animals↗
PubMed1986

Effects of Bay K 8644 and other dihydropyridines on basal and potassium-evoked output of MSH from mouse melanotrophs in vitro.

Dihydropyridines that have been shown in studies on other tissues either to facilitate Ca influx (BAY K 8644) or depress it (nimodipine and nifedipine) were examined for their effects on the secretory activity of the melanotrophs. Isolated mouse neurointermediate lobes, cultured for a week or longer to allow the nerves to degenerate, were perifused and output of MSH activity was measured by bioassay. The Ca-channel agonist BAY K 8644 augmented secretion under basal conditions and potentiated secretion evoked by 30 mM K+, a submaximally depolarizing concentration. The stimulant effect on secretion under basal conditions persisted in the presence of tetrodotoxin (which blocks the action potentials, Na spikes, in the melanotrophs) but was lost when Ca2+ was omitted or nimodipine added. The results are considered to support the view that the prominent basal secretory activity in these cells, as well as that evoked by excess K+, involve the inward flux of Ca2+ through dihydropyridine-sensitive Ca channels. If the stimulant and inhibitory effects of the dihydropyridines on basal secretion are to be attributed to actions on voltage-regulated Ca channels, as the results from other tissues would suggest, then such channels in the melanotrophs are different from those previously described in other tissues.

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

Pharmacological and ionic features of gamma-aminobutyric acid receptors influencing electrical properties of melanotrophs isolated from the rat pars intermedia.

Characteristics of the gamma-aminobutyric acid receptors on melanotrophs of the rat pars intermedia were studied by intracellular recording. Muscimol and 3-amino-1-propanesulfonic acid, but not baclofen or glycine, mimicked the depolarization and conductance increase produced by gamma-aminobutyric acid on the melanotrophs. These effects appeared to be due to an increase in chloride ion conductance since the null potentials for all three drugs were the same and were affected by changes in external or internal chloride ion concentration but not by changes in the concentrations of other ions present in the recording solution or by the addition of the calcium-channel blocker cobalt. Bicuculline abolished the effect of muscimol. Picrotoxin reduced the effect of gamma-aminobutyric acid; so too did furosemide. Muscimol mimicked the ability of gamma-aminobutyric acid to reduce the depolarization produced by excess potassium and this effect was also blocked by bicuculline. Rat melanotrophs thus appear to possess gamma-aminobutyric acid receptor-ionophore complexes similar to the classical sort found in neurons in the mammalian central nervous system. Furthermore, the parallels between the electrical responses observed and secretory effects previously noted, reinforce the view that electrical activity may participate in stimulus-secretion coupling in melanotrophs.

Animals↗
PubMed1985

Survival in adult respiratory distress syndrome caused by blastomycosis infection.

A 32-year-old man with diabetes had rapid development of acute respiratory failure and severe hypoxemia. Radiologic and hemodynamic evaluation confirmed the clinical diagnosis of adult respiratory distress syndrome, and open-lung biopsy disclosed blastomycosis as the etiologic agent. The survival of this patient, after amphotericin therapy, to our knowledge is the first reported recovery from substantiated adult respiratory distress syndrome secondary to blastomycosis.

Acute Disease↗
PubMed1985

Amiodarone pulmonary toxicity. Assessment by bronchoalveolar lavage.

Bronchoalveolar lavage was used to demonstrate morphologic changes in alveolar macrophages characteristic of amiodarone effect in lung tissue obtained by biopsy. This procedure may be useful in the assessment of abnormal chest x-ray findings in patients suspected to have amiodarone toxicity.

Amiodarone↗