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Biomedical subjects

D Cassel

Publications and source records attributed to D Cassel.

At least 37 records · Page 2Linked to original sources
PubMed1995

Use of a tantalum-178 generator and a multiwire gamma camera to study the effect of the Mueller maneuver on left ventricular performance: comparison to hemodynamics and single photon emission computed tomography perfusion patterns.

During the Mueller maneuver, there is a decrease in intrathoracic pressure and an increase in transmural left ventricular pressure. The changes in loading conditions cause transient left ventricular dysfunction. This study examined the effects of the Mueller maneuver on left ventricular performance using tantalum (Ta)-178 (half-life 9.3 min) and a multiwire gamma camera. First-pass radionuclide angiograms were obtained at baseline and during Mueller maneuver in 41 patients aged 58 +/- 10 years. In 34 patients, stress single photon emission computed tomography (SPECT) myocardial perfusion imaging with thallium-201 or sestamibi was also performed. Hemodynamic measurements during the Mueller maneuver (n = 10) showed a decrease in systemic pressure (139 +/- 25 mm Hg vs 123 +/- 24 mm Hg, p < 0.001) and pulmonary artery pressure (24 +/- 6 mm Hg vs 14 +/- 12 mm Hg, p = 0.01) and an increase in heart rate (67 +/- 10 bpm vs 75 +/- 14 beats/min, p = 0.001). Among the 34 patients who had perfusion imaging, the left ventricular ejection fraction remained unchanged or increased in 17 patients (group 1) (48% +/- 19% vs 49% +/- 21%, p not significant) and decreased (> or = 5%) in 17 patients (group 2) (55% +/- 13% vs 40% +/- 16%, p = 0.001). The stress SPECT images showed no or only fixed defects in 11 (65%) patients in group 1 and 3 (18%) patients in group 2 (p = 0.02), and reversible defects in 6 (35%) patients in group 1 and 14 (82%) patients in group 2 (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Results of adenosine single photon emission computed tomography thallium-201 imaging in hemodynamic nonresponders.

Systolic blood pressure typically decreases during adenosine infusion because of stimulation of A2b receptors, resulting in systemic vasodilation. This study examined the results of adenosine single photon emission computed tomography (SPECT) thallium-201 imaging in patients who did not show such a decrease in blood pressure during peak adenosine effect (nonresponders). The 102 nonresponders and 341 responders had no significant differences in age, gender, history of diabetes mellitus, hypertension, or previous myocardial infarction. The extent of coronary artery disease (CAD) by angiography was also similar. The sensitivity of SPECT thallium-201 imaging in patients with one-vessel disease was 82% in nonresponders and 84% in responders (p value not significant [NS]); in patients with multivessel disease, it was 90% in nonresponders and 94% in responders (p = NS) and for all CAD, it was 87% in non-responders and 91% in responders (p = NS). Thus lack of hemodynamic systemic response during adenosine infusion does not affect sensitivity for detecting CAD.

Adenosine↗
PubMed1995

Free choice of sickness funds: economic implications and ethical aspects of the 1992 health care reform in Germany.

To properly comply with the Health Sector Act of 1992 a functioning competition should be introduced in the interests of the insured of the German Statutory Health Insurance, while still maintaining the principle of solidarity. This is a critical order-political aim, because the principles of solidarity and self-responsibility as typically understood are functionally in contradiction. This paper analyzes the important measures of the Organizational Reform and concludes, that the principle of self-responsibility ought to obtain priority. Therefore, the German legislature ought to focus on further competitively oriented reform steps.

Community Participation↗
PubMed1995

Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors.

Platelet aggregation by ADP plays a major role in the development and extension of arterial thrombosis. The antithrombotic thienopyridine compounds ticlopidine and clopidogrel have proved useful tools to investigate the mechanisms of ADP-induced platelet activation. In essence, although clopidogrel has been shown to completely and selectively block ADP-induced platelet aggregation, G protein activation and inhibition of adenylyl cyclase, this drug does not affect shape change and Ca2+ influx. Binding studies, using the non-hydrolysable ligand [33P]2MeSADP, have shown that human platelets contain about 600 high-affinity binding sites for 2MeSADP (Kd approximately 5 nM). These sites present pharmacological characteristics of a P2T receptor. Clopidogrel treatment reduces the number of sites by 70% on rat platelets (from 1200 to 450) and leaves the residual binding sites resistant to clopidogrel. Moreover, patients with congenital impairment of ADP-induced platelet aggregation but normal shape change display very low levels of [33P]2MeSADP binding sites. The current data thus strongly suggest the presence of two ADP receptors, one responsible for shape change and rapid Ca2+ influx and the other a Gi protein-coupled receptor responsible for Ca2+ mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation.

Adenosine Diphosphate↗
PubMed1994

Prognostic implications of normal exercise tomographic thallium images in patients with angiographic evidence of significant coronary artery disease.

This study examines the prognostic implications of normal exercise tomographic thallium images in medically treated patients with angiographic evidence of coronary artery disease (CAD). There were 97 patients aged 60 +/- 10 years; 52 had 1-, 30 had 2-, and 15 had 3-vessel CAD (> or = 50% diameter stenosis). The exercise test was submaximal in 51 patients (53%); ST-segment depression during exercise occurred in 20 patients (21%), and angina during exercise occurred in 23 patients (24%). Most patients (71%) were receiving antianginal therapy. During a mean follow-up of 32 months, only 3 patients had cardiac events: 2 died of cardiac causes and 1 had nonfatal myocardial infarction (event rate 1.1%/year). None of those 3 patients had positive ST response during exercise. Thus, medically treated patients with CAD (including those with multivessel CAD) have a benign prognosis in the presence of normal exercise thallium images. These results have important implications in patient management and cost of health delivery.

Coronary Angiography↗
PubMed1994

Aluminum fluoride acts on the reversibility of ARF1-dependent coat protein binding to Golgi membranes.

The GTP-dependent interaction of ADP ribosylation factor 1 (ARF1) with Golgi membranes is required for the binding of cytosolic coatomer proteins to those membranes. Whereas both GTP and GTP gamma S can support coatomer binding to membranes, by using partially purified components, GTP-driven binding is rapidly reversible (t1/2 of 2 min) while that driven by GTP gamma S is more stable (t1/2 of over 30 min). In the presence of GTP, aluminum fluoride, an activator of trimeric G proteins, promotes the stable ARF-dependent binding of coatomer to membranes, even though this reagent does not itself activate ARF. Aluminum fluoride appears to act, like GTP gamma S, to make the binding of coatomer relatively irreversible. It acts to inhibit ARF-GTP hydrolysis catalyzed by the membrane and thus makes the ARF-GTP active state persistent. This effect is not dependent on the presence of any cytosolic component, such as the coatomer. The number of molecules of ARF that can be protected from hydrolysis by aluminum fluoride, however, is only a fraction of the total amount of ARF that can bind to membranes in the presence of GTP gamma S. We propose that this population defines a set of binding sites that are sufficient for coat protein assembly onto the membrane.

ADP-Ribosylation Factor 1↗
PubMed1992

ADP-ribosylation factor, a small GTP-binding protein, is required for binding of the coatomer protein beta-COP to Golgi membranes.

The coatomer is a cytosolic protein complex that reversibly associates with Golgi membranes and is implicated in modulating Golgi membrane transport. The association of beta-COP, a component of coatomer, with Golgi membranes is enhanced by guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), a nonhydrolyzable analogue of GTP, and by a mixture of aluminum and fluoride ions (Al/F). Here we show that the ADP-ribosylation factor (ARF) is required for the binding of beta-COP. Thus, beta-COP contained in a coatomer fraction that has been resolved from ARF does not bind to Golgi membranes, whereas binding can be reconstituted by the addition of recombinant ARF. Furthermore, an N-terminal peptide of ARF, which blocks ARF binding to Golgi membranes, inhibits GTP[gamma S]- as well as the Al/F-enhanced binding of beta-COP. We show that Golgi coat protein binding involves a sequential reaction where an initial interaction of ARF and GTP[gamma S] with the membrane allows subsequent binding of beta-COP to take place in the absence of free ARF and GTP[gamma S]. The fungal metabolite brefeldin A, which is known to prevent the association of coat proteins with Golgi membrane, is shown to exert this effect by interfering with the initial ARF-membrane interaction step.

ADP-Ribosylation Factors↗
PubMed1992

Side effects during adenosine thallium imaging with single-port or double-port infusion protocols.

The double-port infusion protocol during adenosine thallium imaging involves the use of two infusion systems, one for adenosine and one for thallium. The single-port infusion protocol, on the other hand, uses one infusion system; both adenosine and thallium are injected via a "Y" connection. This study examined the possibility that the single infusion system, by displacing a column of blood filled with adenosine, may be responsible for a greater incidence of side effects. In a parallel study, 140 patients underwent adenosine thallium imaging with the single-port system (group 1) and 140 patients underwent imaging with the double-port system (group 2). Both groups were comparable in age (67 +/- 10 years vs 64 +/- 11 years), gender (men comprised 56% of patients in group 1 and 64% in group 2), resting heart rate, and systolic blood pressure. More patients in group 1 had chest pains (57% vs 44%; p = 0.03), ST-segment depression (25% vs 9%; p = 0.005), nausea (11% vs 4%; p = 0.04), and second- or third-degree atrioventricular block (11% vs 5%; p less than 0.08) than did patients in group 2. The other side effects were similar, and peak heart rate and peak systolic blood pressure were also similar. The thallium images that used single-photon emission computed tomography were abnormal in 61% of patients in group 1 and in 65% of patients in group 2 (p = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1992

Tomographic myocardial perfusion imaging with technetium-99m teboroxime during adenosine-induced coronary hyperemia: correlation with thallium-201 imaging.

Single-photon emission computed tomographic imaging with technetium-99m teboroxime during exercise has been found to be feasible and the results correlate with those obtained with thallium-201. This study examined the feasibility of this technique and compared tomographic imaging with technetium-99m teboroxime during adenosine-induced coronary hyperemia with thallium-201 imaging. With the patient positioned on the imaging table, adenosine was infused at a rate of 140 micrograms/kg per min for 6 min. At 4 min, 20 to 25 mCi (740 to 925 MBq) of technetium-99m teboroxime was injected intravenously and imaging was started as soon as the infusion was completed with use of a 180 degrees anterior arc and 32 stops at 10 s/stop (total imaging time 7.8 min). Rest images were obtained 60 to 90 min later with use of a similar dose of technetium-99m teboroxime. Exercise tomographic thallium images were obtained within 2 weeks of the teboroxime studies. In the 20 patients studied, the teboroxime images were normal in 2 (50%) of 4 normal subjects and abnormal in 15 (94%) of 16 patients with coronary artery disease; 4 of the 15 had a fixed defect and 11 a reversible defect. There was agreement between teboroxime and thallium studies in 16 patients (80%), in 319 (80%) of 400 segments and in 50 (83%) of 60 vascular segments (p less than 0.05). In two normal subjects, an apparent fixed defect involving the inferior wall was seen on the teboroxime but not the thallium images and was thought to be due to an attenuation artifact secondary to extracardiac activity in the left lobe of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1991

Leishmania donovani: characterization of a 38-kDa membrane protein that cross-reacts with the mammalian G-protein transducin.

We investigated the presence in Leishmania donovani promastigotes of proteins with homology to the G-proteins known to mediate signal transduction in other organisms. [alpha 32P]GTP binding experiments revealed the presence in the promastigote membrane of GTP-binding sites with high affinity and specificity. Experiments with antisera directed against mammalian G-proteins showed that the promastigotes possess a 38-kDa protein (p38) which strongly reacts with an antiserum directed against a decapeptide containing the C-terminal sequence of transducin, the G-protein that mediates visual signal transduction. The interaction of p38 with the antiserum is specifically blocked by the decapeptide antigen. p38 is enriched in plasma membranes and is absent in cytosol and in a mitochondria-enriched fraction. p38 was also detected in two other Leishmania species, L. mexicana and L. major. The migration of p38 upon sucrose gradient centrifugation of detergent extract of L. donovani membranes corresponded to Mr of approximately 70,000, indicating that p38 is part of an oligomeric structure. The findings suggest that p38 may be a component of a transmembrane signal transduction system in Leishmania.

Amino Acid Sequence↗
PubMed1989

Identification and purification of a renal amiloride-binding protein with properties of the Na+-H+ exchanger.

The aim of this study was to identify and purify the Na+-H+ exchanger from rabbit renal brush border membranes by use of affinity chromatography. Triton-solubilized membranes were equilibrated with an affinity matrix consisting of the amiloride analogue A35 (5-N-(3-aminophenyl)amiloride) covalently coupled to Sepharose CL-4B beads through a triglycine spacer arm. The matrix was then washed extensively with buffer and sequentially eluted with buffer, buffer containing 5 mM amiloride, and 1% sodium dodecyl sulfate (SDS). Eluates were concentrated and subjected to SDS-polyacrylamide gel electrophoresis. The silver-stained gel revealed a 25-kDa protein that was not visible in the initial solubilized brush border membrane extract, was not eluted from the affinity matrix by buffer alone, but was eluted with 5 mM amiloride. A subsequent elution with 1% SDS did not release any more of the 25-kDa protein, indicating that it had been completely eluted from the affinity matrix by amiloride. The presence of 5 mM amiloride during equilibration of the solubilized brush border extract with the affinity matrix completely blocked adsorption of the 25-kDa protein. The relative abundance of this protein correlated closely with Na+-H+ exchange activity when preparations of cortical brush border membrane vesicles, outer medullary brush border membrane vesicles, and cortical basolateral membrane vesicles were compared. Moreover, binding of the protein to the affinity matrix was inhibited by amiloride and amiloride analogues with a rank order identical to that for inhibition of Na+-H+ exchange activity. These findings strongly suggest that the 25-kDa protein is a structural component of the Na+-H+ exchanger.

Amiloride↗
PubMed1989

2-Iodoimipramine, a novel ligand for the serotonin transporter.

Iodoimipramine was synthesized by iodinating imipramine with ICI. Iodoimipramine competitively inhibits [3H]imipramine binding with a KI of 0.52 nM and also inhibits [3H]serotonin transport competitively, suggesting that serotonin, imipramine, and iodoimipramine all bind to the same site on the serotonin transporter. Association of [125I]iodoimipramine to platelet membranes in Na+ requires 20 min to reach equilibrium at 25 degrees and 1.5 hr at 0 degrees. [125I] Iodoimipramine binding at equilibrium is saturable and Na+ dependent, with a KD of 0.58 nM and a Bmax of 1.3 pmol/mg at 25 degrees. Serotonin competitively inhibits [125I]iodoimipramine binding, with a KI of 1.3 microM. [125I]Iodoimipramine bound at 0 degrees in the presence of Na+ does not dissociate unless the temperature is raised or Na+ is removed from the medium. At 25 degrees, dissociation of [125I] iodoimipramine from platelet membranes in the presence of Na+ is only partial, with 40% of the ligand remaining persistently bound over 5 hr after a 50-fold dilution.

Binding, Competitive↗
PubMed1988

Characterization of Na+-linked and Na+-independent Cl-/HCO3- exchange systems in Chinese hamster lung fibroblasts.

The PS120 variant of Chinese hamster lung fibroblasts which lacks Na+/H+ exchange activity was used to investigate bicarbonate transport systems and their role in intracellular pH (pHi) regulation. When pHi was decreased by acid load, bicarbonate caused pHi increase and stimulated 36Cl- efflux from the cells, both in a Na+-dependent manner. These results together with previous findings that bicarbonate stimulates 22Na+ uptake in PS120 cells (L'Allemain, G., Paris, S., and Pouyssegur, J. (1985) J. Biol. Chem. 260, 4877-4883) demonstrate the presence of a Na+-linked Cl-/HCO3- exchange system. In cells with normal initial pHi, bicarbonate caused Na+-independent pHi increase in Cl(-)-free solutions and stimulated Na+-independent 36Cl- efflux, indicating that a Na+-independent Cl-/HCO3- exchanger is also present in the cell. Na+-linked and Na+-independent Cl-/HCO3- exchange is apparently mediated by two distinct systems, since a [(tetrahydrofluorene-7-yl)oxy]acetic acid derivative selectively inhibits the Na+-independent exchanger. An additional distinctive feature is a 10-fold lower affinity for chloride of the Na+-linked exchanger. The Na+-linked and Na+-independent Cl-/HCO3- exchange systems are likely to protect the cell from acid and alkaline load, respectively.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1988

Preparation of 6-125I-labeled amiloride derivatives.

Amiloride and certain of its derivatives are effective inhibitors of Na/H antiporters and of epithelial Na channels. We describe a simple method for the preparation of a variety of pharmacologically active 6-iodoamiloride derivatives that are labeled with 125I at high specific radioactivity. 6-Dechloroamiloride derivatives (bearing a hydrogen atom instead of the chlorine at the 6 position of the amiloride molecule) are reacted with 125ICl, prepared by the oxidation of the iodide in Na125I preparations. The 125I-labeled derivatives are separated from free 125I by anion exchange chromatography, or purified by thin layer chromatography. Both 6-dechloroamiloride and 5-(N-alkyl)-6-dechloroamiloride derivatives can be labeled by this method, with yields varying between 10 and 70%, depending on the ICl concentration and the structure of the 5-N-alkyl group. Efficient radiolabeling at high specific radioactivity also depends on the use of freshly prepared batches of 125I. Using carrier-free 125I, [125I]6-iodoamiloride and [125I]6-iodo-5-(N-tert-butyl)amiloride were prepared with yields of 27 and 22%, respectively. Potential applications of the 125I-labeled amiloride derivatives include ligand binding and affinity labeling experiments.

Amiloride↗
PubMed1987

A dextran-bound amiloride derivative is a selective inhibitor of Na+/H+ antiport. Application for studying the role of the antiporter in cellular proliferation in human fibroblasts.

Inhibitors of Na+/H+ exchange from the amiloride series are known to accumulate within the cell and cause an inhibition of a variety of cellular functions. In order to render the amiloride molecule impermeable to cells, we have synthesized a potent amiloride analog, 5-N-(3-aminophenyl)amiloride (compound A35, Ki = 60 nM). The isothiocyanate derivative of A35 (A35-NCS) was coupled to soluble dextrans of 15-20 kDa that have been derivatized with diaminoalkane spacer groups. Dextran-bound amiloride derivatives showed good inhibition of Na+/H+ exchange in human foreskin fibroblasts and A431 cells. Among several spacer groups tested, dextran derivatized with ethylenediamine showed the highest inhibitory activity. The intrinsic inhibitory potency of this polymer increased with increasing degree of substitution with A35, approaching that of free A35 with substitution of approximately 3 mol of A35 per mole of dextran. Coupling to dextran largely diminished side effects of the amiloride derivative on cells such as the inhibition of protein synthesis. A35-dextran was an effective inhibitor of serum-induced reinitiation of DNA synthesis in human foreskin fibroblasts in a bicarbonate-free medium, pH 7.1, but had little effect when either the pH of the medium was more alkaline or when the medium contained a bicarbonate buffer. These findings suggest that the selective inhibition of Na+/H+ antiport by A35-dextran prevents the reinitiation of DNA synthesis when the external conditions are such that the antiporter activity is required for the establishment of a permissive intracellular pH. Polymer-bound amiloride analogs should be useful as selective inhibitors in studies of the physiological role of the Na+/H+ antiporter, as well as for affinity purification of the antiporter.

Amiloride↗
PubMed1987

Coupling of photoexcited rhodopsin to inositol phospholipid hydrolysis in fly photoreceptors.

Fly photoreceptor membranes were used to test the effect on defined biochemical reactions of light and of compounds causing photoreceptor excitation. Complementary electrophysiological studies examined whether putative second messengers excite the fly photoreceptor cells. This analysis revealed the following sequence of events: photoexcited rhodopsin activates a G protein by facilitating GTP binding. The G protein then activates a phospholipase C that generates inositol trisphosphate, which in turn acts as an internal messenger to bring about depolarization of the photoreceptor cell. Binding assays of GTP analogs and measurements of GTPase activity showed that there are 1.6 million copies of G protein per photoreceptor cell. The GTP binding component is a 41-kDa protein, and the light-activated GTPase is dependent on photoconversion of rhodopsin to metarhodopsin. Analysis of phospholipase C activity revealed that this enzyme is under stringent control of the G protein, that the major product formed is inositol trisphosphate, and that this product is rapidly hydrolyzed by a specific phosphomonoesterase. Introduction of inositol trisphosphate to the intact photoreceptor cell mimics the effect of light, and bisphosphoglycerate, which inhibits inositol trisphosphate hydrolysis, enhances the effects of inositol trisphosphate and of dim light. The interaction of photoexcited rhodopsin with a G protein is thus similar in both vertebrate and invertebrate photoreceptors. These G proteins, however, activate different photoreceptor enzymes: phospholipase C in invertebrates and cGMP phosphodiesterase in vertebrates.

Animals↗