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Biomedical subjects

Y C Ng

Publications and source records attributed to Y C Ng.

At least 37 records · Page 2Linked to original sources
PubMed1993

Hypokalemia downregulates cardiac alpha 1 and skeletal muscle alpha 2 isoforms of Na+,K(+)-ATPase in ferrets.

K+ deficiency decreases amount of Na+,K(+)-ATPase in cardiac and skeletal muscle (SM) and differentially regulates alpha- and beta-subunit isoforms. Expression of the alpha 3 isoform during K+ deficiency is unknown, however. In the myocardium of normal adult ferrets, alpha 1 and alpha 3 isoforms are expressed. Therefore, we examined in ferrets the effects of K+ deficiency in levels of alpha- and beta-subunit isoforms. A K+ deficient diet greatly reduced plasma K+ concentrations. Tissue K+ content in myocardium remained unchanged, whereas that of SM decreased markedly. Corresponding to these changes, Na+,K(+)-ATPase enzyme activity decreased in SM but not in heart. Levels of alpha 1 in heart and alpha 2 in SM decreased, whereas those of alpha 3 in heart and alpha 1 in SM remained unchanged; beta 1 remained unchanged in both tissues. Thus, in ferrets, K+ deficiency differentially regulated the levels of Na+,K(+)-ATPase isoforms in an isoform- and tissue-dependent manner.

Animals↗
PubMed1993

Alterations in levels of Na(+)-K(+)-ATPase isoforms in heart, skeletal muscle, and kidney of diabetic rats.

In streptozotocin (STZ)-induced diabetic rats, activities of Na(+)-K(+)-ATPase and the Na pump have been shown to be altered. Cellular mechanisms underlying such changes remain unclear. The present studies examined by immunoblotting the levels of Na(+)-K(+)-ATPase subunit isoforms in heart, skeletal muscle, and kidney of diabetic rats. Effects of insulin treatment on these levels were also studied. In cardiac muscle, STZ-induced diabetes caused a marked decrease in alpha 2-levels, a moderate decrease in beta 1-levels, and no significant change in alpha 1-levels. Corresponding to these changes, Na(+)-K(+)-ATPase activity, estimated by K(+)-dependent p-nitrophenylphosphatase activity, also decreased. By contrast, there were significant increases in alpha 1- and alpha 2-levels in skeletal muscle and in alpha 1- and beta 1-levels in kidneys of diabetic rats. There was also a detectable, but not significant, increase in beta 1-levels in diabetic skeletal muscle. In kidney, the increase in subunit levels was associated with significantly increased Na(+)-K(+)-ATPase activity, whereas, in skeletal muscle, no increase in enzyme activity was observed. In diabetic rats, 7 days of insulin treatment (10 U/kg sc) partially reversed the decreased alpha 2- and beta 1-levels in diabetic cardiac muscle, without significant effect on alpha 1-levels. In skeletal muscle, insulin treatment also partially reversed the elevated alpha 1- and alpha 2-levels but was without significant effect on beta 1-levels. It is concluded that STZ-induced diabetes exerted isoform- and tissue-specific regulation of the Na(+)-K(+)-ATPase subunit isoforms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Expression of Na(+)-K(+)-ATPase alpha 1- and alpha 3-isoforms in adult and neonatal ferret hearts.

We have demonstrated previously that in adult ferret heart two alpha-subunit isoforms of the Na(+)-K(+)-ATPase, alpha(+) and alpha, are expressed. The alpha(+)-isoform may comprise either alpha 2-, or alpha 3-, or both isoforms. The present studies further characterize the alpha(+)-isoform. The alpha(+)-isoform of ferret heart did not react with an alpha 2-specific monoclonal antibody, but rather with two different alpha 3-specific polyclonal antibodies. Electrophoretic mobility of the alpha(+)-isoform in sodium dodecyl sulfate polyacrylamide gel electrophoresis is slower than that of the alpha 2-isoform, but similar to that of the alpha 3-isoform. Limited proteolytic peptide mapping was performed using Staphylococcus aureus V8. Proteolytic fragments were then immunostained with an alpha 3-specific antibody. The peptide maps of ferret heart alpha(+)-isoform and rat brain alpha 3-isoform were identical, as were those of ferret heart alpha(+)-isoform and ferret brain alpha 3-isoform. These results indicate that the alpha(+)-isoform of ferret heart is an alpha 3-isoform. During postnatal development, the same isoforms expressed in the adult ferret heart (alpha 1 and alpha 3), were also expressed in neonatal heart. In adult or neonatal heart alpha 2-isoform was not detectable. Relative abundances of the isoforms in ventricular and atrial tissues differed. Compared with ventricular tissue, left and right atrial tissues expressed much less alpha 3 than alpha 1. It is concluded that, unlike rat heart, alpha 1- and alpha 3-isoforms are expressed in adult ferret heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Digitalis sensitivity of Na+,K(+)-ATPase, myocytes and the heart.

Cardiac Na+,K(+)-ATPase, the receptor molecule for digitalis glycosides, have isoforms with different intrinsic affinities for the glycosides. Expression of these isoforms are under developmental and hormonal regulation. Switching in isoforms to those with lower intrinsic affinity may decrease digitalis sensitivity of the heart. In addition to the intrinsic affinity of the cardiac Na+,K(+)-ATPase for the glycoside, increases in the rate of Na+ influx and decreases in extracellular K+ concentrations increase glycoside sensitivity of the heart and also reduces the margin of safety by reducing reserve capacity of the sodium pump. Reserve capacity of the sodium pump is also reduced by pathological conditions or aging, resulting in reduced margin of safety for the glycoside. Events that follow sodium pump inhibition also affect sensitivity of the heart to digitalis toxicity. These are hypercalcemia and magnesium depletion. It is now feasible to predict digitalis sensitivity of the heart, not empirically but based on the understanding of the mechanisms responsible for the positive inotropic and toxic actions of the glycoside.

Child↗
PubMed1990

Depressant effects of chloroquine on the isolated guinea-pig heart.

Some anti-malarials have deleterious effects upon the heart. The actions of two of these, chloroquine and quinacrine, were compared on isolated guinea-pig atria and Langendorff preparations to assess their effects on several calcium pools. Both compounds decreased developed tension in a concentration (chloroquine 10-100 microM; quinacrine 3-100 microM) and time-dependent manner, with quinacrine being twice as potent as potent as chloroquine. Ventricular muscle was much more sensitive to chloroquine than was atrial muscle. Concentrations of chloroquine, comparable to that found in the serum of patients ingesting toxic doses, caused significant inhibition of developed tension. The effects of chloroquine were almost completely reversed on washout; quinacrine, however, was less readily reversible. Chloroquine also had a direct negative chronotropic effect, substantially reduced force-frequency relationships and developed tension in partially depolarized atrial preparations; while post-rest contraction and the positive inotropic effect of ouabain were unaffected. Increases in extracellular calcium antagonized the negative inotropic effect. Quinacrine had a marked effect on post-rest contraction and attenuated the positive inotropic action of ouabain. It is concluded that the action of chloroquine may involve a superficial calcium pool, while quinacrine may act upon several calcium pools.

Animals↗
PubMed1990

ORERP (Off-Site Radiation Exposure Review Project) internal dose estimates for individuals.

A method was developed to reconstruct the internal radiation dose to off-site individuals who were exposed to fallout from nuclear weapons tests at the Nevada Test Site (NTS). By this method, committed absorbed doses can be estimated for 22 target organs of persons in four age groups and for selected organs of the fetus. Ingestion doses are calculated by combining age-group dose factors and intakes specific for age group, test event, and location as calculated by the PATHWAY food-chain model. Inhalation doses are calculated by combining age-group dose factors and breathing rates, and time-integrated air concentrations that are derived from the ORERP Air-Quality Data Base. Dose estimates are calculated for the radionuclides that contribute significantly to the total dose; these number 20 via the ingestion pathway and 46 via the inhalation pathway. Internal doses to nonspecified individuals and nonspecified fetuses are being reconstructed for each location in the ORERP Town Data Base for which exposure rates and cloud-arrival times are listed. Examples of reconstructing internal dose are presented. This method will also be adapted to reconstruct internal doses from NTS fallout to specific individuals in accordance with the person's age, past residence, life-style, and living pattern.

Aerosols↗
PubMed1990

Familial incidence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis.

C3 nephritic factor is an IgG autoantibody that causes complement activation by stabilizing the alternative pathway C3 convertase. It is associated with partial lipodystrophy and membrano-proliferative glomerulonephritis. The occurrence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis, whether singly or in any combination, is usually sporadic. We describe the coexistence of all three of these conditions in members spanning two generations of a single family. This suggests that the pathogenesis of these conditions may be linked and that genetically determined factors may, in some circumstances, contribute to disease susceptibility.

Biopsy↗
PubMed1989

Modification of the positive inotropic effects of catecholamines, cardiac glycosides and Ca2+ by the orally active male contraceptive, gossypol, in isolated guinea-pig heart.

Gossypol is an orally active male contraceptive with cardio-depressant side effects. To understand the mechanism of its cardiac actions, the interaction of gossypol with positive inotropic drugs was examined in isolated atrial muscle preparations obtained from guinea-pig heart. Gossypol delayed the onset of arrhythmias caused by digoxin. In the presence of gossypol, the positive inotropic effect of isoproterenol declined rapidly, and the effect of isoproterenol to increase tissue cyclic AMP concentrations was smaller. Pretreatment of atrial muscle with the combination of gossypol and isoproterenol markedly reduced effects of isoproterenol on developed tension and cyclic AMP concentrations when these effects were tested after the washout of the first dose of isoproterenol. These effects, however, were not specific to isoproterenol. The gossypol-isoproterenol pretreatment reduced the positive inotropic effect of ouabain or extracellular Ca2+. These results indicate that gossypol has pharmacodynamic interactions with several positive inotropic agents that are known to enhance developed tension by increasing intracellular Ca2+ transients.

Animals↗
PubMed1989

Tissue-specific isoform regulation of Na+-K+-ATPase by thyroid hormone in ferrets.

We have shown previously that in the ferret heart there are two isoforms of Na+-K+-ATPase, alpha(+) and alpha, and that these isoforms undergo developmental changes. In the present study, we examine regulation of the isoenzymes by thyroid hormone, which is well known to increase activity of Na+-K+-ATPase in different tissue preparations. Ferrets were injected with L-thyroxine (T4) (0.5 mg/kg, sc) for 3 wk. The T4-treated ferrets gained 58 +/- 32 g body wt compared with 366 +/- 24 g for the control ferrets. Plasma 3,5,3'-triiodothyronine concentrations of the T4-treated animals increased about eightfold 16-18 h after the last injection. The number of alpha(+)- and alpha-subunits in heart homogenates estimated by [3H]ouabain binding was 3.5 +/- 0.1 and 2.5 +/- 0.1 pmol/mg protein, respectively [alpha(+)/alpha = 1.40]. In the T4-treated ferrets, there was no significant increase of the alpha(+)-isoform (3.2 +/- 0.2 pmol/mg protein), whereas the number of alpha-isoform increased significantly to 4.1 +/- 0.3 pmol/mg protein [alpha(+)/alpha = 0.78]. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of partially purified cardiac plasma membrane preparations reveals similar pattern of changes of the isoenzymes. In the kidney, however, there was no significant change in the number of alpha-isoform, which is the predominant isoform in the kidney, and T4 does not appear to induce synthesis of alpha(+)-isoform in the kidney. It is concluded that thyroid hormone induces both isoform- and tissue-specific regulation of the Na+-K+-ATPase alpha-subunits in the ferret. These specific regulations of the isoforms seem to suggest important physiological roles of the isoenzymes.

Animals↗
PubMed1989

The role of hypocomplementaemia and low erythrocyte complement receptor type 1 numbers in determining abnormal immune complex clearance in humans.

Defective clearance of immune complexes (IC) may contribute to the pathogenesis of diseases such as SLE. We studied the effect of hypocomplementaemia and the influence of erythrocyte complement receptor type 1 (CR1, CD35) number on the clearance of radiolabelled tetanus toxoid (TT)-anti-TT IC from the circulation. These were injected intravenously into 9 normal subjects and 15 patients with diseases characterized by IC formation and/or hypocomplementemia, including 2 with hereditary complement deficiency. IC were found to bind to erythrocyte CR1 in a complement-dependent manner and their degree of uptake was directly correlated with CR1 numbers. Two phases of IC clearance were identified. The first was rapid, occurring within 1 min. Since this phase might represent inappropriate deposition of IC in target organs we called it trapping. It was seen predominantly in subjects with low CR1, low complement, and low binding of complexes to red cells. The second phase was monoexponential with a mean elimination rate of 14.1%/min; it was inversely correlated with CR1 numbers and binding of complexes to red cells. In a second study each individual was injected with IC bound to autologous erythrocytes in vitro using normal serum so that the effects of complement deficiency were eliminated. Up to 81.4% of these bound IC were released in vivo from erythrocytes in 1 min, and the proportion was inversely correlated with CR1 numbers. Only five patients showed trapping, and these had low CR1 numbers and high percentage release of IC. The second phase of elimination was inversely correlated with CR1 numbers and the proportion of IC remaining bound to red cells at 1 min. The two complement-deficient patients had normal CR1: when IC were injected, trapping and very fast clearance rates were observed; however complexes that had been opsonized and bound to erythrocytes were cleared at a slower rate without evidence for trapping. These studies show that complement and erythrocyte CR1 may determine the physiological clearance of certain types of IC and suggest that this system may function abnormally when CR1 number or complement function are reduced.

Antigen-Antibody Complex↗
PubMed1988

Cardiac Na+,K+-ATPase isoenzymes: sensitivity to prednisolone bisguanylhydrazone.

Prednisolone-3,20-bisguanylhydrazone (PBGH), a steroid derivative, has been shown to inhibit Na+,K+-ATPase isolated from guinea-pig heart or kidney in concentrations significantly lower than those required to inhibit the enzyme obtained from other sources. Because Na+,K+-ATPases obtained from guinea-pig heart or kidney are predominantly of the alpha isoform, the hypothesis that PBGH selectively inhibits the alpha isoform over alpha (+) isoform of the enzyme was tested. Sodium dodecylsulfate polyacrylamide gel electrophoresis of the enzyme preparations revealed the presence of only the higher mobility, alpha isoform in guinea-pig heart and ferret kidney, whereas those from guinea-pig brain, dog brain and ferret heart showed both high and low mobility isoforms corresponding to alpha and alpha (+) isoforms. Na+,K+-ATPase obtained from the guinea-pig heart was most sensitive to PBGH and those isolated from ferret heart or ferret kidney had the lowest sensitivity. Enzyme preparations obtained from dog brain, dog heart or guinea-pig brain had intermediate sensitivity. This spectrum of enzyme sensitivity to PBGH was markedly different from that to ouabain. In ferret heart Na+,K+-ATPase, a low concentration of PBGH preferentially inhibited [3H]ouabain binding to the high affinity ouabain binding sites (alpha(+) isoform). These results indicate that PBGH is not a specific inhibitor of the alpha isoforms of Na+,K+-ATPase. Affinity of the enzyme for PBGH is determined by the species and tissue rather than isoforms of Na+,K+-ATPase.

Animals↗
PubMed1988

Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes.

We sought biochemical evidence for a role of C receptors types 1 (CR1) and 2 (CR2) in B cell activation. A flow cytometer was used to measure the fluorescence of tonsillar cells that had been loaded with the calcium-dependent indicator indo-1, and cells were stimulated by cross-linking cell-bound DA4.4 anti-IgM, Yz-1 anti-CR1 or HB5 anti-CR2 with goat anti-mouse IgG. There was a direct dose-response relationship between the proportion of cells having increased cytoplasmic free calcium concentration (Cai) after addition of second antibody and the amount of cell-bound Fab' DA4.4. In contrast, no rise in Cai was observed after cross-linking bound Yz-1 or HB5. To determine whether CR1 or CR2 could modify the increase in Cai induced by cross-linking membrane IgM, Cai was monitored after addition of second antibody to cells bearing combinations of either Yz-1 or HB5 with a limited amount of DA4.4. The combination of Yz-1 with DA4.4 yielded little or no further increase in the percentage of cells responding to cross-linking with elevated Cai compared with DA4.4 alone. However, the combination of HB5 with limited DA4.4 synergistically enhanced this response, resulting in stimulation that was equivalent to that obtained with optimal concentrations of DA4.4. The synergistic effect of CR2 was also observed with avidin as the cross-linking reagent for bound biotinylated HB5 and DA4.4, occurred in the presence of EGTA, and did not require T cells. Studies of the proliferation of B cell-enriched PBMC demonstrated that, whereas HB5 coupled to Sepharose alone induced little or no DNA synthesis, the combination of HB5 with limited DA4.4 on Sepharose induced a dose-related synergistic increase in the incorporation of [3H]thymidine.

B-Lymphocytes↗
PubMed1988

The clearance of tetanus toxoid/anti-tetanus toxoid immune complexes from the circulation of humans. Complement- and erythrocyte complement receptor 1-dependent mechanisms.

The role of complement and its receptor on erythrocytes (CR1) in the physiologic elimination of large immune complexes from the circulation of humans was assessed. Large radiolabeled soluble tetanus toxoid- anti-tetanus toxoid complexes were injected i.v. into three normal individuals and three patients with SLE. These complexes were prepared in antibody excess and were 45S in size, fixed C and bound to E CR1 in vitro. The percentage of complexes bound in vitro was directly proportional to CR1 number/E in four normal subjects and three SLE patients. After i.v. injection into normal subjects, complexes were cleared rapidly, with a monoexponential rate constant (10.3 to 11% complexes cleared/min). In the SLE patients, clearance was best explained by two phases: the first occurred within the first minute indicating immediate trapping of a fraction of the complexes (19.5 to 25.3% of injected complexes trapped), the second was monoexponential and was similar to the normal range. A large fraction of complexes bound within the first minute to E in vivo; the percentage of binding was variable, ranging from 16.3% to 71.5% and was related to E CR1 number. In a second study complexes were injected that had been attached to autologous E by opsonization with C in vitro. Their elimination was similarly monoexponential, except in one SLE patient in whom there was significant initial trapping (30.9%). A fraction of these complexes were released from E within the first minute, the percentage release being greatest in the patient with the lowest CR1 number (81.4%). E bearing immune complexes remained in the circulation and were not transiently sequestered in the liver or spleen. This is the first study of the clearance of soluble immune complexes in vivo in humans and shows that C and CR1 on E participate in immune complex clearance reactions, and that abnormal clearance can be detected in the form of rapid removal of immune complexes from the circulation.

Adult↗
PubMed1988

Monoclonal rheumatoid factor-IgG immune complexes. Poor fixation of opsonic C4 and C3 despite efficient complement activation.

Monoclonal IgM rheumatoid factor forms complexes with IgG in essential mixed cryoglobulinemia. We demonstrate that such complexes fix C3 and C4 poorly, although efficient fluid-phase C3 conversion can occur. Fixation of small amounts of C4 may be sufficient to generate a C3 convertase, but may prevent subsequent fixation of C3 by competing for binding sites on the complex. These complexes bind inefficiently to normal erythrocyte complement receptor type 1 (CR1) in vitro, and are undetectable on erythrocytes of patients with essential mixed cryoglobulinemia in vivo. Clearance of such phlogistic complexes from tissues by CR1-bearing cells may be inefficient.

Antibodies, Monoclonal↗
PubMed1988

Clearance of cryoglobulins in man.

From the foregoing it is evident that the defective clearance of immune complexes may contribute to tissue damage seen in patients with cryoglobulins. Hypocomplementaemia, decreased erythrocyte CR1, and the nature of the immune complexes may all contribute to decreased binding of immune complexes to erythrocytes with the potential consequence of increased availability for deposition and decreased processing of immune complexes. In addition, in type II cryoglobulinaemia the nature of the immune complex namely IgM RF/IgG complexes, has been shown in some circumstances to fix C3 and C4 inefficiently in spite of detectable fluid phase complement activation. The poor C3 fixation results not only in decreased transport by erythrocytes to the RES but also in inefficient removal of immune complexes by phagocytic cells, since the Fc receptor on these cells would be acting alone without the synergy of occupied complement receptors. Persistence of immune complexes in tissues in these circumstances has two potential consequences. First, the multivalency of IgM may contribute to enlargement of these immune complexes in situ by successive trapping of antigen and antibody complexes; this process may be aided by local factors such as low temperature at the peripheries and increased protein concentration in glomerular capillary loops, which favour "cryo" precipitation. The higher avidity of RF for IgG that is surface bound rather than monomeric would also favor immune complex formation in these circumstances. Second, although there is no opsonization of the immune complex complement activation results in bystander fixation of C4 and C3 to the surrounding tissues resulting in tissue injury.

Antigen-Antibody Complex↗
PubMed1988

Immunogenetics of SLE and primary Sjögren's syndrome.

SLE is a syndrome defined by clinical criteria and by the presence of autoantibodies reactive with nucleic acids and proteins concerned with transcription and translation. Breeding experiments in mice have illustrated the enormous genetic heterogeneity of this syndrome, of which the final common pathway is a widespread immune complex disease. The causes of SLE in humans are likely to be equally multifactorial. Family studies have demonstrated that genetic factors exist, but each factor appears to be a relatively weak disease-susceptibility gene. The major exceptions to this are the very rare complete deficiencies of classical pathway complement components, which are almost invariably accompanied by the development of SLE. Observations of these patients have led to the formulation of hypotheses relating complement and its receptor, CR1, to the defective removal of immune complexes from the circulation.

Animals↗