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T Wang

Publications and source records attributed to T Wang.

At least 757 records · Page 42Linked to original sources
PubMed1987

Phosphoenzyme decomposition in dog cardiac sarcoplasmic reticulum Ca2+-ATPase.

A five-syringe quench-flow apparatus was used in the transient-state kinetic study of intermediary phosphoenzyme (EP) decomposition in a Triton X-100 purified dog cardiac sarcoplasmic reticulum (SR) Ca2+-ATPase at 20 degrees C. Phosphorylation of the enzyme by ATP in the presence of 100 mM K+ for 116 ms gave 32% ADP-sensitive E1P, 52% ADP- and K+-reactive E2P, and 16% unreactive residual EPr. The EP underwent a monomeric, sequential E1P 17 s-1----E2P 10.5 s-1----E2 + Pi transformation and decomposition in the ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid quenched Ca2+-devoid medium. The calculated rate constant for the total EP (i.e., E1P + E2P) dephosphorylation was 7.8 s-1. The E1P had an affinity for ADP with an apparent Kd congruent to 100 microM. When the EP was formed in the absence of K+ for 116 ms, no appreciable amount of the ADP-sensitive E1P was detected. The EP comprised about 80% ADP- and K+-reactive E2P and 20% residual EPr, suggesting a rapid E1P----E2P transformation. Both the E2P's formed in the presence and absence of K+ decomposed with a rate constant of about 19.5 s-1 in the presence of 80 mM K+ and 2 mM ADP, showing an ADP enhancement of the E2P decomposition. The results demonstrate mechanistic differences in monomeric EP transformation and decomposition between the Triton X-100 purified cardiac SR Ca2+-ATPase and deoxycholate-purified skeletal enzyme [Wang, T. (1986) J. Biol. Chem. 261, 6307-6319].

Adenosine Diphosphate↗
PubMed1987

Concurrent generation of methylamine and nitrite during denitrosation of N-nitrosodimethylamine by rat liver microsomes.

With the goal of identifying the organic amine product(s) of enzymatic N-nitrosodimethylamine (NDMA) denitrosation, 4 mM NDMA was incubated with liver microsomes from ethanol-treated rats. The concentrations of dimethylamine and methylamine were determined by derivatization with 2,4-dinitrofluorobenzene followed by gas chromatography-mass spectrometry. There was no net increase in the concentration of dimethylamine during incubation, but the yield of methylamine was equimolar with that of nitrite. Additional incubations of NDMA using acetone-induced microsomes, 1 mM and 0.1 mM substrate, gave methylamine/nitrite ratios of 0.9 and 0.7, respectively, confirming the quantitative linkage between these two products. Control incubations conducted with pure methylamine or dimethylamine indicated that the secondary amine is not a significant intermediate in the metabolic generation of the primary amine. Experiments with 15N-labeled NDMA showed that the methylamine nitrogen came from the amino moiety of the nitrosamine. The results suggest that NDMA metabolism is best viewed as a competition between at least two important pathways, demethylation and the presumably deactivating denitrosation route, a formulation which seems to account for the previously reported detection of methylamine as a urinary metabolite of NDMA and for the production of less than theoretical yields of labeled dinitrogen gas during NDMA metabolism.

Acetone↗
PubMed1987

Cellular junctions on the free surface of human placental syncytium.

Chorionic villi of human placenta at full term have been studied in thin section. On the free surface of syncytium, cellular junctions such as desmosomes, desmosome-like junctions and tight junctions, but not gap junctions, are present. Theories regarding the formation and functions of the junctions on the syncytial free surface are discussed.

Chorionic Villi↗
PubMed1987

Decay of the oocyte-type heat shock response of Xenopus laevis.

Xenopus oocytes have a complex heat shock response. During transition of the oocyte into fertilized egg, the heat shock response undergoes several qualitative and quantitative changes culminating in its complete extinction. Heat shock induces oocytes to synthesize four heat shock proteins (hsps): 83, 76, 70, and 57. After ovulation, two additional proteins (hsps 22 and 16) are inducible. The heat shock response of spawned eggs can be modified by changing the ionic configuration of the external medium and by adding pyruvate and oxaloacetate to the media. Since Xenopus eggs do not synthesize mRNA, these modifications to the external medium apparently alter the utilization of preexisting messenger RNAs in protein synthesis. Artificial activation terminates inducibility of hsps 76, 57, and 16 and diminishes the hsp 70 response. Two new heat shock proteins-66 and 48-are also inducible in artificially activated eggs. Fertilization, on the other hand, terminates the heat shock response; no hsps can be induced. However, hsp 70 appears to be made constitutively in fertilized eggs. RNA blot analyses reveal that oogenic hsp 70 messenger RNA is retained in eggs and early embryos. This messenger is apparently used for heat-induced synthesis of hsp 70 before fertilization and for constitutive synthesis of hsp 70 in zygotes.

Animals↗
PubMed1987

Nucleolar channel system in the human fetal endometrium.

Endometrial tissue from 3 human fetuses was examined electron microscopically. In 2 of the fetuses the nucleolar channel system was found within the nuclei of the endometrial epithelium. This finding demonstrates that the development of the system is not dependent on ovulation. We speculate that an appropriate concentration ratio between estrogen and progesterone might induce the development of nucleolar differentiation.

Cell Nucleolus↗
PubMed1987

Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences.

The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 +/- 2.1 vs 17.2 +/- 8.0, p less than .001), lower average plasma concentration (Cp) (1.1 +/- 0.6 vs 2.5 +/- 0.5 ng/ml/mg daily dosage, p less than .001), and higher oral clearance (1115 +/- 1238 vs 264 +/- 48 ml/min, p less than .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p less than .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype.

Adult↗
PubMed1986

Transient-state kinetics of phosphoenzyme transformation in the rabbit skeletal sarcoplasmic reticulum calcium-dependent adenosine triphosphatase reaction. Two distinct modes of ADP and K+ regulation.

We have observed two modes each of ADP and K+ regulation of phosphoenzyme (EP) intermediates formed in the early phase of skeletal sarcoplasmic reticulum hydrolysis of ATP at 20 degrees C, using, for the first time, a five-syringe quench flow apparatus for transient-state kinetic measurements. The total acid-stable EP formed for 20.5 and 116 ms in the K+ medium appears to be composed of either two monomers in rapid equilibrium, E1P in equilibrium E'1P, or a dimer of the two subunits, PE1E'1P. The ADP-sensitive E1P may form an acid-labile ADP X E1P (or ATP X E1) complex rapidly, giving ATP as a consequence of acid quenching. The ADP may also induce decomposition of the ADP-reactive E'1P. Monomeric and dimeric mechanisms are introduced to account for the hyperbolic relation between the rate constant of the ADP-induced E'1P decomposition and [ADP], consistent with the fact that the E'1P may also give ATP in the presence of ADP. As to the K+ effects, the K+, which is bound to the unphosphorylated enzyme and possibly becomes occluded during EP formation, may either facilitate the one-to-one E1P in equilibrium E'1P equilibrium or maintain the dimeric functional unit. The subsequent forward transformation of the E'1P to the ADP-insensitive K+-sensitive E'2P, possibly the rate-determining step for the catalytic cycle, is found to be K+ independent. The major effect of the K+ in the medium is its catalytic cleavage of the E'2P, which is detected as the missing EP under these conditions. When K+ is not involved in the EP formation, the forward sequential transformation E1P----E'1P----E'2P----E2P or PE1E'1P----PE'2E2P is apparent in the time range from 20.5 to 116 ms after EP formation, and the E'2P may accumulate in the K+ devoid medium and be detected as the major component of the total acid-stable EP. The Mg2+-sensitive E2P represents the EP missing in the medium containing no ADP and K+.

Adenosine Diphosphate↗
PubMed1986

Concentration-dependent pharmacologic properties of sotalol.

Sotalol is a nonselective beta-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of beta-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). The responders to sotalol included 8 patients in whom therapy with conventional beta-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.

Arrhythmias, Cardiac↗
PubMed1986

The biodistribution of radiolabeled antilymphocyte monoclonal antibody in the rat.

The biodistribution of radiolabeled mouse anti-pan T monoclonal antibody (W3/13) against rat lymphocytes was examined in normal rats. Monoclonal antibody to human prostate-associated antigens (PAA) served as a control. In vitro studies demonstrated a 38% maximum binding of radiolabeled W3/13 to lymphocytes, which was significant (P less than 0.001) when compared with the control (PAA) value of 3.4%. In vivo, intravenously administered 111In labeled W3/13 and 131I labeled W3/13 exhibited similar tissue distribution patterns. The localization of W3/13 in lymphoid tissue was significantly greater than that achieved with PAA. W3/13, however, did not demonstrate significant localization in the intact thymus and accumulated to a higher degree (6-10% ID/g) than expected in bone marrow at 24 h. These findings suggest that radiolabeled anti-lymphocyte monoclonal antibodies may not be well suited for the treatment of lymphoreticular neoplasms and allograft rejection in patients.

Animals↗
PubMed1986

Encainide disposition in patients with renal failure.

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.

Acute Kidney Injury↗
PubMed1986

Encainide disposition in patients with chronic cirrhosis.

The antiarrhythmic agent encainide undergoes extensive first-pass hepatic metabolism after oral dosing. The active metabolites O-desmethylencainide and 3-methoxy-O-desmethylencainide are formed in subjects who are extensive metabolizers (EMs), a phenotypic trait that cosegregates with that of debrisoquin. Because of the possibility that drug metabolism is altered by liver dysfunction, the disposition of encainide and its metabolites was studied in six such EMs with cirrhosis and compared with that in eight normal subjects of the same phenotype. Patients with cirrhosis had lower systemic and oral clearances of encainide, resulting in a threefold increase in oral bioavailability. The plasma concentration of encainide was significantly higher among the patients with cirrhosis, whereas the plasma levels of the respective metabolites were comparable with those in normal subjects, resulting in no change in the patient's ECG intervals. Encainide is, therefore, an example of a drug in which cirrhosis causes a three- to fourfold increase in parent drug concentrations. However, because no change occurs in the levels of the pharmacologically active metabolites, dosage adjustment is probably not required in patients with cirrhosis.

Administration, Oral↗
PubMed1986

Co-inheritance of the polymorphic metabolism of encainide and debrisoquin.

O-demethylation of the investigational antiarrhythmic encainide was found to be correlated with the genetically determined hydroxylation of debrisoquin in 20 randomly selected and unrelated subjects and in five members of one family. Extensive metabolizers of debrisoquin had a mean (+/- SD) encainide elimination t1/2 of 1.19 +/- 0.98 hours (range 0.25 to 3.4 hours). Poor metabolizers of debrisoquin (two normal subjects and three family members) had a mean t1/2 of 13.2 +/- 0.73 hours (range 7.8 to 22.4 hours). The elimination rate constant of encainide and the fractional excretion of O-desmethyl encainide in urine were linearly related to the fractional urinary excretion of 4-hydroxy-debrisoquin. Poor metabolizers could be identified after a 50 mg dose of encainide by the fractional excretion of O-desmethyl encainide in urine or the absence of (1) measurable ECG changes or (2) O-desmethyl encainide in plasma. The correlation between excretion of O-desmethyl encainide and 4-hydroxy-debrisoquin suggests that significant numbers of the caucasian population (7% to 9%) are likely to be poor metabolizers of encainide and to have markedly different pharmacokinetics and plasma concentration-response relationships than extensive metabolizers.

Administration, Oral↗
PubMed1986

Presynaptic calcium channels in rat cortical synaptosomes: fast-kinetics of phasic calcium influx, channel inactivation, and relationship to nitrendipine receptors.

Fast-mixing and rapid-filtration techniques were used to analyze the kinetics of potassium-depolarization-dependent (delta K+ = 47.5 mM) influx of 45Ca into synaptosomes, in the time range from 50 msec to 5 sec. The results are consistent with the presence in synaptosomes of a homogeneous population of voltage-sensitive Ca channels. With 1 mM Cao in the medium, the delta K+-dependent Ca influx has a single-exponential time course with the half-life, t1/2 approximately 0.5-0.7 sec. Ca influx, measured between 0.1 and 10 mM Cao, shows half-saturation (KCa) at 1.5 mM Cao and has the limiting value (JCamax) of 5.9 nmol/sec/mg protein, or a current of approximately 0.06 pA/micron2 surface area. The estimated density of functional Ca channels is 0.6-6 micron-2. Voltage- and time-dependent inactivation of Ca channels was measured in synaptosomes predepolarized in 52.5 mM Ko+ with Ca omitted from the medium. Channel inactivation is a single-exponential process with a half-life of t1/2 approximately 2.3 sec. Channel recovery in 5 mM Ko+ media is likewise a single-exponential process with a half-life of t1/2 approximately 4.3 sec. The slower rate of voltage-dependent channel inactivation than of decay of Ca influx suggests that Ca entry into synaptosomes terminates by a mechanism that depends on Ca influx itself. Synaptosomes contain 200 fmol/mg protein, or approximately 6 micron-2 high-affinity (KD = 0.12 nM) 3H-nitrendipine binding sites; however, nitrendipine at concentrations greater than 10(4) X KD is without effect on the phasic influx of Ca measured at 215 msec with either 1.0 or 0.1 mM Cao. This suggests that Ca channels characterized in this study belong to a class of dihydropyridine-insensitive channels.

Animals↗