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T Yang

Publications and source records attributed to T Yang.

At least 19 recordsLinked to original sources
PubMed1995

Mechanism of block of a human cardiac potassium channel by terfenadine racemate and enantiomers.

1. The cardiac toxicity of racemic terfenadine (marked QT prolongation and polymorphic ventricular arrhythmias) is probably due to potassium channel blockade. To test whether one of its enantiomers would be a less efficient potassium channel blocker, we compared the mechanism of action of the racemate with that of the individual enantiomers. 2. We synthesized the individual enantiomers of terfenadine and examined under whole cell voltage-clamp conditions the mechanism of action of the racemate, both enantiomers and a major metabolite on a cloned human cardiac potassium channel, hKv1.5. This delayed rectifier is sensitive to quinidine, clofilium and other 'class III' antiarrhythmic drugs at clinically relevant concentrations. 3. Upon depolarization, racemic terfenadine and its enantiomers induced a fast decline of hKv1.5 current towards a reduced steady state current level. During subsequent repolarization the tail currents deactivated more slowly than the control, resulting in a 'crossover' phenomenon. 4. The voltage-dependence of block was biphasic with a steep increase in block over the voltage range of channel opening (-30 to 0 mV), and a more shallow phase positive to 0 mV (where the channel is fully open). The latter was consistent with a binding reaction sensing 21% of the transmembrane electrical field (with reference to the cell interior). 5. The EC50 for hKv1.5 block by racemic terfenadine was 0.88 microM, while the values for R- and S-terfenadine were 1.19 microM and 1.16 microM, respectively. In contrast, the acid metabolite reduced hKv1.5 current by only 5% at a concentration of 50 microM. 6. These findings suggest that terfenadine blocks the hKvl.5 channel after it opens by entering into the internal mouth of the channel. We have previously shown that quinidine blocks hKvl.5 in a similar manner but with an apparent affinity of ~6 micro M. Thus, terfenadine and its enantiomers are approximately equipotent open state blockers of this human K+ channel and about 6 times more potent than quinidine. The similar state-, time-, and voltage-dependence of hKvl.5 block by both enantiomers also indicates that the chiral centre does not significantly constrain the orientation of critical binding determinants of terfenadine with respect to the receptor site.

Animals↗
PubMed1995

Expression of mRNAs for different types of IP3 receptors in rat kidneys.

Cloning studies have extensively characterized two types of inositol 1,4,5-trisphosphate (IP3) receptors from the rat. An IP3 receptor from the cerebellum is referred to as type 1, and a second, recently described, receptor is referred to as the type 2 IP3 receptor. The significance of different types of IP3 receptors, especially in vivo in the kidney, is not fully understood. We investigated the localization of mRNAs encoding these two types of IP3 receptors in microdissected nephron segments of rats using reverse transcription and polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Type 1 IP3 receptor mRNA displayed a widespread, although not uniform, distribution along the nephron. In contrast, type 2 IP3 receptor mRNA was confined almost exclusively to collecting ducts, suggesting specific expression of type 2 IP3 receptor in collecting ducts. We then detected mRNAs for the two types of IP3 receptors in collecting ducts in dehydrated rats. Dehydration downregulated type 2 IP3 receptor mRNA in cortical collecting duct, outer medullary collecting duct, and the initial part of inner medullary collecting duct (IMCD), but not in the terminal part of IMCD. It had no effect on type 1 IP3 receptor mRNA expression in collecting ducts. We propose that different types of IP3 receptors may have different functions in the rat kidney. the initial part of inner medullary collecting duct (IMCD), but not in the terminal part of IMCD. It had no effect on type 1 IP3 receptor mRNA expression in collecting ducts. We propose that different types of IP3 receptors may have different functions in the rat kidney.

Animals↗
PubMed1995

Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K+ current.

The rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs, respectively), which have different physiological properties have been identified in cardiac cells from several species, including humans. Although expression of the minimal K+ channel protein (minK) cDNA in some systems results in a current resembling IKs, the role of this gene product in channel function remains controversial. In atrial tumor myocytes (AT-1 cells), no IKs is recorded, but minK mRNA is detected, raising the possibility that expression of the minK gene serves an as-yet-unidentified function. In these experiments, AT-1 cells were exposed to antisense oligonucleotides targeting the 5' translation start site of the minK cDNA cloned from an AT-1 library. Cell size, IKr, and L-type and T-type Ca2+ currents were measured 24 to 48 hours after exposure and compared with data in cells exposed to the corresponding sense oligonucleotide or grown in medium only. Antisense oligonucleotide significantly reduced IKr compared with sense and medium-only control cells in 0 of 2 experiments (n = 3 to 6 cells per treatment in each experiment) at 50 nmol/L, 1 of 2 at 250 nmol/L, 6 of 6 at 1000 nmol/L, and 2 of 2 at 10,000 nmol/L. At 1000 nmol/L, maximum tail current in antisense-exposed cells was 2.5 +/- 0.1 pA/pF (mean +/- SEM, n = 28, 6 separate experiment), 6.6 +/- 0.4 pA/pF in sense-exposed cells (n = 27), 5.4 +/- 0.6 pA/pF in medium-only cells (n = 21), and 5.8 +/- 0.7 pA/pF in cells exposed to a random oligonucleotide (n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

[The changes and clinical significance of interleukin 1 beta in pleural effusion].

An enzyme linked immunosorbent assay was set up by using anti-recombinant human interleukin 1 beta monoclonal antibodies. The interleukin 1 beta, anti-interleukin 1 beta autoantibody and interleukin 1 beta containing immune complex were detected in pleural effusion of 28 patients with bacterial infection cases pleurisy and 13 with lung cancer. The results showed that free interleukin 1 beta could be detectable in the early stage of pleurisy, and then transformed to the immune complex. The interleukin 1 beta containing immune complex were detectable in the pleeural effusions of all the 28 patients with pleurisy, but only two patients with lung cancer. The results suggested that this cytokine behaves differently in these two different kinds of diseases.

Antibodies, Monoclonal↗
PubMed1995

[The human fetal development time table of the major limb bones-ultrasonic bone age].

B-ultrasonic technique was used to examine 297 Chinese fetuses in normal pregnancy woman of completed week age from 12 to 38 weeks. The lengths of the major limb bones were measured and statistical analysis showed that the positive linear correlation between the development of fetuses' limb bones and the completed fetal age is significant.

Bone Development↗
PubMed1995

Metabolic approach for regulation of IL-1 beta in vivo.

IL-1 beta, the autoantibodies to IL-1 beta and IL-1 beta-containing immune complex in pleural effusion and cerebrospinal fluid were detected using anti-recombinant human IL-1 beta monoclonal antibody. The results indicate that IL-1 beta is detectable in some cases, and the amounts decrease gradually with the chemotherapy following the autoantibodies and the specific detectable immune complex. These autoantibodies may have a feedback effect, inhibiting the IL-1 beta activity, and forming the immune complex to speed the clearance of activated IL-1 beta.

Antibodies, Monoclonal↗
PubMed1994

Sequential activation of Raf-1 kinase, mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase by hyperosmolality in renal cells.

In the renal medulla during antidiuresis, the extracellular fluid becomes hyperosmotic. Madin-Darby canine kidney (MDCK) epithelial cells adapt in hyperosmotic conditions and serve as a useful tissue culture model for cellular responses to hyperosmolality. We demonstrate that hyperosmolality stimulates phospholipase C, Raf-1 kinase mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase activities and that it increases phosphorylation of Raf-1 kinase, and p42 MAP kinase in MDCK cells. Stimulation of these kinases is osmolality-dependent (from 300 to 600 mosm/kg H2O). The time course of activation is sequential; the peak stimulation for Raf-1 kinase is at 5 min, at 10 min for MAP kinase kinase and MAP kinase, and at 20 min for S6 kinase. The activation of Raf-1 kinase and MAP kinase is inhibited by phorbol 12-myristate 13-acetate pretreatment in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein, herbimycin) do not significantly suppress hyperosmolality-induced MAP kinase activity. The increase of Ins-1,4,5-P3 levels by hyperosmolality suggests that activation of these kinases is mediated at least partially via activation of phospholipase C. Thus, hyperosmolality stimulates the serine/threonine kinases, Raf-1 kinase, MAP kinase kinase, MAP kinase, and S6 kinase, via predominantly protein kinase C-dependent, tyrosine kinase-independent pathways in MDCK cells.

Amino Acid Sequence↗
PubMed1994

[Reconfirmation of golgiphobic dendrites of the motoneurons in rat spinal cord].

With CB-HRP method (injections into 5 muscles of anterior and posterior extremities) and Golgi technique, the corresponding sections of spinal cords were observed on same aged rats of the identical parent rats. Comparing the cell numbers of the lateral groups of anterior horns, the former (CB-HRP) revealed twice as many as the cell numbers of the latter (Golgi). As to the surface densities of the white matter dendrites (WMD) in the lateral funiculi from the neurons of the lateral groups of the anterior horns, the density revealed by injection of CB-HRP to the tibialis anterior is 2-9 times more than that in Golgi sections. All of WMD revealed in CB-HRP sections could extend into the peripheral portions of the lateral funiculi, and quite a few of them even form a subpial marginal plexus, that is one example of Golgiphobic dendrites (GBD). For labeled medial cell groups of the anterior horn with CB-HRP, their dendrites could reach to the ependymal layer of the central canal (another GBD). These two types of GBD were not present on the Golgi material. The significance of GBD was also discussed.

Animals↗
PubMed1993

MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.

During their lifespan, immature cells normally pass through sequential transitions to a differentiated state and eventually undergo cell death. This progression is aberrant in cancer, although the transition to differentiation can be reestablished in inducible leukemia cell lines. This report describes a gene, MCL1, that we isolated from the ML-1 human myeloid leukemia cell line during phorbol ester-induced differentiation along the monocyte/macrophage pathway. Our results demonstrate that expression of MCL1 increases early in the induction, or "programming," of differentiation in ML-1 (at 1-3 hr), before the appearance of differentiation markers and mature morphology (at 1-3 days). They further show that MCL1 has sequence similarity to BCL2, a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation. MCL1 and BCL2 do not fall into previously known gene families. BCL2 differs from many oncogenes in that it inhibits programmed cell death, promoting viability rather than proliferation; this parallels the association of MCL1 with the programming of differentiation and concomitant maintenance of viability but not proliferation. Thus, in contrast to proliferation-associated genes, expression of MCL1 and BCL2 relates to the programming of differentiation and cell viability/death. The discovery of MCL1 broadens our perspective on an emerging MCL1/BCL2 gene family and will allow further comparison with oncogene families.

Amino Acid Sequence↗
PubMed1992

Analysis of vagally induced sinus arrhythmias.

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.

Arrhythmias, Cardiac↗
PubMed1992

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle.

The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). These changes were accompanied by a small shortening of APD90, but with an increase in ERP; i.e., the ERP/APD90 ratio was increased. Dofetilide also significantly lengthened APD90 at 10 mM [K+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.

Action Potentials↗
PubMed1992

Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.

OBJECTIVE: The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia. METHODS: Hypoxia was induced by superfusing guinea pig right ventricular papillary, muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [PO2 = 5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+ channels) in the absence (n = 6) and presence of dofetilide (n = 6) or glibenclamide (n = 4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer. RESULTS: During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p < 0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p < 0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p < 0.05), ERP by 48(4)% (p < 0.05) and developed force by 71(6)% (p < 0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p < 0.05), ERP by 44(6)% (p < 0.05), and developed force by 69(10)% (p < 0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, ERP, and developed force. CONCLUSIONS: Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia.

Action Potentials↗
PubMed1992

Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.

We studied the hemodynamic and metabolic effects of the novel class III antiarrhythmic agent dofetilide (UK-68,798) in acute ischemic heart failure. In pentobarbital-anesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 27 +/- 2 mm Hg was achieved. Embolization depressed LV systolic pressure, LV dP/dtmax, LV dP/dtmin, and cardiac output. None of these parameters were changed following i.v. infusion of dofetilide 5, 10, or 25 micrograms/kg, during spontaneous and paced cycle length of 300 ms (n = 9). Heart rate decreased by 12 +/- 8, 19 +/- 7, and 21 +/- 7 beats/min (p less than 0.05), while QT time increased by 23 +/- 7, 33 +/- 9, and 40 +/- 10 ms (p less than 0.05) after 5, 10, and 25 micrograms/kg, respectively. Ventricular effective refractory period increased from 128 +/- 10 to 153 +/- 11 ms after 25 micrograms/kg (n = 4). Arterial concentration and net myocardial uptake of glucose, lactate, and free fatty acids were not significantly influenced by dofetilide. In conclusion, dofetilide, at doses that prolonged repolarization, was devoid of cardiodepressive effects in acute ischemic heart failure.

Animals↗
PubMed1992

Electromechanical action of dofetilide and D-sotalol during simulated metabolic acidosis in isolated guinea pig ventricular muscle.

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group): (a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 microM). At normal extracellular pH (pH = 7.32 +/- 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18-20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization (Vmax), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 +/- 0.01) was simulated by reducing the bicarbonate concentration of the Tyrode's solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased Vmax and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in Vmax and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.

Acidosis↗
PubMed1992

Class III antiarrhythmic action and inotropy: effects of almokalant in acute ischaemic heart failure in dogs.

We studied the haemodynamic and metabolic effects of the novel class III antiarrhythmic agent almokalant (H 234/09) in acute ischaemic heart failure at a dose prolonging ventricular repolarization. In pentobarbital anaesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular end-diastolic pressure (LVEDP) of 32 +/- 2 mmHg was achieved. Embolization depressed LV dP/dt(max), LV dP/dt(min), left ventricular systolic pressure (LVSP) and cardiac output. After intravenous infusion of almokalant (0.35 micrograms/kg) LV dP/dt(max) and LV dP/dt(min) were not significantly changed at paced cycle length of 300 msec., whereas LVSP and aortic pressure decreased both at spontaneous and paced cycle length of 300 msec. LVEDP remained unchanged. Heart rate decreased from 185 +/- 7 to 167 +/- 5 beats/min., and corrected QT-time (QTc) increased from 9.5 +/- 0.3 to 10.4 +/- 0.5 msec. Arterial concentration and net myocardial uptake of glucose, lactate and free fatty acids were not significantly influenced by almokalant. In conclusion, almokalant at a dose prolonging ventricular repolarization had no negative inotropic effect in acute ischaemic heart failure.

Acute Disease↗
PubMed1992

Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart.

We determined the influence of differences in the time of initiation of sympathetic and vagal stimulation (both at 10 Hz) on the cardiac autonomic interactions in 16 open-chest anesthetized dogs. We always ended the concurrent sympathetic and vagal stimulations simultaneously. Sympathetic stimulation alone for 1 minute increased heart rate by 90 +/- 7 (mean +/- SEM) beats per minute, and vagal stimulation alone for 1 minute decreased heart rate by 67 +/- 5 beats per minute; i.e., the algebraic sum of these responses was an increase of 23 beats per minute. However, combined sympathetic and vagal stimulation for 1 minute actually decreased heart rate by 35 beats per minute; i.e., the vagal effects predominated. When vagal stimulation was initiated first, the chronotropic responses to combined stimulation were not significantly affected by the duration of antecedent vagal stimulation. However, when sympathetic stimulation was initiated first, the vagal predominance (disparity between the summated individual responses and the combined response) progressively diminished as we increased the duration of antecedent sympathetic stimulation. The vagal predominance diminished from a value of 67 +/- 21 beats per minute when the stimulations were initiated simultaneously to a value of 37 +/- 21 beats per minute when the duration of antecedent sympathetic stimulation was 10 minutes. Sympathetic stimulation releases not only norepinephrine but also neuropeptide Y, and this neuropeptide inhibits vagal neurotransmission. Our data suggest, therefore, that the longer the antecedent sympathetic stimulation, the greater the inhibition of vagal neurotransmission (presumably by the neuropeptide Y) and, therefore, the less pronounced the vagal predominance.

Animals↗
PubMed1992

Stabilities and properties of multilinked hemoglobins.

Crosslinking of both human and dog hemoglobin has been done with a variety of reagents to produce singly, doubly and multiply crosslinked hemoglobins. Succinate and glutarate diaspirins did not crosslink deoxy human hemoglobin in good yield, in contrast to the fumarate analog (DBSF). Deoxy dog Hb did not react well with DBSF, but oxy dog Hb did react, giving crosslinked tetramers as well as dimers on SDS electrophoresis. Crosslinking with a short, rigid reagent (difluorodinitrobenzene) resulted in a similar product for both oxy and deoxy hemoglobin that had high stability and oxygen affinity. The trilinker, tris-chloroethylamine, produced a more stable product than the corresponding crosslinker, bis-chloroethylamine. Double crosslinking oxy Hb with DBSF and dimethylpimelimidate or with DBSF followed by deoxygenation and recrosslinking with DBSF gave products with higher denaturation temperatures. The diaspirin double crosslinked product had high oxygen affinity.

Animals↗