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Biomedical subjects

L Chi

Publications and source records attributed to L Chi.

At least 55 records · Page 3Linked to original sources
PubMed1997

Temporal glucocorticoid treatment: modulation of periodic endometrial responses during decidualization and pregnancy in rats.

The synthetic glucocorticoid, dexamethasone (Dex) was administered subcutaneously (1.5 mg/day/rat) in 3-days pretreatment regimens (Days 2-4, 4-6, 6-8, 8-10 and 10-12) to pseudopregnant rats in which decidualization was surgically induced and to pregnant rats. Variability in endometrial growth during decidualization and in the fetoplacental homeostasis of pregnancy was assessed at the end of each treatment period (Days 4, 6, 8, 10 and 12). During decidualization, endometrial growth (wet weight, protein and DNA) displayed significant (p < 0.05) time-dependent inhibitory profiles which rose steeply from Day 4 to Day 6 and declined thereafter to Day 10 in fairly well defined linear patterns. For the endometrial enzymes (isocitrate dehydrogenase, alkaline phosphatase and the matrix metalloproteinases--72 and 92 kDa), although the inhibitory patterns were inconsistent, a Days 6-8 treatment regimen seemed to be critical. By contrast Dex treatment induced progressive inhibition in serum progesterone concentrations from Day 2, to peak levels by Day 12. This indicates that time-related Dex inhibition of endometrial growth appeared not to be progesterone-mediated since the endometrial and progesterone inhibitory profiles were not in synchrony. The inhibitory effect of Dex under the pregnancy status demonstrated that birth potentials, fetal and placental weights, all had similar response patterns which rose from Day 4 to Day 8 and then underwent reductions to Day 12. Collectively, the results indicate that there was time dependency in growth inhibition by Dex at the endometrial and fetoplacental levels. Maximal sensitivity to drug exposure essentially coincided with the immediate post-traumal (decidualization) and postimplantation (pregnancy) periods.

Animals↗
PubMed1997

Adrenergic-dependent Effect of Adenosine-induced Ventricular Fibrillation in the Isolated Rabbit Heart.

BACKGROUND: The present study examined the contributory role of endogenous catecholamines in adenosine-induced ventricular fibrillation in isolation rabbit hearts. METHODS AND RESULTS: Cardiac catecholamine depletion was induced in eleven rabbits by the administration of 6-hydroxydopamine (2 x 30 mg/kg, every 12 hours intramuscularly). Hearts were removed 24 hours later, and subjected to 12 minutes of hypoxic perfusion followed by 40 minutes of reoxygenation while heart rate was maintained with atrial pacing. One of six, and one of five hearts from 6-hydroxydopamine treated rabbits developed ventricular fibrillation during hypoxia-reoxygenation when exposed to 3,7-dimethyl-1-propargylzanthine (DMPX) (10 µM) + adenosine (ADO) (1 µM) and DMPX (10 µM) + ADO (10 µM), respectively. In hearts from a control group, not exposed to 6-hydroxydopamine, ventricular fibrillation developed in each of five (100% incidence) hearts when perfused in the presence of DMPX (10 µM) + ADO (10 µM) (P <.05). Nadolol (1 µM), a beta-adrenoceptor DMPX (10 µM) + ADO (10 µM) treated hearts (n = 6, P <.05 vs DMPX + ADO treated hearts). To ensure catecholamine depletion, spontaneously beating isolated hearts from vehicle and 6-hydroxydopamine treated rabbits were perfused under normoxic conditions while exposed to increasing concentrations of tyramine (1, 3, 10 mM) and the change in heart rate was determined. A concentration-related, positive chronotorpic response to tyramine was obtained in hearts from the vehicle treated group that was absent in hearts from 6-hydroxy-dopamine treated rabbits or hearts perfused in the presence of nadolol. CONCLUSIONS: The results demonstrate that inhibition of the cardiac adenosine A(2) receptor, unmasks an adenosine A(1) receptor profibrillatory effect that is dependent upon endogenous cardiac catecholamines and beta-adrenoreceptor activation during myocardial hypoxia-reoxygenation.

Journal Article↗
PubMed1997

The therapeutic potential of novel anticoagulants.

Conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin. These agents display liabilities prompting the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins(LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and, more recently, approval for their use in the USA. Paralleling the development of LMWHs has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors exert their effects independent of either antithrombin III (ATIII) or heparin cofactor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases)direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of the senatural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant peptide-5 (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness, and sometimes relative ineffectiveness,in arterial and venous thromboembolic disorders has been demonstrated. They are being tested for their potential as new antithrombotic agents that act via direct enzyme inhibition. Thus,the clinician should in future be able to target different thrombotic conditions with proven, specific anticoagulant interventions.

Journal Article↗
PubMed1996

5-hydroxydecanoate fails to attenuate ventricular fibrillation in a conscious canine model of sudden cardiac death.

The electrophysiologic and antifibrillatory properties of 5-hydroxydecanoate, a KATP channel antagonist, were studied in a conscious canine model of sudden cardiac death. After a surgically induced myocardial infarction, animals were subjected to programmed electrical stimulation to identify those at risk for sudden cardiac death. 5-Hydroxydecanoate was administered as a bolus (10 mg/kg i.v.) followed by an infusion, 10 mg/kg/h (group 1, n = 12) or 30 mg/kg bolus followed by an infusion, 30 mg/kg/h (group 2, n = 8) i.v., while vehicle treated animals received a 0.9% sodium chloride solution (group 3, n = 11). The administration of 5-hydroxydecanoate did not alter the ventricular effective refractory period or the QTc interval. Anterior wall myocardial infarcts, expressed as a percentage of the left ventricle, did not differ among groups. Infusions of 5-hydroxydecanoate did not confer significant protection from sudden cardiac death (death within 60 min of posterolateral ischemia) due to ventricular fibrillation: group 1, 50%; group 2, 38%; and group 3, 18%. The data demonstrate that a continuous infusion of 5-hydroxydecanoate (10 and 30 mg/kg/h, i.v.) does not provide protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine.

Action Potentials↗
PubMed1996

Successful 14-day preservation of rat skin using a two-layer cold-storage method.

Skin-graft preservation for the purpose of delayed autografting to burn patients is a basic tool of plastic and burn surgery. This study was undertaken to evaluate the efficacy of the two-layer (physiological saline/perfluorochemical (PFC)) cold-storage method for skin preservation. In Wistar rats, a full-thickness skin graft, 3 cm in diameter, was harvested from the back, and separated from the dermis to obtain the epidermal sheet. This epidermal sheet was preserved at 4 degrees C using physiological saline (group 1, n = 15), physiological saline bubbled with a 95 per cent oxygen, 5 per cent carbon dioxide mixture (group 2, n = 15) or a two-layer method with bubbling with 95 per cent oxygen and 5 per cent carbon dioxide mixture (group 3, n = 15). The epidermal skin sheets were then autotransplanted to the backs of the original donor rats 7, 10 and 14 days after the start of preservation. The success rate of the skin autotransplantation was determined by measuring the ratio of viable area to total graft area 7 days after grafting. In group I, the success rates after 7, 10 and 14 days' perservation were 56.4, 47.4 and 0.09 per cent, respectively. In group 2, the corresponding success rates were 62.0, 48.4 and 0.8 per cent respectively, showing no improvement with oxygenated saline. In clear contrast, the success rates were significantly improved by the two-layer method, the values being 92.1, 87.9 and 77.6 per cent after 7, 10 and 14 days of perservation, respectively (P < 0.01 vs. groups 1 and 2 for all preservation durations). Based on these results, we concluded that the two-layer method is useful for not only improving the quality of the skin graft but also extending the preservation time of the skin graft up to 14 days.

Animals↗
PubMed1996

Electrical injuries from graphite fishing rods.

High tension electrical injuries have a high morbidity and mortality. Carbon fibre and graphite used in the manufacture of fishing rods gives them superconductor qualities. The resistance of a fishing rod with a carbon content of more than 70 per cent is very low, ranging from 0.9 to 10.5 k omega. Nine cases are reported, which teach an important lesson not only in the management of those severe injuries, but also in their prevention.

Adult↗
PubMed1996

Effects of tedisamil (KC-8857) on cardiac electrophysiology and ventricular fibrillation in the rabbit isolated heart.

1. The direct cardiac electrophysiological and antifibrillatory actions of tedisamil (KC-8857) were studied in rabbit isolated hearts. 2. Tedisamil (1, 3, and 10 microM), prolonged the ventricular effective refractory period (VRP) from 120 +/- 18 ms (baseline) to 155 +/- 19, 171 +/- 20, and 205 +/- 14 ms, respectively. Three groups of isolated hearts (n = 6 each) were used to test the antifibrillatory action of tedisamil. Hearts were perfused with 1.25 microM pinacidil, a KATP channel activator. Hearts were subjected to hypoxia for 12 min followed by 40 min of reoxygenation. Ventricular fibrillation (VF) developed during hypoxia and reoxygenation in both the control and 1 microM tedisamil-treated groups (5/6 and 4/6, respectively). Tedisamil (3 microM) reduced the incidence of VF (0/6, P = 0.007 vs. control). 3. In a separate group of hearts, VF was initiated by electrical stimulation. The administration of 0.3 ml of 10 mM tedisamil, via the aortic cannula, terminated VF in all hearts, converting them to normal sinus rhythm. 4. Tedisamil (3 microM) reversed pinacidil-induced negative inotropic effects in rabbit isolated atrial muscle which were equilibrated under normoxia, as well as in atrial muscle subjected to hypoxia and reoxygenation. 5. The results demonstrate a direct antifibrillatory action of tedisamil in vitro. The mechanism responsible for the observed effects may involve modulation by tedisamil of the cardiac ATP-regulated potassium channel, in addition to its antagonism of IK and Ito.

Animals↗
PubMed1996

Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewis(x).

BACKGROUND: Available data suggest that the accumulation of neutrophils within the myocardium following an ischemic event plays an important role in the pathogenesis of myocardial ischemia/reperfusion injury. It is of interest, therefore, to develop pharmacologic agents designed to inhibit neutrophil adhesion to the endothelium. METHODS AND RESULTS: A synthetic carbohydrate analog to the P-selectin ligand sialyl Lewis(x) (sLe(x)) was evaluated for its ability to protect the myocardium from ischemia/reperfusion injury. Open chest anesthetized rabbits were subjected to 30 minutes occlusion of the left circumflex artery followed by 5 hours of reperfusion. Vehicle or sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog was significantly reduced when compared to rabbits treated with vehicle (28 +/- 9% vs 57 +/- 10% of the area at risk, p <.05). The compound did not alter circulating neutrophil counts or myocardial oxygen demand as determined by the rate-pressure product. Furthermore, neutrophil accumulation within the ischemic region was decreased by 44% (P <.05) in the hearts of animals receiving sLe(x) analog as compared to vehicle. CONCLUSIONS: Carbohydrate derivatives of sLe(x) may be effective in reducing the degree of myocardial injury after ischemia/reperfusion.

Journal Article↗
PubMed1996

Protective Effects of Ranolazine on Ventricular Fibrillation Induced by Activation of the ATP-Dependent Potassium Channel in the Rabbit Heart.

BACKGROUND: The authors studied the antifibrillatory effects of the adenosine-triphosphate (ATP)-sparing metabolic modulator ranolazine in a rabbit isolated heart model in which ventricular fibrillation occurs under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener pinacidil. METHODS AND RESULTS: Ten minutes after ranolazine or vehicle administration, addition of pinacidil (1.25 µM) to the buffer was followed by a 12-minute hypoxic period and 40 minutes of reoxygenation. At a reduced concentration of ranolazine (10 µM), ventricular fibrillation occurred in 60% of the hearts, compared to 89% in the control group (P = NS). In contrast, only three of nine hearts (33%) treated with 20 µM ranolazine developed ventricular fibrillation (P <.05 vs vehicle). Hemodynamic parameters including coronary perfusion pressure, left ventricular developed pressure, and +/-dP/dt were not affected by the presence of ranolazine in the perfusion medium. Ranolazine did not prevent or modify the negative inotropic or coronary vasodilator actions of pinacidil, suggesting a mechanism of action independent of potassium channel antagonism. CONCLUSIONS: Ranolazine significantly reduced the incidence of ventricular fibrillation in the hypoxic/reoxygenated heart exposed to the ATP-dependent potassium channel opener, pinacidil. The reported ability of ranolazine to prevent the decrease in cellular ATP during periods of a reduced oxygen supply may account for its observed antifibrillatory action. By maintaining intracellular ATP, ranolazine may modulate or prevent further opening of the ATP-dependent potassium channel in response to hypoxia and/or pinacidil.

Journal Article↗
PubMed1996

Tedisamil Attenuates Ventricular Fibrillation in a Conscious Canine Model of Sudden Cardiac Death.

BACKGROUND: The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857;3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]-nonane dihydrochloride) were studied in a conscious canine model of sudden cardiac death. METHODS AND RESULTS: Three to five days after surgically induced myocardial infarction (2-hour occlusion of the left anterior descending coronary artery), animals were subjected to programmed electrical stimulation to identify those at risk for ischemia-induced ventricular fibrillation. Sixty minutes after tedisamil (10 mg/kg, administered orally) PES was repeated. Tedisamil increased the ventricular effective refractory period from 106 +/- 6 to 134 +/- 7 ms (P <.05) compared to placebo treatment, which did not alter the ERP (123 +/- 6 to 116 +/- 5 ms). Tedisamil prolonged the QTc interval, from a predrug value of 308 +/- 14 to 327 +/- 14 ms, postdrug. The extent of the surgically induced anterior wall myocardial infarct did not differ between groups, tedisamil, 29 +/- 2%, and placebo, 28 +/- 2% of the left ventricle. CONCLUSIONS: Tedisamil conferred protection against ischemia induced ventricular fibrillation; 7 of 10 tedisamil-treated dogs survived, compared to 4 of 14 surviving in the vehicle treated group (P <.05). Although we observed instances of vomiting and/or diarrhea in several dogs after a single oral administration of tedisamil, the data indicate that oral administration of tedisamil provides protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine. The mechanism by which tedisamil achieves its antifibrillatory effect may be related to its ability to prolong the ERP of the ventricular myocardium without altering ventricular conduction velocity.

Journal Article↗
PubMed1995

A locus of the gonadotropin-releasing hormone receptor that differentiates agonist and antagonist binding sites.

The decapeptide gonadotropin-releasing hormone controls reproductive function via interaction with a heptahelical G protein-coupled receptor. Because of molecular model of the receptor predicts that Lys121 in the third transmembrane helix contributes to the binding pocket, the function of this side chain was studied by site-directed mutagenesis. Substitution of Arg at this position preserved high affinity agonist binding, whereas Gln at this position reduced binding below the limits of detection. Leu and Asp at this locus abolished both binding and detectable signal transduction. The EC50 of concentration-response curves for coupling to phosphatidyl inositol hydrolysis obtained with the Gln121 receptor was more than 3 orders of magnitude higher than that obtained for the wild-type receptor. In order to determine whether the increased EC50 obtained with this mutant reflects an altered receptor affinity, the effect of decreases in wild-type receptor density on concentration-response curves was determined by irreversible antagonism. Progressively decreasing the concentration of the wild-type receptor increased the EC50 values obtained to a maximal level of 2.4 +/- 0.2 nM. Comparison of this value with the EC50 of 282 +/- 52 nM observed with the Gln121 receptor mutant indicates that the agonist affinity for this mutant is reduced more than 100-fold. In contrast, antagonist had comparable high affinities for the wild-type, Arg121, and Gln121 mutants. The results indicate that a charge-strengthened hydrogen bond donor is required at this locus for high affinity agonist binding but not for high affinity antagonist binding.

Amino Acid Sequence↗
PubMed1995

Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor.

A conserved helix 2 Asp is required for the proper function of many G-protein-coupled receptors. To reveal the structural basis for the role of this residue, the additive effects of mutations at this locus and at a conserved helix 7 locus were investigated in the 5-HT2A receptor. All mutant receptors studied retained high affinity agonist and antagonist binding. Whereas an Asp-->Asn mutation in helix 2 eliminated coupling, interchanging the residues at the two positions by a second mutation of Asn-->Asp in helix 7 restored receptor function. These data suggest that these residues are adjacent in space and interact. The loss of function observed with Ala at either position is consistent with each side chain forming hydrogen bonds. Molecular dynamics simulations were performed on three-dimensional computational models of agonist-receptor complexes of both the wild-type receptor and the Asp-->Asn mutant receptor. Consonant with the lack of coupling observed for the mutant construct, introducing the mutation into the computational model produced a conformational change in a direction opposite to that seen from computational simulations of activation of the wild-type receptor model. These results implicate both loci in a common hydrogen-bonding network underlying receptor activation by agonist.

Mutation↗
PubMed1995

Multi-sample confirmatory factor analysis of the Task and Ego Orientation in Sport Questionnaire.

The Task and Ego Orientation in Sport Questionnaire (TEOSQ; Duda, 1989; Duda & Nicholls, 1992) was designed to assess individual differences in the proneness for task and ego involvement in athletic settings. The purpose of this study was to independently and simultaneously test the measurement model assumed to underlie the TEOSQ across intercollegiate athletes (n = 143), college students enrolled in skill classes (n = 270), high school athletes (n = 310), and junior high school sport participants (n = 234). Single-sample confirmatory factor analysis (CFA) was employed to establish and to evaluate the tenability of a baseline model in terms of each sample. A series of multi-sample CFAs were then conducted to test the invariance of the measurement and factor structure of the TEOSQ across the four groups. The measures of overall fit for the hypothetical two-factor structure of the TEOSQ were generally acceptable, albeit weaker in the case of the college students. Further, the results of the multi-sample CFA did not support the assumption for intergroup invariance of the TEOSQ. This finding indicated that the 13 items and structure of the TEOSQ were not equally valid across the present four samples.

Adolescent↗
PubMed1995

MS-551 protects against ventricular fibrillation in a chronic canine model of sudden cardiac death.

We studied the electrophysiologic and antifibrillatory properties of MS-551 (1,3-dimethyl-6-((2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino) 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious canine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI: 2-h occlusion of the left anterior descending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden cardiac death. MS-551 was administered (2.0, 3.0, or 4 x 2.0 mg/kg intravenously, i.v.). Vehicle-treated animals received 0.9% sodium chloride solution for injection. MS-551 (multiple-dose regimen) increased ventricular effective refractory period (VERP) from 112 +/- 4 to 137 +/- 4 ms (p < 0.05) as compared with vehicle treatment, which did not alter VERP (125 +/- 6 to 121 +/- 5 ms). MS-551 prolonged QTc interval from a predrug value of 293 +/- 8 to 333 +/- 18 ms postdrug. The size of surgically induced MI did not differ among groups: 2.0 mg/kg, 23 +/- 4%; 3.0 mg/kg, 28 +/- 2%; 4 x 2.0 mg/kg, 25 +/- 3%; and vehicle, 28 +/- 3% of the left ventricle. Single bolus administration of MS-551 (2.0 or 3.0 mg/kg i.v.) did not confer significant protection against sudden cardiac death. However, repeated administration of MS-551 protected against sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in the vehicle-treated group (p < 0.05). The data indicate that a multiple-dose regimen of MS-551 provides protection against ischemia-induced ventricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depends on its ability to prolong VERP of myocardium without altering ventricular conduction velocity.

Animals↗
PubMed1994

Antiarrhythmic agent, MS-551, protects against pinacidil + hypoxia-induced ventricular fibrillation in Langendorff-perfused rabbit isolated heart.

We studied the electrophysiologic and antifibrillatory effects of the class III agent MS-551 in a rabbit isolated heart model in which ventricular fibrillation (VF) occurs reproducibly under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener, pinacidil. Ten minutes after MS-551 or vehicle administration, addition of pinacidil (1.25 microM) to the buffer was followed by a 12-min hypoxic period and 40-min reoxygenation. At a low concentration of MS-551 (1.0 microM), VF occurred in 5 of 6 hearts, the same incidence as in the control group (5 of 6). In contrast 0 of 6 hearts treated with 15 microM MS-551 developed VF (p < 0.05 vs. vehicle). Ventricular effective refractory period (VERP) was determined in a separate group of isolated hearts (n = 13). Pinacidil alone, during normoxic perfusion, decreased VERP 48 +/- 11% (p < 0.05) 15 min after exposure. Five minutes of hypoxia alone also decreased VERP (57 +/- 8%, p < 0.05). Under normoxic conditions, MS-551 increased ERP 31 +/- 10% (p < 0.05 vs. baseline). VERP prolongation by MS-551 was reduced in the presence of pinacidil but remained 22 +/- 6% (p < 0.05) above baseline. The results suggest that VERP shortening owing to pinacidil-mediated ATP-dependent K+ channel opening is associated with development of VF in isolated heart. MS-551 attenuates the pinacidil-mediated decrease in VERP and prevents pinacidil+hypoxia-reoxygenation-induced VF. Because pinacidil and hypoxia open myocardial KATP channels, putatively decreasing VERP, MS-551 may exert its antifibrillatory effect through partial blockade of KATP channels.

Animals↗