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Biomedical subjects

L Chi

Publications and source records attributed to L Chi.

At least 73 records · Page 4Linked to original sources
PubMed1994

Antifibrillatory effects of clofilium in the rabbit isolated heart.

1. This study was designed to determine whether clofilium exhibits antifibrillatory activity in a pinacidil + hypoxia-induced model of ventricular fibrillation (VF) in Langendorff-perfused hearts. 2. Ten minutes after exposure to vehicle or clofilium (0.1, 1.0 and 10.0 microM), hearts were exposed to pinacidil (1.25 microM), then subjected to 12 min of hypoxia and reoxygenated. Onset to VF was recorded. Additional groups of hearts were pretreated with UK-68,798 (1.0, 3.0 and 10.0 microM), a delayed rectifier channel blocker, and 5-hydroxydecanoate (10 microM), a known ATP-dependent K+ channel blocker, and subjected to an identical protocol. 3. Clofilium decreased the incidence of VF in a concentration-dependent manner; 7/9 control hearts developed VF vs 1/9 hearts (P = 0.007, Fisher's Exact) treated with 10.0 microM clofilium. In addition, 5-hydroxydecanoate protected hearts from VF, while UK-68,798 pretreatment did not. 4. In a separate group of hearts, electrically-induced VF was converted to sinus rhythm in 10/11 hearts after clofilium was introduced as a bolus. 5. Clofilium is capable of preventing VF in the rabbit isolated heart in a concentration-dependent manner. We have data to suggest that the ability of clofilium to attenuate the effects of pinacidil+hypoxia in our model may include blockade of metabolically active K+ channels, i.e., KATP (glibenclamide-sensitive) channel.

Action Potentials↗
PubMed1994

Effect of Ado A1- and A2-receptor activation on ventricular fibrillation during hypoxia-reoxygenation.

We examined the hypothesis that adenosine (Ado)-induced alterations in ventricular electrophysiology may contribute to arrhythmogenesis in a setting of myocardial hypoxia through activation of Ado A1 and A2 receptors in the rabbit isolated perfused heart. There was a 20% incidence of ventricular fibrillation (VF) in control hearts subjected to perfusion conditions of hypoxia and reoxygenation. The incidence of VF was increased to 50% in the presence of 1 microM Ado when hearts were exposed to hypoxia-reoxygenation. The incidence of VF was 20% when Ado was increased to 10 microM. Inhibition of the Ado A2 receptor with 3,7-dimethyl-l-propargylxanthine (DMPX; 10 microM) increased the incidence of VF to 100% when 10 microM Ado was added to the perfusion medium. The A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 microM), attenuated (from 100% to 20%) VF induced by Ado + DMPX (10 microM each). The ventricular refractory period and monophasic action potential duration were determined in a separate group of hearts. Our findings indicate that 1) Ado A1-receptor stimulation facilitates VF by decreasing action potential duration and refractoriness in hearts subjected to hypoxia and reoxygenation and 2) the arrhythmogenic potential of Ado A1-receptor stimulation is modulated by simultaneous activation of the ventricular A2 Ado receptor.

Action Potentials↗
PubMed1994

Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4.

BACKGROUND: Platelets contain several factors that inhibit heparin. This study was designed to assess the heparin-neutralizing activity present in acute, platelet-rich arterial thrombi formed at sites of arterial injury in animals. METHODS AND RESULTS: Platelet-rich thrombi (n = 3) were induced in pig coronary arteries by balloon catheter-mediated arterial injury. Soluble extracts were prepared from each thrombus and assayed for the capacity to inhibit heparin in an in vitro clotting assay (activated partial thromboplastin time). Mean heparin-neutralizing activity was 28 U of heparin neutralized per milliliter of thrombus, indicating that 1 vol of coronary thrombus completely inhibited the heparin present in 140 vols of therapeutically anticoagulated (0.2 U heparin/mL) plasma. In contrast, thrombus extracts had no effect on the anticoagulant activity of hirudin, a direct-acting thrombin inhibitor. The heparin-neutralizing activity present in coronary thrombi bound to heparin-agarose and was eluted from it by 1.4 mol/L NaCl, suggesting that platelet factor 4 mediated the antiheparin effect of thrombi. Consistent with this hypothesis, a murine monoclonal antibody to rabbit platelet factor 4 nearly completely inhibited the heparin-neutralizing activity present in rabbit thrombi (n = 3) generated by carotid artery injury. CONCLUSIONS: Extracts prepared from platelet-rich arterial thrombi significantly inhibit the in vitro anticoagulant potency of heparin but not of hirudin. This antiheparin effect appears to be mediated by platelet factor 4. These results are consistent with the hypothesis that localized inhibition of heparin at sites of platelet activation may reduce its antithrombotic efficacy. In addition, they suggest an additional mechanism for the apparent superiority of hirudin over heparin as a thrombin inhibitor at sites of arterial injury.

Animals↗
PubMed1993

Antiarrhythmic versus antifibrillatory actions: inference from experimental studies.

Pathophysiology of the coronary circulation is a major contributor to altering the myocardial substrate, rendering the heart susceptible to the onset of arrhythmias associated with sudden cardiac death. Antiarrhythmic drug therapy for the prevention of sudden cardiac death has been provided primarily on the basis of trial and error and in some instances based on ill-suited preclinical evaluations. The findings of the Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before entering into clinical testing. The major deficiency in this area of experimental investigation has been the lack of animal models that would permit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distinguish between pharmacologic interventions that suppresses nonlethal disturbances of cardiac rhythm as opposed to those agents capable of preventing lethal ventricular tachycardia or ventricular fibrillation. Preclinical models for the testing of antifibrillatory agents must consider the fact that the superimposition of transient ischemic events on an underlying pathophysiologic substrate makes the heart susceptible to lethal arrhythmias. Proarrhythmic events, not observed in the normal heart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more closely simulate the clinical state in humans who are at risk. The experimental results show a good correlation with clinical data regarding agents known to reduce the incidence of lethal arrhythmias as well as those showing proarrhythmic actions.

Animals↗
PubMed1993

Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide.

Using a paced Lagendorff-perfused rabbit heart paradigm, we investigated the role of protein kinase C (PKC) in the development of ventricular fibrillation (VF) in hearts subjected to hypoxia (12 min) and re-oxygenation (40 min). We studied the effect of putative activators and inhibitors of PKC on the incidence of VF. Hearts exposed to 4 beta-phorbol,12,13-dibutyrate (PDBu), isophorbol or the membrane permeant diacylglycerol analog, 1-oleoyl-2-acetyl-rac-glycerol (OAG), during the prehypoxic phase had an increased incidence of VF during the hypoxic and reoxygenation periods. The incidence of VF was 90%, 83% and 75% in hearts exposed to PDBu, isophorbol and OAG, respectively (P < 0.05 vs control). Perfusion of hearts with PDBu was associated with a significant increase in the membrane fraction of cardiac PKC activity. In the presence of the inactive phorbol ester 4 alpha-phorbol didecanoate, the incidence of VF was 17% (P > 0.05 vs control). PKC activators were profibrillatory at concentrations that did not affect cardiac function: neither left ventricular developed pressure nor coronary perfusion pressure were affected. The effect of PDBu was antagonized by staurosporine: the incidence of VF was 17% in PDBu+staurosporine treated hearts (P < 0.05 vs control). To further study the profibrillatory effect of PDBu, hearts were exposed to PDBu in the presence of the ATP-dependent potassium channel antagonist glibenclamide. The latter prevented PDBu-induced VF. The results show that under the conditions employed, PDBu-induced activation of PKC induces redistribution of PKC activity and is associated with the development of VF.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Cloning and characterization of the human GnRH receptor.

A cDNA encoding the human GnRH receptor (GnRHR) has been cloned and functionally expressed in both Xenopus oocytes and COS-1 cells. The 2160 bp cDNA encodes a 328 amino acid protein with a predicted amino acid sequence that is 90% identical to that of the mouse GnRHR (Tsutsumi et al. (1992) Mol. Endocrinol. 6, 1163-1169). Injection of synthetic RNA transcript into oocytes led to the development of a depolarizing response to agonists when assayed by voltage-clamp electrophysiology. Consistent with the expression of a mammalian GnRHR, the response was blocked by GnRH antagonists. Following expression of the human GnRHR in COS-1 cells, agonists and an antagonist displaced [125I]GnRH agonist from membrane isolates with nanomolar range dissociation constants similar to those described for displacement from human pituitary membranes. Transfected COS-1 cells manifested a GnRH-stimulated increase in phosphoinositol turnover, with an EC50 of approximately 3 nM, which was inhibited by GnRH antagonists. Northern blot analysis revealed a single band of approximately 4.7 kb expressed in human pituitary which was not detected in testis. The predicted structure of the human GnRHR is similar to that previously reported for the mouse receptor. Although the mammalian GnRHR is a seven transmembrane domain receptor, it differs from other G-protein coupled receptors in several respects, most notably the lack of a cytoplasmic C-terminal domain. The present study demonstrates that the cDNA isolated encodes the human GnRHR and suggests that several unique features conserved among mammalian GnRHRs may be essential for receptor function and/or regulatory control.

Amino Acid Sequence↗
PubMed1993

Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel.

We investigated the effects of the ATP-dependent K+ channel antagonist glyburide and the ATP-dependent K+ channel agonist pinacidil in a Langendorff-perfused rabbit isolated heart subjected to a period of global hypoxia. A class III antiarrhythmic drug, E-4031, also was studied in this model. These studies aimed to define the mechanism of action of putative profibrillatory actions of pinacidil and the mechanism for the antifibrillatory effect of the class III antiarrhythmic drug, E-4031, in the hypoxic heart. After stabilization and determination of baseline functional parameters under normoxic perfusion conditions (95% O2/5% CO2), hearts were subjected to global hypoxia by switching to a 95% N2/5% CO2 saturated perfusion medium for a period of 12 min. After the hypoxic period, normoxia was re-established by switching to the oxygen-carbon dioxide saturated buffer medium for a period of 40 min. The oxygen tension of the perfusion buffer was reduced from approximately 400 mm Hg to below 50 mm Hg during the hypoxic period. All hearts subjected to hypoxia had reduced function: the left ventricular developed pressure and +/- dP/dt were reduced significantly. Myocardial tissue ATP concentrations were reduced (> 50%) in hearts subjected to hypoxia. Under conditions of hypoxic/reoxygenation and in the presence of a low (2.5 mM) potassium concentration ([K+]0), pinacidil (1.25 microM) facilitated the induction of ventricular fibrillation (80% fibrillation in the presence of pinacidil vs. 20% in the absence of pinacidil). Glyburide (10 microM) and E-4031 (1 and 10 microM) significantly reduced the incidence of ventricular fibrillation associated with pinacidil (20% fibrillation in the presence of hypoxia, pinacidil, and glyburide or 10 microM E-4031). Opening of the ATP-dependent K+ channel by pinacidil under normoxia and low K+ also facilitated the induction of ventricular fibrillation (60% ventricular fibrillation). Pinacidil failed to induce ventricular fibrillation under either normoxic or conditions of hypoxic/reoxygenation when the [K+]0 was increased to 5.1 mM. The results of this study demonstrate that K+ channel activators facilitate the induction of ventricular fibrillation under both normoxic conditions and conditions of hypoxic/reoxygenation when the perfusion buffer K+ concentration is reduced.

Adenosine Triphosphate↗
PubMed1993

Antifibrillatory and profibrillatory actions of selected class I antiarrhythmic agents.

We wished to examine selected class I antiarrhythmic agents for their potential to exhibit proarrhythmic or antifibrillatory actions. Quinidine, lidocaine, aprindine, and flecainide were evaluated in an experimental model that made use of rabbit isolated perfused heart. Hearts were stabilized with oxygenated buffer (95% O2/5% CO2) with or without pinacidil (1.25 microM) and then were subjected to hypoxia (95% N2/5% CO2) for 12 min, followed by 40-min normoxic perfusion (95% O2/5% CO2). Test drugs were added to the perfusion medium 5 min before hypoxia was induced. Prevention of spontaneous ventricular fibrillation (VF) was determined. To characterize the electrophysiologic effects of the selected antiarrhythmic agents, we determined the changes in threshold current and effective refractory period (ERP) before and after drug treatment. Addition of the potassium channel agonist, pinacidil, to the perfusion medium invariably resulted in VF during the hypoxic interval or shortly after reoxygenation. Pretreatment of the heart with glibenclamide prevented pinacidil-induced VF. Quinidine, aprindine, lidocaine, and flecainide each were studied at a single concentration. The respective drug concentrations were selected to produce comparable changes in ventricular refractory period. Of the class I agents selected for study, only quinidine prolonged the ventricular ERP and provided significant protection against pinacidil-induced VF. In contrast, aprindine and lidocaine decreased ventricular ERP and did not prevent VF induced by the combination of pinacidil and hypoxia. Quinidine, aprindine, and lidocaine did not exhibit proarrhythmic effects in the presence of hypoxia when pinacidil was not added to the perfusion medium. Flecainide, when added to the perfusion medium without pinacidil elicited proarrhythmic activity leading to VF when the hearts were made hypoxic. Flecainide-induced VF was antagonized by glibenclamide. The data suggest that VF can be provoked by the potassium channel agonist pinacidil or by flecainide under conditions that reduce intracellular ATP concentration. Glibenclamide, a selective antagonist of the KATP channel prevented the profibrillatory actions of pinacidil and flecainide. Quinidine, but not lidocaine and aprindine, prevented VF induced by pinacidil and hypoxia.

Adenosine Triphosphate↗
PubMed1993

Functional consequence of big endothelin conversion: demonstration with isolated neutrophils but not in a postinfarction model.

The role of neutrophils in the conversion of big endothelin (Big-ET) to endothelin-1 (ET-1) was assessed in two models. In rabbit isolated hearts, ET-1 demonstrated significant increases in coronary perfusion pressure (PP) at doses greater than 100 pmol. With Big-ET, significant increases were obtained only at doses greater than 3 nmol. Similarly, this dose of Big-ET did not increase PP in isolated, perfused hearts from rabbits previously subjected to 60 min of coronary artery occlusion and 4 h of reperfusion (n = 7). However, when isolated rabbit neutrophils were incubated with Big-ET (n = 5) or vehicle (n = 4) and 3 nmol aliquots assayed in isolated hearts, results demonstrated a time-dependent conversion to a vasoactive product. These findings suggest that isolated neutrophils are capable of converting Big-ET to an ET-1-like vasoactive substance. The model may be useful in assessing antagonists of endothelin-converting enzyme activity and/or the endothelin receptor.

Animals↗
PubMed1993

Antifibrillatory effects of ibutilide in the rabbit isolated heart: mediation via ATP-dependent potassium channels.

This study determined if ibutilide, a drug with class III activity, exhibited antifibrillatory effects in an isolated heart model of ventricular fibrillation (VF). Langendorff-perfused hearts were randomized among six groups. Group I (n = 9) served as the vehicle-treated control group. Groups II (n = 6), III (n = 10) and IV (n = 9) were pretreated with ibutilide 0.1; 1.0 or 3.0 microM, respectively. Ten minutes after perfusion in the presence of vehicle or ibutilide, hearts were perfused with the ATP-dependent potassium channel opener, pinacidil (1.25 microM) and subjected to a 12-min hypoxic period followed by 40 min of reoxygenation, or until the onset of VF. Groups V and VI were used to investigate electrophysiological effects of ibutilide (n = 12), as well as its chemical defibrillatory activity (n = 9), respectively. Additional experiments involved isometric tension recordings from canine atrial pectinate muscle exposed to increasing concentrations of pinacidil (3-300 microM) in the presence of ibutilide (3-30 microM). Ibutilide decreased the incidence of VF in a concentration-dependent manner; eight of nine control hearts developed VF vs. two of nine hearts (P = .018 chi 2) treated with 3.0 microM ibutilide. In atrial pectinate tissue, ibutilide attenuated the negative inotropic effect of pinacidil. An unexpected finding was the ability of ibutilide to achieve chemical defibrillation when added to the perfusion medium after the electrical induction of ventricular fibrillation in the isolated heart. The antifibrillatory effect of ibutilide may result from inhibition of the ATP-dependent potassium channel made susceptible to opening by pinacidil during hypoxia.

Adenosine Triphosphate↗
PubMed1992

Excimer laser angioplasty in the atherosclerotic rabbit: comparison with balloon angioplasty.

The early and late results of excimer laser angioplasty and balloon angioplasty were compared in atherosclerotic rabbit iliac arteries. Immediately after laser angioplasty (n = 13) with a bare 600 microns fiber, there was a 33% increase in angiographically measured minimum lumen diameter; after balloon angioplasty (n = 12), there was a 53% increase. Restenosis (defined as loss of at least 50% of the gain achieved by angioplasty) occurred in none of six laser-treated rabbits studied 1 month later, compared with four of six balloon-treated rabbits (p = 0.06). Planimetric measurements of cross sections of the arterial wall 1 month after angioplasty showed less intimal and medial tissue in laser-treated (1.8 +/- 0.2 mm2) than in the balloon-treated rabbits (3.0 +/- 0.4 mm2; p less than 0.05). Typical thermal effects were absent on microscopic examination of laser angioplasty sites. It is concluded that in this animal model, excimer laser irradiation results in an immediate increase in lumen diameter comparable with balloon angioplasty, but is associated with less residual atheromatous tissue than balloon angioplasty and a trend toward a lower rate of restenosis.

Angioplasty, Balloon↗
PubMed1990

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.

Action Potentials↗
PubMedDate not supplied

Effect of benomyl and carbendazim on steroid and molecular mechanisms in uterine decidual growth in rats.

The present study examined the influence of two benzimidazole fungicides benomyl and carbendazim (MCB), in dosages of 500 and 1000 mg kg-1 for 5 days, on the capacity of decidual growth in pseudopregnant rats. The aim of the research was to determine whether the antimitotic activity of both chemicals was being mediated by way of hormonal and molecular mechanisms at the uterine level. The results show that both fungicides produced reductions in uterine decidual weight (P < 0.01) and uterine protein content (P < 0.05). However, levels of serum estradiol and progesterone and the binding capacities of cytosol estrogen and progesterone receptors remained essentially unchanged. Subsequently, the antigrowth-antimitotic activity of benomyl and MCB, at 500 and 1000 mg kg-1 dosages, on the decidual uterus is direct, and apparently does not involve steroidal or receptor mechanisms.

Animals↗
PubMedDate not supplied

Hydroxyurea inhibition of cellular and developmental activities in the decidualized and pregnant uteri of rats.

The cytotoxicity of hydroxyurea (HU), currently used to combat various cancers, sickle cell anemia and human immunodeficiency infection, was assessed by exposing decidualized and pregnant uteri of Sprague-Dawley rats to this drug. Consecutive daily doses of HU (500 mg/kg(-1)) for 4 days were injected subcutaneously during decidualization when proliferation of the deciduoma was biochemically analyzed on pseudopregnancy day 9, or injected intraperitoneally during pregnancy when uterine developmental processes were evaluated on gestation day 16. Hydroxyurea displayed prominent antiproliferative effects on decidual growth. These actions were comparable to significantly impaired (P<0.001) developmental responses (increases in post-implantation losses, in resorbed fetuses and in reduced fetal and placental weights) during pregnancy. The cellular components inhibited by HU were DNA, protein, nitric oxide synthase, a matrix metalloproteinase and decidual prolactin-related protein mRNA (P<0.05). Steroid-related endocrine events (serum progesterone concentrations, estrogen receptor and mRNA levels) were unaffected by HU, implying direct cellular action by the drug. Interestingly, endometrial alkaline phosphatase bioactivity was enhanced by HU (P<0.05). Subsequently, the reproductive toxicity of HU was apparently related to mitogenic and differentiation-induced endometrial cellular activities.

Animals↗
PubMedDate not supplied

A mechanistic assessment of 1,3-butadiene diepoxide-induced inhibition of uterine deciduoma proliferation in pseudopregnant rats.

Butadiene diepoxide (BDE), a reactive metabolite of 1,3-butadiene that is an important industrial chemical used in synthetic rubber production causes a dose-dependent inhibition of deciduoma development in pseudopregnant Sprague-Dawley rats. This study used 4 daily i.p. BDE doses of 0.20, 0.25, 0.30, 0.35, or 0.40 to characterize mechanisms that may be responsible for the antideciduoma effect. Pseudopregnant rats were treated either before (pseudopregnancy [PPG] days 1-4) or after (PPG days 5-9) deciduoma induction by endometrial trauma with a blunt needle. Animals were killed on PPG day 9 and evaluated for serum progesterone and endometrial protein and DNA. RT-PCR was used to measure message for estrogen receptor (ER) alpha and pituitary adenylate cyclase-activating polypeptide (PACAP). Substrate zymography and Western blotting were used respectively to measure matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase. The antideciduoma effects of BDE were associated with decreases in endometrial weight, protein, and DNA, with decreases in serum progesterone, and with decreases in PACAP message and MMP-9. A reduction in NOS was identified at the highest dose of BDE. Message for estrogen receptor (ER) alpha was not affected at any dose. We conclude that the reduction in decidual proliferation was direct and appeared to be associated with either 1) a decrease in the effectiveness of the deciduogenic stimulation and/or a weakened endometrial sensitivity to the stimulus; or 2) an effect on deciduoma development. Molecular mechanisms that apparently contributed to BDE inhibition of decidual metabolism included the synthesis of protein and DNA involved in decidual growth, the synthesis and activation of a matrix metalloproteinase for degradation of the extracellular matrix that is essential for tissue remodeling during deciduoma development, and the nitric oxide/nitric oxide synthase and pituitary adenylate cyclase-activating peptide systems that are involved in promoting vasodilation and increased vascular permeability to enhance the availability of substrates for maximal deciduoma growth. The ovotoxicity of BDE, which has previously been established, may indirectly affect decidual proliferation by reducing progesterone, the preeminent endocrine regulator of deciduoma development. The findings also suggest that BDE may possess no estrogenic action since it was associated with endometrial weight loss and unaltered levels of the estrogen receptor alpha mRNA expression.

Animals↗
PubMedDate not supplied

Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents.

Cardiovascular and cerebrovascular diseases continue to be the leading cause of death throughout the world. Over the past two decades, great advances have been made in the pharmacological treatment and prevention of thrombotic disorders (e.g., tissue plasminogen activators, platelet GPIIb/IIIa antagonists, ADP receptor antagonists such as clopidogrel, low-molecular weight heparins, and direct thrombin inhibitors). New research is leading to the next generation of antithrombotic compounds such as direct coagulation FVIIa inhibitors, tissue factor pathway inhibitors, gene therapy, and orally active direct thrombin inhibitors and coagulation Factor Xa (FXa) inhibitors. Animal models of thrombosis have played a crucial role in discovering and validiting novel drug targets, selecting new agents for clinical evaluation, and providing dosing and safety information for clinical trials. In addition, these models have provided valuable information regarding the mechanisms of these new agents and the interactions between antithrombotic agents that work by different mechanisms. This review briefly presents the pivitol preclinical studies that led to the development of drugs that have proven to be effective clinicallly. The role that animal models of thrombosis are playing in the discovery and development of novel antithrombotic agents is also described, with specific emphasis on FXa inhibitors. The major issues regarding the use of animal models of thrombosis, such as the use of positive controls, appropriate pharmacodynamic markers of activity, safety evaluation, species-specificity, and pharmacokinetics, are highlighted. Finally, the use of genetic models in thrombosis/hemostasis research and pharmacology is presented using gene-therapy for hemophilia as an example of how animal models have aided in the development of these therapies that are now being evaluated clinically. In summary, animal models have contributed greatly to the discovery of currently available antithrombotic agents and will play a primary role in the discovery and characterization of the novel antithrombotic agents that will provide safe and effective pharmacological treatment for life-threatening thrombotic diseases.

Animals↗