Contraction of guinea pig inferior vena cava by eicosanoids.

Guinea pig inferior vena cava contracted in response to leukotriene (LT)C4, LTD4, LTE4 U46619, phenylephrine, histamine, and KCl. Although LTC4, LTD4, and U46619 were the most potent agonists, active tension generated by these eicosanoids was only about half that of histamine or KCl. LTE4 and phenylephrine were marginally active.

Sympathoadrenal, metabolic, and regional blood flow responses to cold in fetal sheep.

Because environmental temperature falls when the fetus is delivered from the uterus, the role of cold in stimulating cardiovascular and sympathoadrenal responses at the time of birth was examined in fetal lambs. In eight fetuses (gestational age 140 +/- 2 d), catheters were inserted into hind-limb and neck arteries and veins, and into an umbilical vein. After returning the fetus to the uterus and administering a muscle relaxant (succinylcholine chloride), blood gases, glucose and lactate concentrations, and plasma catecholamine and atrial natriuretic peptide concentrations were measured.

Enkephalin-containing neurons in the inferior mesenteric ganglion projecting to the distal colon of cat: evidence from combined retrograde tracing by fluorescent microspheres and immunohistochemistry.

Retrograde tracing with rhodamine fluorescent microspheres combined with fluorescein immunolabelling of methionine-enkephalin showed the presence of enkephalin-like material in neurons of the inferior mesenteric ganglion (sympathetic prevertebral ganglion) projecting to the distal colon in cat. Two weeks after injecting the microspheres into the wall of the distal colon, the inferior mesenteric ganglion was dissected out and incubated for 24 hours in a colchicine-containing culture medium in order to facilitate the detection of enkephalins in the soma of ganglion neurons. It was observed that retrogradely labelled ganglion cells contained enkephalin-like immunoreactive material.

Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist.

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.

The C/EBP family of transcriptional activators is functionally important for Ig VH promoter activity in vivo and in vitro.

We have examined the functional importance of binding sites for C/EBP family members (E sites), in two Ig VH promoters: VH1, a member of the S107 family, and BCL1, a member of the J558 family. Mutation of the E site in the VH1 promoter diminishes transcription in vivo to 59% of wild-type and transcription from the BCL1 promoter in vitro is inhibited to an average of 39% of wild-type by competition with E site oligonucleotides. Purified E site binding proteins from plasmacytoma cells stimulated BCL1 transcription in vitro 2.

Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction.

Background: Atrioventricular nodal reentrant tachycardia (AVNRT), the most common form of supraventricular tachycardia, results from conduction through a reentrant circuit comprising fast and slow atrioventricular nodal pathways. Antiarrhythmic-drug therapy is not consistently successful in controlling this rhythm disturbance. Catheter ablation of the fast pathway with radiofrequency current eliminates AVNRT, but it can produce heart block.

Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists.

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum.

Development of a series of phenyltetrazole leukotriene D4 (LTD4) receptor antagonists.

A hypothetical model for receptor binding of leukotriene D4 (LTD4) was deduced from conformational analysis of LTD4 and from the structure-activity relationships (SAR) of known LTD4 receptor antagonists. A new structural series of LTD4 receptor antagonists exemplified by 5-[4-(4-phenylbutoxy)phenyl]-2-[4-(tetrazol-5-yl)butyl]-2H-t etrazole was designed in which a phenyltetrazole moiety was incorporated as a receptor binding equivalent of the triene unit of LTD4. A number of these phenyltetrazoles were prepared and found to possess LTD4 receptor antagonist activity.

Amino acid gradients across the intestinal circulation in fetal lambs.

Amino acids, including glutamine, glutamate and asparagine are major metabolic substrates for the adult enterocyte of several species. To determine whether circulating amino acids are utilized by the fetal intestine, we studied nine fetal sheep (mean gestational age 128 +/- 5 days; term: 147 days). Catheters were inserted into the descending aorta (DA) and the mesenteric vein (MV) to allow for simultaneous blood sampling across the intestine.

mTFE3, an X-linked transcriptional activator containing basic helix-loop-helix and zipper domains, utilizes the zipper to stabilize both DNA binding and multimerization.

Southwestern (DNA-protein) screening of a murine L-cell cDNA library by using a probe for the microE3 site in the immunoglobulin heavy-chain enhancer yielded a clone, mTFE3, which is a member of the subset of basic helix-loop-helix (BHLH) proteins that also contain a leucine zipper (ZIP). Since the individual contribution of these domains is not well understood for proteins which contain them both, mutational analyses were performed to assess the functional roles of the HLH and ZIP regions for DNA binding and multimerization. The HLH region is stringently required for DNA binding but not for multimerization.

Effect of endothelium-derived relaxing factor inhibition on the umbilical-placental circulation in fetal lambs in utero.

Objective: The purpose of this study was to examine whether basal endothelium-derived relaxing factor release contributes to regulation of resting umbilical-placental vascular resistance.

Study Design: Because N omega-nitro-L-arginine selectively inhibits the synthesis of nitric oxide, a major endothelium-derived relaxing factor, we investigated the effects of N omega-nitro-L-arginine on umbilical-placental vascular resistance in 10 fetal lambs in utero. We inserted catheters and fitted an umbilical artery electromagnetic flow transducer around the common umbilical artery to measure umbilical blood flow and catheterized the left umbilical arterial hypogastric branch to allow selective umbilical-placental infusion (60 minutes) of pH-matched saline solution (control) or N omega-nitro-L-arginine.

Platelet-induced thrombin generation time: a new sensitive global assay for platelet function and coagulation. Method and first results.

A new sensitive test--platelet-induced thrombin generation time (PITT)--is described, in which the formation of thrombin in partially anticoagulated platelet-rich plasma (PRP) leads to aggregation immediately followed by coagulation of PRP. 0.6 ml PRP are rotated in a disk-shaped cuvette within the light beam of a photometer.

A dominant negative form of transcription activator mTFE3 created by differential splicing.

Transcription factor E3 (mTFE3) is a murine transcription activator that binds to the intronic enhancer of the immunoglobulin heavy chain gene. A naturally occurring splice product of mTFE3 messenger RNA (mRNA) lacked 105 nucleotides that encode an activation domain; both absolute and relative amounts of long and truncated mRNAs varied in different tissues. Cells were cotransfected with complementary DNAs that encoded the two mRNA forms in amounts that corresponded to the amounts of each mRNA found in different cells.

Effect of graded umbilical cord compression in fetal sheep at 0.6-0.7 gestation.

To define responses of immature fetuses to asphyxia, we occluded the umbilical cord of 11 chronically instrumented fetal sheep at 82-94 days gestation and measured hemodynamic and catecholamine responses. The fetuses became acidemic, hypoxemic, and hypercarbic: arterial pH and PO2 decreased from 7.36 +/- 0.

(Phenylmethoxy)phenyl derivatives of omega-oxo- and omega-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists.

Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the omega-[(phenylmethoxy)phenyl]-omega-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5- oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pKB of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.

Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current.

Background: Surgical or catheter ablation of accessory pathways by means of high-energy shocks serves as definitive therapy for patients with Wolff-Parkinson-White syndrome but has substantial associated morbidity and mortality. Radiofrequency current, an alternative energy source for ablation, produces smaller lesions without adverse effects remote from the site where current is delivered. We conducted this study to develop catheter techniques for delivering radiofrequency current to reduce morbidity and mortality associated with accessory-pathway ablation.

Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery.

We examined the effect of graded reduction in uterine blood flow on distribution of cardiac output and oxygen delivery to fetal organs and venous blood flow patterns in 9 fetal sheep using the radionuclide-labeled microsphere technique. We reduced uterine blood flow in two steps, decreasing fetal oxygen delivery to 70% and 50% of normal, and compared the results with those from a similar study from our laboratory on graded umbilical cord compression. With 50% reduction in fetal oxygen delivery, blood flow and the fraction of the cardiac output distributed to the brain, heart, and adrenal gland increased and that to the lungs, carcass, skin, and scalp decreased.

Catheter ablation of atrioventricular junction using radiofrequency current in 17 patients. Comparison of standard and large-tip catheter electrodes.

Background: Two catheter electrode systems were compared for delivering radiofrequency current for ablation of the atrioventricular junction. Seventeen patients with drug-resistant supraventricular tachyarrhythmias were studied.

Methods And Results: A 6F or 7F catheter with six or eight standard electrodes (1.

Atrial natriuretic peptide response to ionic and nonionic contrast left ventriculography.

Atrial natriuretic peptide (ANP) levels were measured prior to and at 1 and 5 minutes postcontrast left ventriculography with an ionic contrast agent (diatrizoate), and a nonionic agent (iopamidol) and the results were compared. Since ionic contrast agents have been found to cause an increase in left ventricular end-diastolic pressure (LVEDP) and nonionic agents have been found to have less of an effect on LVEDP, we investigated the response of ANP levels, which have been found to increase secondary to increased LVEDP (atrial pressure), with both agents. A group of 38 patients who were scheduled for left heart catheterization for suspected coronary artery disease was included (19 in each group) and blood samples for ANP levels were drawn from the left ventricles.

Leukotriene receptor antagonism and augmentation of beta-receptor-mediated events by LY171883.

LY171883, (1-[2-hydroxy-3-propyl-4-[4(1H-tetrazol-5-yl)butoxy)phenyl]etha none), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment beta-receptor-mediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.

Ig/EBP-1: a ubiquitously expressed immunoglobulin enhancer binding protein that is similar to C/EBP and heterodimerizes with C/EBP.

We report the isolation and characterization of cDNA clones that encode a protein with the same DNA binding specificity as the immunoglobulin heavy chain enhancer binding protein E (muEBP-E). We call the gene encoding this protein Ig/EBP-1. A fusion protein encoded by the cDNA binds specifically to muEBP-E-binding sites (E sites) in both the IgH enhancer and the VH1 promoter.

Leukotrienes C4, D4, and E4 in fetal lamb tracheal fluid.

Previously, we demonstrated that either putative leukotriene receptor antagonists or a synthesis inhibitor markedly decreased pulmonary vascular resistance in the near-term fetal lamb and concluded that leukotrienes may play a role in maintaining the high pulmonary vascular resistance in the fetus. To further investigate the role of leukotrienes, we measured concentrations of leukotriene (LT) C4, LTD4, and LTE4 in 17 tracheal fluid samples from 8 of 9 near-term (129-139 days, term = 145 days), chronically-catheterized, fetal lambs during normoxia to evaluate their possible role in regulating resting tone and in seven of the nine before and during hypoxia to evaluate their possible role in hypoxic vasoconstriction. The tracheal fluid samples collected by gravity over 1-3 min, on ice, were immediately treated with cold ethanol, centrifuged, and the supernatant covered with N2 and stored in a -70 degrees C freezer for a maximum of 3 weeks.

Fetal uptake of intraamniotic digoxin in sheep.

To explore the possibility that intraamniotic administration of digoxin is an effective treatment regimen for fetal tachyarrhythmia, we injected digoxin into the amniotic fluid cavity of pregnant sheep and examined the time course of digoxin distribution to the fetal and maternal plasma compartments. Animals were studied in two groups according to digoxin dosage: 0.7-1.