Lack of endothelin ETB receptor-mediated smooth muscle hyperpolarization in rat mesenteric resistance arteries.

The presence of functional endothelin ETB receptors was investigated in rat isolated mesenteric resistance arteries. Neither endothelin-3 (0.1-100 nM) nor the endothelin ETB selective agonists sarafotoxin S6c and BQ 3020 (both 1-100 nM) induced any measurable hyperpolarization or relaxation in stimulated (alpha 1-adrenoceptor agonist; phenylephrine) or unstimulated arteries.

New low-density lipoprotein receptor upregulators acting via a novel mechanism.

The synthesis and biological activity of a new series of benzamides and related compounds that upregulate the expression of the low-density lipoprotein (LDL) receptor in human hepatocytes (HepG2 cells) by a novel mechanism are described. The lead compound, N-[5-[(3-cyclohexylpropionyl)amino]-2-methylphenyl]-4-hydroxybe nzamide (1, RPR102359), increased the expression of the LDL receptors in HepG2 cells by 80% when tested at a concentration of 3 microM. Mevinolin (lovastatin) was found to increase the LDL receptor expression by 70% at the same concentration.

Human central nervous system myelin inhibits neurite outgrowth.

In vitro and animal studies have identified molecules in mammalian CNS myelin which inhibit neuritic extension and which may be responsible, at least in part, for the lack of axonal regeneration after injury in the injured brain, optic nerve and spinal cord. To determine whether such inhibitory activity may be present in human CNS myelin, we used a bioassay to characterize neurite outgrowth on this substrate. Human CNS myelin strongly inhibited neuritic outgrowth from newborn rat dorsal root ganglion neurons and NG-108-15 cells, a neuroblastoma-glioma hybrid cell line.

A convenient in vitro assay for the inhibition of neurite outgrowth by adult mammalian CNS myelin using immortalized neuronal cells.

The adult mammalian CNS contains molecules which inhibit neurite outgrowth and which may be responsible for the lack of successful axonal regeneration after injuries in the brain and spinal cord. We describe an in vitro assay to measure the ability of primary and established lines of neuronal cells to produce neurites in the presence of CNS inhibitory molecules. The assay is suitable for identification of agents and treatments to overcome neurite growth inhibition.

An antineuronal monoclonal antibody that reverses neurite growth inhibition by central nervous system myelin.

A component of adult mammalian central nervous system (CNS) myelin causes collapse of neuronal growth cones and inhibits axonal growth, properties that may be responsible for the lack of regrowth of injured axons in the CNS. The molecules and detailed mechanism through which the inhibitory activity acts are not known. To study the cellular molecules mediating the response to this inhibitor, we have used an in vitro neurite growth inhibition assay to screen a panel of monoclonal antibodies raised against rat neuronal membrane proteins, for clones capable of blocking the response.

Transgenic neural plate contributes neuronal cells that survive greater than one year when transplanted into the adult mouse central nervous system.

Neural plate cells from the early embryo may have a number of important advantages as donor material for the delivery of foreign genes into the diseased adult central nervous system (CNS). Mesencephalic neural plate from transgenic GT4-2 mice was used as a source of marked donor cells to determine whether transgene-expressing embryonic CNS progenitor cells can be used as donor material for implantation into the adult mouse brain. Transgenic mouse embryos from this line express the Escherichia coli beta-galactosidase (beta-gal) gene throughout early CNS development.

Regulation of intracellular calcium and preprotachykinin neurotransmitter precursor gene expression by patterned electrical stimulation in rat sympathetic neurons.

Experiments were performed to test several predictions of the hypothesis that activity pattern-dependent changes in intracellular free calcium concentration ([Ca2+]i) might play a role in the translation of altered patterns of neuronal activity into changes in neurotransmitter gene expression. It was shown that (1) the Ca2+ channel blocker cadmium prevented depolarization-induced preprotachykinin-I (PPT-I) gene repression in rat sympathetic neurons; (2) the magnitudes of transient rises in [Ca2+]i were dependent upon the pattern in which a fixed number of depolarizing stimuli were delivered; and (3) stimulation at 10 Hz for 24 h did not repress PPT-I mRNA, while the same number of pulses delivered in 0.2 s bursts of 50 Hz caused a highly significant reduction to 30 +/- 2.

Sarafotoxin S6c elicits a non-ETA or non-ETB-mediated pressor response in the pithed rat.

Sarafotoxin S6c (Sx6c) is reported to evoke depressor and pressor effects via activation of endothelin (ET) ETB receptors located on the endothelium and smooth muscle, respectively. We have examined the effects of the selective ETB receptor antagonist BQ 788 on the fall and rise in diastolic blood pressure induced by Sx6c (1 nmol/kg, i.v.

Effect of endothelin antagonists with or without BQ 788 on ET-1 responses in pithed rats.

The overall effects of endothelin-1 (ET-1) on blood pressure are caused by a composite activation of constrictor ETA and ETB receptors and dilator ETB receptors. Therefore, it is difficult to accurately compare the ETA activity of selective ETA receptor antagonists (BQ 123 and BMS 182874) with mixed ETA/ETB antagonists (SB 209670 and bosentan) on the cumulative dose-response curve to ET-1. The development of a selective ETB antagonist (BQ 788), which inhibits both the dilator and constrictor ETB receptors, offered the opportunity to investigate the role of ETB receptors in the response to exogenous ET-1 in the pithed rat.

Cromakalim does not protect against skeletal muscle fatigue in an anaesthetized rat model of acute hindlimb ischaemia.

The effects of the potassium (K+) channel opener, cromakalim, on skeletal muscle performance were studied in a model of acute hindlimb ischaemia in the anaesthetized rat. Twitch contractions to direct electrical stimulation of the extensor digitorum and tibialis anterior skeletal muscles were recorded following administration of cromakalim (10-100 micrograms kg-1 i.v.

Cefamandole versus cefazolin in vascular surgical wound infection prophylaxis: cost-effectiveness and risk factors.

Purpose: Recent studies of perioperative antimicrobial prophylaxis have indicated an improved efficacy of beta-lactamase-stable cephalosporins compared with cefazolin, the most commonly used prophylactic agent. Previous studies in our institution have revealed a superiority of cefamandole to cefazolin in patients undergoing heart surgery, although there was no difference between cefazolin and cefuroxime in patients undergoing peripheral vascular surgery. This study was therefore designed to compare cefamandole with cefazolin in wound infection prophylaxis in clean vascular surgery.

The effect of NG-nitro-L-arginine methyl ester upon basal blood flow and endothelium-dependent vasodilatation in the dog hindlimb.

1. The role played by the endothelium-derived relaxing factor (EDRF), nitric oxide (NO) in the regulation of blood flow to the skeletal muscle vasculature of the dog skinned hindlimb has been determined by examining the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) upon (i) basal iliac artery blood flow, (ii) vasodilator responses to endothelium-dependent and -independent agonists and (iii) reactive hyperaemic responses to arterial occlusion. 2.

Comparison of the effects of efaroxan and glibenclamide on plasma glucose and insulin levels in rats.

The effect of efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.

Selectivity profile of the alpha 2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat.

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.

Prophylaxis of atrial fibrillation with magnesium sulfate after coronary artery bypass grafting.

Ninety-nine consecutive consenting patients were prospectively entered into a randomized, double-blind, placebo-controlled trial to determine the efficacy of postoperative magnesium therapy on the incidence of cardiac arrhythmias after elective coronary artery bypass grafting. No patient had documented or suspected arrhythmias preoperatively. Forty-nine patients received 178 mEq of magnesium given over the first 4 postoperative days, and 50 patients received only placebo.

HIV seroprevalence among childbearing women in Connecticut.

A seroprevalence survey of human immunodeficiency virus (HIV) among childbearing women in Connecticut is being conducted as one of the family of HIV seroprevalence surveys funded by the Centers for Disease Control (CDC). Between 1 April 1989 and 30 March 1990 dried blood specimens submitted from all newborns (45,890) for metabolic screening were examined for HIV antibodies by standard laboratory techniques in a blinded manner. The overall HIV prevalence rate was 0.

Regulation of myelin basic protein gene transcription in normal and shiverer mutant mice.

We describe the measurement of myelin basic protein gene transcription rate, and of the accumulation of both mature mRNA and total transcripts from the myelin basic protein gene in brains from mice of wild-type and homozygous shiverer genotypes at several ages spanning postnatal development. In wild-type brains the accumulation of total transcripts as well as mature mRNA, and the transcription rate, all follow the same general pattern of rising sharply from a low level at birth to a peak at 20 days, and continuing at a somewhat reduced level into adulthood. Thus a major factor in the developmental regulation of myelin basic protein expression is the control of transcription rate.

Antibiotic therapy in septic shock.

Septic shock is a life-threatening illness characterized by hypotension, impaired organ function and/or failure, and metabolic abnormalities. Septic shock can develop in patients infected with a variety of gram-positive and gram-negative bacteria, viruses, fungi, rickettsiae, spirochetes, protozoa, and parasites. Immediate recognition, diagnosis, and treatment are key elements in reducing the morbidity and mortality associated with this condition.

Alpha 2-adrenoceptor antisecretory responses in the rat jejunum.

1. Addition of noradrenaline (5 microM), UK-14,304 (0.1 microM) or phenylephrine (100 microM) to the serosal surface of sheets of rat jejunum mounted in Ussing type chambers decreased resting transepithelial short circuit current (SSC).

Selecting cost-effective antimicrobial prophylaxis in surgery: are we getting what we pay for?

The acquisition, administration, and infection-related expenses associated with the use of cefazolin or cefamandole during a prospective randomized comparison of antimicrobial prophylaxis in cardiac surgery were compared. Although the acquisition cost and administration charges related to the use of cefamandole were in excess of those incurred with cefazolin, differences in the charges associated with treating the wound infections that failed prophylaxis with each regimen made cefamandole the more cost-effective prophylactic agent (mean total of $766 per cefazolin recipient vs. $315 per cefamandole recipient).

Post-transcriptional events are responsible for low expression of myelin basic protein in myelin deficient mice: role of natural antisense RNA.

Myelin deficient mice (mld) are characterized by tandem duplication of the gene coding for myelin basic protein (MBP). The upstream gene contains a large inversion of the 3' region which includes exons 3-7, and therefore it cannot give rise to mature mRNA and functional protein. MBP and MBP mRNA concentrations in mld brains constitute only approximately 2% of the concentrations present in normal mice.

Heteroaromatic analogues of the alpha 2-adrenoreceptor partial agonist clonidine.

A 1,4-dioxane analogue (1) of the alpha 2-adrenoreceptor partial agonist clonidine (2) has previously been shown to possess an interesting but complex pharmacological profile. In this study, from a series of other heterocyclic analogues of clonidine, the 1,4-oxazines 6 and 12 were found to resemble 1 in that they are partial alpha 2-agonists in the periphery and are excluded from the central nervous system. However, when given directly into the brain, they behave as pure alpha 2-antagonists.