Reduced Plasma Protein Research Articles

Lack of effect of corticosteroids and tamoxifen on suramin protein binding and in vitro activity

Stout and colleagues [ Proc Am Assoc Cancer Res 1993, 34, p. 298] previously reported that both hydrocortisone and tamoxifen increased the free fraction of suramin in human plasma. We examined several corticosteroids as well as tamoxifen for their effects on suramin protein binding and also evaluated hydrocortisone for its ability to modulate suramin activity in PC-3 and MCF-7 cells. Greater than 99% of the suramin was protein bound in undiluted human plasma. However, the free fraction of suramin was increased with the reduced plasma protein levels and increased suramin concentrations. At concentrations ranging from 1 to 30 μM, neither tamoxifen, hydrocortisone, prednisone nor dexamethasone had any effect on the binding of suramin to human plasma, regardless of protein concentrations. Similar results were observed with fetal calf serum. Hydrocortisone also had no effect on suramin activity against PC-3 and MCF-7 cell in vitro. We conclude from these studies that neither corticosteroids nor tamoxifen affect suramin protein binding or its cytotoxic activity.

Simultaneous measurement of plasma protein extravasation and carotid vascular resistance in the rat

Stimulation of the right trigeminal ganglion in pentobarbital anaesthetised rats increased mean arterial blood pressure and decreased right carotid vascular resistance but had no effect on left carotid vascular resistance. Sumatriptan (0.3 mg/kg i.v.) pretreatment did not significantly affect basal levels or stimulation induced changes in blood pressure or carotid vascular resistance. Trigeminal stimulation produced plasma protein extravasation (measured using a fluorescent marker) into the dura mater on the ipsilateral side which was significantly reduced by sumatriptan. These studies show that sumatriptan can reduce plasma protein extravasation while having no measurable effect on total carotid blood flow.

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Theophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedure, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described. Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter. Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes. Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

Identification of Eight Point Mutations in Protein S Deficiency Type I – Analysis of 15 Pedigrees

We described molecular genetic studies of 15 patients with protein S deficiency type I (i.e. reduced total protein S antigen). All the exons of the PROS 1 gene were analyzed both by PCR and direct sequencing in all 15 probands. This analysis led to the identification of point mutations affecting eight individuals. One of these mutations (codon-25, insertion of T) has been described previously in a Dutch pedigree. The other mutations are novel and all are located in exons that code for the protein S domain that is homologous to the steroid hormone binding globulins. They include two amino acid replacements (one individual with 340 Gly--> Val, and two individuals with 467 Val --> Gly), and four frameshift mutations due to either one bp deletions (in codon 261 deletion of T and in codon 267 deletion of G) or insertions (in codon 565 insertion T and after codon 578 insertions of C). Studies performed in six families (totalling 43 subjects) showed cosegregation of the genetic abnormality with reduced plasma protein S levels, and provided genetic evidence for a heterozygous protein S deficiency in 25 of them. The yield of mutations in this study (53%) confirms that the percentage of protein S deficient cases in which a point mutation is found remains low.

Pharmacokinetics in children.

The first year of life is associated with major changes in the processes affecting the absorption, distribution, metabolism and excretion of drugs. Drug absorption by the oral route is affected by reduced gastric emptying so that this route is unreliable in the neonate. The intramuscular route is also unreliable but transdermal absorption is often greater, with risks of toxicity. The volume of distribution of many drugs is often markedly increased in the neonate, partly because of reduced plasma protein binding (both to albumin and to alpha-1-acid glycoprotein) but also because of an increased volume of extracellular fluid relative to total body water. These factors both result in increased half-life of elimination of drugs. Metabolic processes are often immature at birth and this results in reduced clearance rates and prolonged half-life of elimination of those drugs for which metabolism is a significant mechanism for elimination. Renal excretion in the newborn is reduced although glomerular filtration rate (a passive process) and active tubular secretory rate increase relatively rapidly during infancy. Since these processes tend to be the most important drug elimination mechanism for antibiotics, dose adjustment is particularly important; methods using calculated glomerular filtration rate and the role of therapeutic drug monitoring are described. Finally, the pharmacokinetic processes develop at different rates during the first year of life and an understanding of these factors can help in the safe and effective prescribing of antibiotics.

Photochemical inactivation of pathogenic bacteria in human platelet concentrates

Platelet concentrates (PC) may be infrequently contaminated with low levels of bacteria that can cause septicemia and death in patients receiving transfusion therapy. We evaluated the efficacy of a photochemical decontamination (PCD) technique using 8-methoxypsoralen (8-MOP) and long wavelength UV light (UVA) to inactivate bacteria in standard therapeutic PC. Twelve phylogenetically distinct pathogenic bacteria, 5 gram-positive and 7 gram-negative organisms, were seeded into PC to a final challenge dose ranging from 10(5) to 10(7) colony- forming units (CFU)/mL. Contaminated PC were treated with 8-MOP (5 micrograms/mL) and 5 J/cm2 of UVA, a PCD treatment regimen found to adequately preserve in vitro platelet function. Greater than 10(5) CFU/mL of all 5 gram-positive (Staphylococcus aureus, Streptococcus epidermidis, Streptococcus pyogenes, Listeria monocytogenes, and Corynebacterium minutissimum) and 2 of the gram-negative (Escherichia coli and Yersinia enterocolitica) organisms were inactivated. The remaining 5 gram-negative organisms were more resistant, with less than 10(1) to 10(3.7) CFU/mL inactivated under these conditions. The inactivation efficiency for this resistant group of gram-negative organisms was improved when PC were resuspended in a synthetic storage medium with reduced plasma protein concentration (15%) and an increased 8-MOP concentration (23.4 micrograms/mL). Illumination with 3 J/cm2 of UVA in this system inactivated greater than 10(5) CFU/mL of 4 resistant gram-negative organisms (Salmonella choleraesuis, Enterobacter cloacae, Serratia marcescens, and Klebsiella pneumoniae) and 10(4.1) CFU/mL of the most resistant gram-negative organism (Pseudomonas aeruginosa). This level of PCD treatment did not adversely affect in vitro platelet function. These results demonstrate that PCD using 8-MOP (5 to 23.4 micrograms/mL) effectively inactivated high levels of pathogenic bacteria in PC with adequate preservation of in vitro platelet properties.

Photochemical Inactivation of Pathogenic Bacteria in Human Platelet Concentrates

AbstractPlatelet concentrates (PC) may be infrequently contaminated with low levels of bacteria that can cause septicemia and death in patients receiving transfusion therapy. We evaluated the efficacy of a photochemical decontamination (PCD) technique using 8-methoxypsoralen (8-MOP) and long wavelength UV light (UVA) to inactivate bacteria in standard therapeutic PC. Twelve phylogenetically distinct pathogenic bacteria, 5 gram-positive and 7 gram-negative organisms, were seeded into PC to a final challenge dose ranging from 105 to 107 colony-forming units (CFU)/mL. Contaminated PC were treated with 8-MOP (5 μg/mL) and 5 J/cm2 of UVA, a PCD treatment regimen found to adequately preserve in vitro platelet function. Greater than 105 CFU/mL of all 5 gram-positive (Staphylococcus aureus. Streptococcus epid-ermidis, Streptococcus pyogenes. Listeria monocytogenes, and Corynebacterium minutissimum) and 2 of the gram-negative (Escherichia coli and Yersinia enterocolitica) organisms were inactivated. The remaining 5 gram-negative organisms were more resistant, with less than 101 to 103.7 CFU/mL inactivated under these conditions. The inactivation efficiency for this resistant group of gram-negative organisms was improved when PC were resuspended in a synthetic storage medium with reduced plasma protein concentration (15%) and an increased 8-MOP concentration (23.4 μg/mL). Illumination with 3 J/cm2 of UVA in this system inactivated greater than 105 CFU/mL of 4 resistant gram-negative organisms [Salmonella choleraesuis, Enterobacter cloacae, Serratia marcescens, and Klebsiella pneumoniae) and 104.1 CFU/mL of the most resistant gram-negative organism (Pseudomonas aeruginosa). This level of PCD treatment did not adversely affect in vitro platelet function. These results demonstrate that PCD using 8-MOP (5 to 23.4 μg/mL) effectively inactivated high levels of pathogenic bacteria in PC with adequate preservation of in vitro platelet properties.

Disruption of a binding site for hepatocyte nuclear factor 1 in the protein C gene promoter is associated with hereditary thrombophilia.

A heterozygous T-->C transition was detected in the putative promoter region of the protein C (PROC) gene in a patient with type I protein C deficiency and a history of recurrent venous thrombosis. This mutation occurred 14 bp upstream of the transcription initiation site and within a sequence strongly homologous to the consensus binding site for the liver-enriched transcription factor, hepatocyte nuclear factor 1 (HNF-1). Transfection experiments demonstrated that a CAT reporter gene construct containing 626 bp of the putative PROC gene promoter was capable of driving CAT expression in HepG2 hepatoma cells. Levels of CAT expression from constructs bearing the mutation were found to be drastically reduced by comparison with the wild-type, consistent with the reduced plasma protein C antigen levels observed in the patient. Gel retardation and cotransfection experiments demonstrated that the mutation abolished both the binding and the transactivating ability of HNF-1 observed with the wild-type PROC gene promoter. Further, the ability of the mutation to disrupt HNF-1 binding appears to be a function not only of the nature of the nucleotide substitution and its position within the recognition sequence, but also of the relative affinity of the wild-type binding site for HNF-1. This analysis is therefore indicative of a vital role for HNF-1 in the expression of the PROC gene in vivo. Taken together with the identification of a human hepatoma cell line which contains HNF-1 but which does not express protein C, these findings are consistent with the view that HNF-1 is necessary although not sufficient for PROC gene expression in the liver.

Preparation of sterically stabilized human serum albumin nanospheres using a novel Dextranox-MPEG crosslinking agent.

Human serum albumin (HSA) nanospheres with a size less than 200 nm in diameter were prepared using a modified coacervation method and crosslinking with methyl polyethylene glycol modified oxidized Dextram (Dextranox-MPEG) which created a sterically stabilizing polyethylene oxide surface layer surrounding the nanospheres. The crosslinking efficiency and the surface characteristics of glutaraldehyde and Dextranox-MPEG crosslinked HSA nanospheres were determined and compared. The zeta potential of the Dextranox-MPEG crosslinked particles was significantly lower than that of glutaraldehyde stabilized particles. The existence of a hydrated steric barrier surrounding the nanospheres was confirmed by an electrolyte and pH induced flocculation test. The Dextranox-MPEG crosslinked nanospheres showed a significantly reduced plasma protein adsorption on the particle surface compared with glutaraldehyde crosslinked nanospheres.

Clinical pharmacokinetics of alprazolam. Therapeutic implications.

Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 micrograms/L for each daily dosage change of 1 mg/day. Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women. Coadministration of cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin. Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 micrograms/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoproteinemia slows lung liquid clearance in young lambs

To determine whether hypoproteinemia slows the rate at which liquid is cleared from the lung lumen, we studied 36 lambs, 18 of which underwent repeated plasmapheresis, reducing plasma protein concentration by 37% and plasma protein osmotic pressure by 39%. We killed 29 lambs (14 hypoproteinemic and 15 normoproteinemic) and removed their lungs 1, 2, or 6 h after intratracheal instillation of isotonic saline (6 ml/kg body wt). We measured extravascular lung water and determined the percentage of tracheally instilled liquid that was cleared from the lungs by comparison with control lambs that did not receive saline into their airways. The percent liquid cleared from the lungs after 1 and 2 h was significantly less in hypoproteinemic than in normoproteinemic lambs (37 vs. 65% at 1 h, 58 vs. 75% at 2 h, respectively). By 6 h nearly all the liquid (> 92%) was cleared from the lungs of all lambs. Thus hypoproteinemia slows the initial rate of clearance of liquid from the lungs of lambs. To determine whether reduced plasma protein osmotic pressure might redirect this liquid into lung lymphatics, we measured lung lymph flow (Q1) in five lambs (7.7 +/- 1.4 kg, 19 +/- 4 days old) for > or = 2 h before and 6 h after tracheal instillation of saline. In each lamb, paired studies were done 3-6 days apart; between studies the lambs underwent plasmapheresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in anion gap following cardiopulmonary bypass

To evaluate the changes in the anion gap and their relation to hyperlactatemia and alterations in plasma proteins after cardiopulmonary bypass. Prospective study. Cardiothoracic intensive therapy unit. One hundred eleven consecutive patients after cardiopulmonary bypass. Data were collected before cardiopulmonary bypass and every 6 hrs for 24 hrs after cardiopulmonary bypass. Results were analyzed for the entire cohort and for hyperlactatemic subgroups. The major finding of this study was that the anion gap decreased significantly at all sampling periods relative to precardiopulmonary bypass values, despite the presence of clinically important hyperlactatemia. No correlation between the decrease in plasma protein concentrations and the decrease in anion gap could be demonstrated. The decrease in anion gap after cardiopulmonary bypass appears to represent a balance between the influences of increased serum chloride and lactate concentrations and reduced plasma protein concentrations. This analysis demonstrates the limitations of the anion gap in the evaluation of a metabolic acidosis after cardiopulmonary bypass.

Influence of the plasma protein concentration on renal function

1. The effect of the plasma protein concentration on renal function remains controversial. Most, but not all, experimental studies suggest that a reduced plasma protein concentration perfusing the kidney may reduce tubular sodium reabsorption. Hypoproteinaemic disease states are usually associated with sodium retention, which is not always volume-dependent. 2. We induced a 21% and 24% reduction in plasma total protein and plasma albumin, respectively, in unanaesthetized sheep by acute extracorporeal plasmapheresis. Arterial pressure did not change, and changes in circulatory volume were minimised by infusion of crystalloid to maintain pulmonary artery occlusion pressure, measured using a Swann-Ganz pulmonary artery catheter. 3. After plasmapheresis, there was no significant change in creatinine clearance, sodium excretion, plasma renin activity or urinary kallikrein excretion. 4. After plasmapheresis, there was no significant reduction in plasma osmolality, increase in urine osmolality and fall in free water clearance. 5. The results suggest that in the absence of detectable changes in circulating volume or arterial pressure, acute hypoproteinaemia is associated with significant changes in renal water handling, but has no direct effect on sodium excretion or on renal release of renin and kallikrein.

Plasma protein binding of bupivacaine in pregnant women at term

The increased toxicity of bupivacaine in parturients is a well-known phenomenon. The reduced plasma protein binding of bupivacaine is one of the possible reasons. Therefore, we measured the free fraction of bupivacaine in plasma samples of parturients and non-pregnant volunteers. The free fraction was significantly higher in parturients (8.2% vs 5.4%) associated with a lower concentration of the alpha-1-acid glycoprotein (0.42 vs 1.01 g/l) and a higher concentration of progesterone (156 vs 0.4 ng/ml). The addition of progesterone to plasma samples of non-pregnant volunteers did not influence the free fraction of bupivacaine, whereas the addition of alpha-1-acid glycoprotein to the plasma of parturients decreased the free fraction significantly. Therefore, the lower concentration of this protein is the principal reason for the higher free fraction of bupivacaine in pregnancy and possibly one of the causes of the higher incidence of toxic side effects of bupivacaine in obstetric use.

Preclinical toxicology of the anticonvulsant calcium valproate

The oral toxicity of the anticonvulsant calcium valproate with selected comparisons to valproic acid and sodium valproate was evaluated in mice, rats and Beagle dogs. Median lethal doses of the three forms of valproate in rodents ranged from 1100 to 3900 mg/kg. Clinical signs in acute studies and reductions in body weight or body weight gain and food consumption at high doses in rats and dogs during 2-, 13- and 52-week studies were considered to be central nervous system related. In the 13-week study in rats (calcium valproate at 200, 400, 800, 1200 and 1600 mg/kg and sodium valproate at 1200 mg/kg), reduced plasma globulin levels and low white blood cell counts due to suppressed neutrophil maturation were noted at doses of 800 mg/kg and higher. Platelet counts were reduced at 1200 and 1600 mg/kg. Testicular atrophy occurred at 1200 and 1600 mg/kg. In dogs given calcium valproate at 100, 200 and 400 mg/kg for 13 weeks, testicular atrophy was seen at 400 mg/kg and mild hepatocellular changes at all doses. In rats given calcium valproate at 125, 250 and 500 mg/kg for 1 year, reduced plasma protein and globulin levels and a dose-dependent increased incidence and severity of atrophic pancreatitis were noted at 250 and 500 mg/kg. Calcium valproate, given for 1 year to dogs at doses of 50, 100 and 200 mg/kg, was well tolerated. These studies indicated that calcium valproate has a toxicity profile similar to other forms of valproate.

Protein C : Rouen, a new hereditary protein C abnormality with low anticoagulant but normal amidolytic activities

A family is described in which venous thrombo-embolic disease is associated with reduced plasma protein C anticoagulant activity but normal levels of protein C amidolytic activity and antigen. The partial characterization of the heterozygous defect is described using crossed immunoelectrophoresis (CIE) with or without calcium and seven functional assays which differ by activators (thrombin-thrombomodulin complex, bovine thrombin and Protac snake venom) and by an eventual preliminary adsorption on insoluble salts. PC activity was thereafter determined either by chronometric or amidolytic assays. The results indicate that this abnormal protein C (PC) is normally activated and at least partially carboxylated. Three hypothesis are proposed to explain the discrepancy between normal amidolytic and low anticoagulant activities.

A Mutation in the Protein S Pseudogene Is Linked to Protein S Deficiency in a Thrombophilic Family

Probands from 15 unrelated families with hereditary protein S deficiency type I, that is having a plasma total protein S concentration fifty percent of normal, were screened for abnormalities in their protein S genes by Southern analysis. Two probands were found to have a deviating DNA pattern with the restriction enzyme MspI. In the two patients the alteration concerned the disappearance of a MspI restriction site, CCGG, giving rise to an additional hybridizing MspI fragment. Analysis of relatives of both probands showed that in one family the mutation does not co-segregate with the phenotype of reduced plasma protein S. In the family of the other proband, however, complete linkage between the mutated gene pattern and the reduced total protein S concentration was found: 12 heterozygous relatives showed the additional MspI fragment but none of the investigated 26 normal members of the family. The mutation is shown to reside in the PS beta gene, the inactive protein S gene. The cause of type I protein S deficiency, a defect PS alpha gene has escaped detection by Southern analysis. No recombination has occurred between the PS alpha gene and the PS beta gene in 23 informative meioses. This suggests that the two protein S genes, located near the centromere of chromosome 3, are within 4 centiMorgan of each other.

The role of albumin in nutritional support.

Hypoalbuminemia is considered one of the hallmarks of protein-calorie malnutrition and chronic liver disease. Recently, serum albumin has also been proposed as a critical predictor of the response to nutritional support and tolerance to enteral feeding in critically ill patients. Albumin is essential for maintenance of plasma colloidal osmotic pressure, prevention of edema, and transport of certain drugs and nutrients. Experimental studies have shown that rapid plasma expansion and reduced plasma protein concentration and osmotic pressure induce a net secretion of sodium and water into the small intestinal lumen. However, the effects of chronic hypoalbuminemia per se on intestinal absorption, independent of malnutrition, have not been fully studied. It is documented that both chronic illness and malnutrition may profoundly affect intestinal anatomical structure and function, inducing some degree of malabsorption. In the last few years, some have advocated albumin infusion to improve clinical response to patients with hypoalbuminemia receiving parenteral nutritional support or to reduce intestinal intolerance and diarrhea in patients receiving enteral tube feeding. A review of the literature shows that both clinical and experimental data to support these suggestions are scarce and further investigations are needed. Hypoalbuminemia is one of many parameters of malnutrition, and it is unlikely that correction of a single parameter for a short time would lead to major clinical benefits.

Long-term hypotensive effect of beta-agonist in conscious dogs.

The purpose of this study was to investigate the arterial pressure response to long-term administration of beta-agonists in the chronically instrumented conscious animal model. Chronically instrumented dogs were given intravenous infusions of ritodrine (2 micrograms.kg-1.min-1) for a period of 2 wk. Several cardiovascular and renal parameters were monitored before, during, and after the ritodrine infusion, and renal function curves were constructed. After the 1st wk of infusion, a new steady state was reestablished, and this was characterized by hypotension, reduced plasma protein concentration, elevated cardiac output, expanded extracellular fluid space, and near normal levels of activity of renin-angiotensin-aldosterone systems. The renal function curve during ritodrine infusion shifted to the left with no change in slope. We propose the following: 1) the persistence of hypotension is most probably related to the resetting of the arterial pressure-kidney blood volume servocontrol mechanisms, and 2) the persistent elevation of cardiac output and reduction in peripheral resistance are most probably related to increased oxygen and nutrient demand during beta-agonist infusions.

MB1, a quail leukocyte/vascular endothelium antigen: characterization of the lymphocyte-surface form and identification of its secreted counterpart as α2-macroglobulin

A monoclonal antibody (α-MB1) binds to a cell surface marker expressed throughout ontogeny and adult life by vascular endothelial and hemopoietic cells of the quail, with the exception of erythrocytes, although it was raised against the heavy chain of quail immunoglobulin M. In addition to an 80 kDa polypeptide accounting for immunoglobulin μ chain, α-MB1 stains intensely a 180-kDa band on Western blots of reduced plasma proteins. We have previously characterized MB1 antigens of quail endothelial cells as glycoproteins of apparent molecular masses ranging from 80 to 200 kDa and provided evidence for the participation of vascular endothelium in the secretion of α-MB1-positive plasma components. We demonstrate here that this circulating material is the proteinase inhibitor α 2-macroglobulin. Furthermore, the MB1 antigens immunoprecipitated from lymphocytes are shown to be essentially similar to their endothelial counterparts, suggesting that the same molecular complex is expressed by all the elements of the hemangioblastic cell lineage. Finally, the cross reactivity of the α-MB1 antibody with immunoglobulin μ chain is confirmed and shown to occur via a carbohydrate epitope.