Neuromuscular actions of endothelin on smooth, cardiac and skeletal muscle from guinea-pig, rat and rabbit

The peptide endothelin (human, porcine) was investigated for effects on basal muscle tone and on responses to transmural nerve stimulation in a series of smooth muscle preparations, as well as in guinea-pig atrium and rat and guinea-pig diaphragm. Endothelin lacked effect on basal tone or on spontaneous and electrically driven contractions in skeletal and atrial muscle. It contracted guinea-pig ileum, pulmonary and femoral arteries, rat anococcygeus, vas deferens and urinary bladder and rabbit taenia coli, whereas guinea-pig taenia was relaxed. Guinea-pig urinary bladder and vas deferens and rabbit iris sphincter were unaffected up to 3 x 10(-8) M. Endothelin thus has a unique pattern of smooth muscle effects, exhibiting mostly contractile but also relaxing effects. Endothelin modified contractile responses to transmural nerve stimulation, yielding marked and persistent enhancement, in guinea-pig and rat vas deferens, and enhancement also in guinea-pig pulmonary artery. In guinea-pig and rat vas deferens the response to exogenous ATP was increased by endothelin, thus suggesting a strong post-junctional enhancement of neurotransmission. In guinea-pig ileum nerve-induced responses were inhibited by endothelin, whereas exogeneous acetylcholine was enhanced, an effect suggesting a simultaneous pre-junctional inhibition and post-junctional enhancement. The Ca2+ channel blocker felodipine counteracted the stimulatory effects of endothelin on tone and transmurally induced contractions. Tachyphylaxis to endothelin action was sometimes evident, but the anococcygeus being less prone to this might be useful for studies on endothelin antagonism. Endothelin thus has prominent post-junctional, and also probably pre-junctional, effects, lending further support for a distinct biological role of this peptide.     

Evolution of neurotransmitter receptor systems

The presence of hormones, neurotransmitters, their receptors and biosynthetic and degradative enzymes is clearly not only associated with the present and the recent past but with the past several hundred million years. Evidence is mounting which indicates substantial conservation of protein structure and function of these receptors and enzymes over these tremendous periods of time. These findings indicate that the evolution and development of the nervous system was not dependent upon the formation of new or better transmitter substances, receptor proteins, transducers and effector proteins but involved better utilization of these highly developed elements in creating advanced and refined circuitry. This is not a new concept; it is one that is now substantiated by increasingly sophisticated studies. In a 1953 article discussing chemical aspects of evolution (Danielli, 1953) Danielli quotes Medawar, "... endocrine evolution is not an evolution of hormones but an evolution of the uses to which they are put; an evolution not, to put it crudely, of chemical formulae but of reactivities, reaction patterns and tissue competences." To also quote Danielli, "In terms of comparative biochemistry, one must ask to what extent the evolution of these reactivities, reaction patterns and competences is conditional upon the evolution of methods of synthesis of new proteins, etc., and to what extent the proteins, etc., are always within the synthetic competence of an organism. In the latter case evolution is the history of changing uses of molecules, and not of changing synthetic abilities." (Danielli, 1953). Figure 4 outlines a phylogenetic tree together with an indication of where evidence exists for both the enzymes that determine the biosynthesis and metabolism of the cholinergic and adrenergic transmitters and their specific cholinergic and adrenergic receptors. This figure illustrates a number of important points. For example, the evidence appears to show that the transmitters and their associated enzymes existed for a substantial period before their respective receptor proteins. While the transmitters and enzymes appear to exist in single cellular organisms, there is no solid evidence for the presence of adrenergic or cholinergic receptors until multicellular organisms where the receptors appear to be clearly associated with specific cellular and neuronal communication (Fig. 4). One can only speculate as to the possible role for acetylcholine and the catecholamine in single cell organisms.(ABSTRACT TRUNCATED AT 400 WORDS)     

Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection

In chronically HIV infected individuals, a number of functional B cell abnormalities have been described. However, the immediate changes that occur in the B cell compartment following viral exposure and how they affect the long-term course of infection are not well understood. We report the longitudinal analysis of B cell repertoires during early infection in untreated and treated individuals receiving highly active antiretroviral therapy (HAART). Analysis was based on IgG heavy chain gene utilization and CDR3 length measurement and relationship with CD4/CD8 counts, viral load, and total serum IgG, and anti-HIV antibodies levels. Repertoires were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. The findings indicate a stable peripheral B cell repertoire during the first 72 weeks following infection, particularly in the HAART treated patients. A modest association between B cell repertoire integrity and viremia levels as well as treatment was detected.     

Decreased phenylalanine uptake and turnover in patients with vitiligo

The human epidermis has the full machinery for autocrine L-phenylalanine turnover to L-tyrosine in keratinocytes and melanocytes. Phenylalanine hydroxylase (PAH) activities increase linearly with inherited skin colour (skin phototype I-VI, Fitzpatrick classification) yielding eightfold more activities in black skin compared to white skin. Moreover, UVB irradiation (1 MED) significantly increases epidermal PAH activities 24 h after exposure. Importantly, L-phenylalanine uptake and turnover in the pigment forming melanocytes is vital for initiation of melanogenesis. In this context it was shown that the uptake of this amino acid is regulated by calcium. The depigmentation disorder vitiligo provides a unique model to follow impaired L-phenylalanine turnover in the skin as well as in serum because affected individuals hold an impaired epidermal 6BH4 de novo synthesis/recycling and regulation including low epidermal PAH activities. After overnight fasting and oral loading with L-phenylalanine (100 mg/kg body weight), 29.6% of 970 patients tested (n=287/970) yielded serum phenylalanine/tyrosine ratios >or=4 and 35.3% (n=342/970) had mild to moderate hyperphenylalaninaemia (HPA), while 9.3% (n=90/970) had both serum L-phenylalanine levels >or=2.0 mg/dl and phe/tyr ratios >or=4.0. Isolated HPA was found in 26% (n=252/970), whereas 20.3% had only increased ratios (n=197/970). None of the patients had phenylketonuria and the family history for this metabolic disease was negative. The IQ followed normal Gaussian distribution. In vitro L-phenylalanine uptake/turnover studies on primary epidermal melanocytes originating from these patients demonstrated a significantly decreased calcium dependent L-phenylalanine uptake and turnover compared to healthy control cells. Based on our observation, we would like to propose that phenylalanine uptake/turnover is under tight control by calcium which in turn could offer an additional novel mechanism in the aetiology of HPA.     

Diagnosis and management of acute aortic dissection, clinical and radiological follow-up

A clinical series of acute aortic dissections is presented. Twenty cases were of type A and 10 of type B. Acute severe chest pain was common, in type A also blood pressure difference between the arms and aortic regurgitation. The diagnosis was established by echocardiography, computerized tomography and/or aortography. Antihypertensive therapy was instituted immediately after diagnosis and was in type A cases followed by acute surgery unless definite contraindications existed. Of 14 surgically treated type A patients 13 survived the operation. On follow-up 1.5-3.5 years later, 12 patients were still alive and doing well, but the false channel remained open in all cases where it had not been resected totally. Only one of six conservatively treated type A patients survived. Type B dissections were operated on only if conservative therapy failed. Four of five conservatively and two of five surgically treated type B patients survived.     

Radiometric detection of carbohydrate catabolism by pathogenic Neisseria.

A liquid scintillation procedure for the catabolism of D-[1-14C]glucose and [U-14C]maltose by pathogenic Neisseria was tested. Definitive results were obtained within a 30-min incubation period.     

Hirndurchblutung und cerebraler Stoffwechsel bei Kranken mit chronischer Niereninsuffizienz

Zusammenfassung 1. Bei 24 Kranken mit chronischer Niereninsuffizienz und Urämie wurden die Hirndurchblutungsgröße quantitativ mit der Stickoxydulmethode und der cerebrale Stoffwechsel mit enzymatischen Methoden untersucht.2. Bei einem Harnstoff-N von 142 mg-% und einem arteriellen pH von 7,31 lag die Hirndurchblutungsgröße mit 63,0 ml/100 g · min gering über der Norm. Der cerebrale O₂-Verbrauch (2,77 ml/100 g · min) und der cerebrale Glucoseverbrauch (3,75 mg/100 g · min) waren stark vermindert. Der Glucose-Oxydationsquotient war mit 1,13 gering reduziert. Die cerebrale Lactat- und Pyruvatabgabe unterschieden sich nicht sicher von der Norm. Der respiratorische Quotient lag mit 0,89 tiefer als normal.3. Die Aufschlüsselung des Materials in acidotische (pH<7,35) und nichtacidotische (pH>7,35) Urämien ergab unterschiedliche Resultate:a) Bei 15 acidotischen Urämien war die Hirndurchblutungsgröße mit 69,0 ml/100 g · min erhöht. Die Korrelationsberechnung zeigt, daß eine gesicherte negative Beziehung zwischen pH und Hirndurchblutungsgröße besteht: Je stärker die Acidose, desto höher die Durchblutung.Die cerebrale O₂-Aufnahme war mit 2,62 ml/100 g · min und die Glucoseaufnahme mit 3,33 mg/100 g · min signifikant vermindert. Der Glucose-Oxydationsquotient war mit 0,98 sehr stark reduziert.b) Bei 9 nichtacidotischen Urämien lag die Hirndurchblutung mit 52,9 ml/100 g · min im Normbereich, während der O₂-Verbrauch mit 2,96 ml/100 g · min und der Glucoseverbrauch mit 4,52 mg/100 g · min reduziert waren. Der Glucoseverbrauch war deutlich weniger vermindert als bei den acidotischen Urämien. Daher unterscheidet sich in dieser Gruppe der Glucose-Oxydationsquotient nicht signifikant von der Norm.4. Es besteht eine statistisch gesicherte positive Korrelation von pH und O₂- bzw. Glucoseverbrauch, d.h. je stärker die Acidose, desto niedriger sind O₂- und Glucoseaufnahme. Zur Höhe des Harnstoff-N besteht keine Korrelation.5. Unter der Therapie mit Abfall des Harnstoff-N und Anstieg des pH besserten sich cerebrale O₂- und Glucoseaufnahme und normalisierte sich der Glucose-Oxydationsquotient.6. Es besteht eine Beziehung von cerebraler Funktion (Sensorium klar, getrübt, Praecoma, Coma) zu den cerebralen O₂- und Glucoseutilisationswerten, nicht hingegen zur Durchblutungsgröße.7. Die urämische Encephalopathie ist Folge einer acidotisch-toxischen Stoffwechseldepression und geht nicht mit einer cerebralen Zirkulationsstörung einher.Meinen akademischen Lehrern Prof. Dr. Dr. G. Bodechtel und Prof. Dr. A. Bernsmeier zu ihren Geburtstagen im März 1972.     

The lipid A immunity system. I. Induction of heterophile antibodies by enterobacterial lipopolysaccharides and their lipid A component

Mice were immunized either with lipopolysaccharides (LPS) or with the respective lipid A components. After four days an increase in the number of direct plaque-forming cells with complement-dependent antibody against sheep red cells was seen. Cross-reactions were observed with red cells of cattle, goats, horses and rabbits. All LPS investigated, of Shigella, Escherichia coli, and S and R form Salmonella, as well as the lipid A component evoked this immune response. We therefore conclude that all enterobacterial LPS induce an antibody which cross-reacts with SRC and that the lipid A component is responsible for this reaction. Evidence is presented that these effects, such as toxicity, fever, pyrogen tolerance, leucopenia/leucocytosis, nonspecific immunity, and tumor inhibition are mediated by lipid A-induced antibodies.