Die Wirkung länger dauernder Hydrochlorothiazid-Gaben auf die Plasma-Renin-Aktivität und die Aldosteron-Exkretionsrate bei Normalpersonen

Zusammenfassung Die Wirkung von Hydrochlorothiazid auf die Plasma-Renin-Aktivität (PRA) und die Aldosteron-Exkretionsrate (AER) wird bei 10 Normalpersonen untersucht. Gleichzeitig werden Bestimmungen der Serum- und Urinelektrolyte, des Hämatokrits und der Flüssigkeitsbilanz durchgeführt. In derjenigen Gruppe, die während 7 Tagen täglich 50 mg Hydrochlorothiazid (Esidrex®) erhielt, steigen die PRA am 2. und 4. Tag und die AER am 3. Tag nach Beginn der Diuretikagabe signifikant an, während am 6. bzw. am 7. Tag ein Abfall beider Parameter zur Norm einsetzt. Wesentliche Änderungen der Serumelektrolyte und des Hämatokrits werden nicht registriert. Die Stimulation des Renin-Angiotensin-Aldosteron-Systems (RAAS) kann mit einer erhöhten Natriurese und Diurese korreliert werden. Die Kaliurese steigt ebenfalls deutlich an, so daß der Na/K-Quotient im Urin unter 1 abfällt.In derjenigen Gruppe, die während 6 Wochen täglich 50 mg Hydrochlorothiazid erhielt, werden nach 2, 4 und 6 Wochen der Diuretikaverabreichung keine signifikanten Veränderungen der PRA, AER, Serumelektrolyte und des Hämatokrits festgestellt. Es entwickelt sich demnach unter längerdauernden Saluretikagaben kein sekundärer Hyperaldosteronismus.Die Wirkung sowohl einer Natriumrestriktion als auch einer saluretikainduzierten Natriumexkretion auf das RAAS wird besprochen. Schließlich werden die Möglichkeiten diskutiert, die einen Rückgang der Stimulation des RAAS trotz andauernder Diuretikagaben bewirken können.

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Summary The effect of hydrochlorothiazide on plasma renin activity (PRA) and aldosterone excretion rate (AER) were examined in 10 normal persons. At the same time, determinations of serum and urine electrolytes, of hematocrit and of fluid balance were carried out. In that group which recieved 50 mg hydrochlorothiazide (Esidrex®) daily for 7 days, the PRA rose significantly on the 2nd and 4th day and the AER on the 3rd day after the beginning of diuretic treatment. A decline to normal in both parameters set in on the 6th and 7th day, respectively. Considerable changes in serum electrolytes and hematocrit were not registered. The stimulation of the renin-angiotensin-aldosterone system (RAAS) could be correlated with elevated natriuresis and diuresis. Kaliuresis rose considerably as well so that the Na/K quotient in urine fell under 1.In that group which recieved 50 mg hydrochlorothiazide daily for a period of 6 weeks, no significant changes were noticed in PRA, AER, serum electrolytes or hematocrit after 2, 4 and 6 weeks of diuretic treatment. There was no development of secondary hyperaldosteronism under extended saluretic treatment.The effect of sodium restriction as well as saluretica-induced sodium excretion on the RAAS is discussed. Finally, the possibilities are discussed which can cause a retreat in stimulation of the RAAS despite extended treatment with diuretics.

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Diese Arbeit wurde durch die Hilfe des Schweizerischen Nationalfonds zur Förderung der wissenschaftlichen Forschung und der Stiftung zur wissenschaftlichen Forschung an der Universität Zürich ermöglicht.     

Hemodynamic profile of arpromidine and its F2-substituted derivatives in comparison to impromidine in congestive heart failure

There is considerable evidence that congestive heart failure (CHF) is paralleled by a decrease in the number of sarcolemmal β-receptors due to excessive levels of circulating endogenous catecholamines [1, 2]. In contrast, the myocardial H₂-receptor system is not affected. The first clinically available specific H₂-receptor agonist impromidine proved to be a potent inotrope in patients with CHF which were insensitive to catecholamine stimulation [3, 4]. Though the overall results of these initial studies were beneficial, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of impromidine limited its broad clinical application in large scale clinical trials. Recently developed phenylpyridylalkylguanidines [5] were investigated underin vitro andin vivo conditions in the guinea pig under physiologic and pathophysiologic conditions using impromidine as reference. Compounds tested were arpromidine and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H₂-agonists with additional H₁-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart, all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established underin vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and impromidine, respectively, in augmenting LV dp/dt, LVP, cardiac output and systemic blood pressure, but all compounds were revealed to have less chronotropic and arrhythmogenic potential. In the vasopressin-induced acute heart failure model, BU-E-76 and BU-E-75 normalized within minutes all contractile parameters in contrast to arpromidine and impromidine. It is thus concluded that these new H₂-receptor agonists may represent a promising therapeutic improvement for treatments of CHF patients, with a cardiovascular profile superior to impromidine and conventional catecholamines.

     

The pharmacological stimulation of NMDA receptors via co-agonist site: an fMRI study in the rat brain

d-Serine has been proposed as an endogenous modulator at the co-agonist glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. There is still some debate as to whether this site is saturated in vivo, but it seems likely that this depends on regional differences in local glycine or d-serine concentrations. In order to identify areas where the co-agonist site was not fully activated in vivo, we studied the effect of intraperitoneal d-serine administration in the rat brain using functional magnetic resonance imaging (fMRI). Using contrast agent injection, the variations in the relative cerebral blood volume (CBVrel) in several regions of interest were evaluated. d-Serine (50 mg/kg) elicited a significant statistical increase in the CBVrel in the hippocampus. This effect was inhibited by the specific full antagonist of the co-agonist glycine site L-701,324 indicating that the hippocampal activation occurred through the binding of the agonist d-serine to the glycine-binding site of NMDA receptors. This result demonstrates that in the hippocampus, the co-agonist sites of NMDA receptors are not endogenously saturated under our experimental conditions, suggesting an important role of d-serine in the modulation of receptor function in the hippocampus.     

Cell membrane destabilizes progressively during repetitive mechanical rupture events

The postfusion oscillation cycle method of electrofused cells was applied to red blood cell membranes to induce repetitive membrane ruptures and test the mechanical membrane resistance against sequential events of membrane strain and rupture. After producing doublets from pairs of electrofused cells, they entered the oscillation cycle, providing a sequence of at least four consecutive colloidosmotic-driven rupture events. Different gradations of colloidosmotic pressure loads between 3230 Pa and 8640 Pa were established with various buffer types. The independence of buffer type and geometrical and mechanical observations has been verified independently for both parts of the oscillation sequence. With decreasing colloidosmotic inducement, caused by repetitive oscillation cycles, an increasing susceptibility of the cell membrane against membrane rupture was measurable. Since side-effects had been eliminated, it could be concluded that the cell membrane resistance against repetitive mechanical ruptures decreases.     

Korrelation zwischen der Blutkörperchensenkung und Plasmaproteinen

Zusammenfassung Die BKS und 12 Plasmaproteine von 21 Kranken mit unterschiedlichen Krankheiten wurden statistisch miteinander verglichen. Dabei ergaben sich positive Korrelationen zwischen der BKS und dem sauren ₁-Glykoprotein und der BKS und dem ₁-Antitrypsin, eine negative Korrelation zwischen der BKS und dem Transferrin. Außerdem korrelierten das saure ₁-Glykoprotein und das ₁-Antitrypsin sowie das saure ₁-Glykoprotein und das Transferrin miteinander. Bei der Deutung dieser Ergebnisse müssen einerseits Gemeinsamkeitskorrelationen in Betracht gezogen werden, zum anderen die Möglichkeit, daß zwischen bestimmten Proteinmustern und der BKS Zusammenhänge bestehen.     

Myotonia congenita in northern Finland: an epidemiological and genetic study.

An epidemiological and genetic investigation of myotonia congenita was carried out in northern Finland. Altogether 58 patients were identified (of whom 54 lived in the study area) in 23 families, with a prevalence of 7.3 per 100000. The majority of the families originated from a sparsely populated area in western Lapland. The mean age at onset of the disease was 11 years with a range of 2 to 45 years. The mean time that had passed before verification of the clinical disease was 18 (SD 14) years. The sex ratio M/F was 2.2/1.0. Forty-seven cases were familial and 11 were sporadic. In six families/pedigrees the inheritance was compatible with autosomal recessive and in two families with autosomal dominant inheritance. In five additional families, in which autosomal recessive inheritance seemed most plausible, vertical transmission was also noticed. This could be explained either by consanguinity of the parents or by variant expression of the mutation(s) involved. Our results suggest that myotonia congenita is unusually frequent in northern Finland, most probably as a consequence of an enrichment of the gene mutation(s) in the population.     

Molecular mechanism of temperature sensing by the circadian clock of Neurospora crassa

Expression levels and ratios of the long (l) and short (s) isoforms of the Neurospora circadian clock protein FREQUENCY (FRQ) are crucial for temperature compensation of circadian rhythms. We show that the ratio of l-FRQ versus s-FRQ is regulated by thermosensitive splicing of intron 6 of frq, a process removing the translation initiation site of l-FRQ. Thermosensitivity is due to inefficient recognition of nonconsensus splice sites at elevated temperature. The temperature-dependent accumulation of FRQ relative to bulk protein is controlled at the level of translation. The 5'-UTR of frq RNA contains six upstream open reading frames (uORFs) that are in nonconsensus context for translation initiation. Thermosensitive trapping of scanning ribosomes at the uORFs leads to reduced translation of the main ORF and allows adjustment of FRQ levels according to ambient temperature.     

Lipopolysaccharide-binding proteins of Limulus amebocyte lysate.

Limulus amebocyte lysate, obtained from horseshoe crab (Limulus polyphemus) blood cells, contains a coagulation system which is activated by bacterial lipopolysaccharide (LPS). A chromatographic fraction of Limulus lysate, containing the endotoxin-sensitive factor(s) which initiates the coagulation cascade, was studied. We utilized a photoreactive, cleavable, radiolabeled derivative of Salmonella minnesota LPS, LPS-(p-azidosalicylamido)-1,3'-dithiopropionamide (LPS-ASD), to identify LPS-binding proteins. The lysate fraction was incubated with LPS-ASD, and LPS-binding proteins were identified by autoradiography of sodium dodecyl sulfate-polyacrylamide gels. An 82-kDa protein, a major protein component of this fraction from Limulus lysate, was identified as a LPS-binding protein in a majority of lysates. Incubation of whole Limulus lysate with antiserum to this protein resulted in enhanced sensitivity of the lysate to LPS, suggesting that this 82-kDa protein is a negative regulator of coagulation. A minor 50-kDa protein component of lysate also was identified as a LPS-binding protein and is a candidate for the LPS-sensitive coagulation protein in L. polyphemus.     

Three patients with hallucal polydactyly and WAGR syndrome, including discordant expression of Wilms tumor in MZ twins

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, Aniridia, Genito-urinary abnormalities, and growth and mental retardation which is invariably associated with an 11p13 deletion. We report two monozygotic twins and a third, unrelated patient with WAGR syndrome and additional clinical features not usually associated with WAGR. Both twins had developmental delay, growth deficiency, severe ocular involvement (nystagmus, aniridia, cataracts), atrial septal defect and two uncommon findings: agenesis of the corpus callosum and duplication of the halluces. One twin developed Wilms tumors aged 19 months while her sister remained tumor free by the age of 6.5 years. The singleton patient showed typical WAGR syndrome and preaxial hallucal polydactyly. Molecular cytogenetic studies refined the identification of the extent of the deleted segments, which were not identical in the two families. The two deletions included the PAX6 and WT1 genes as previously reported in typical WAGR patients. The unusual anomalies described in this report, may represent the expression of low penetrant traits associated with haploinsufficency of one or more of the genes present in the deletion (PAX6 is expressed in CNS) or may indicate epistatic influences of modifier genes on the expression of gene(s) present in the WAGR region.