Sodium regulation of agonist and antagonist binding to β-adrenoceptors in intact and Ns-deficient membranes

Summary Agonist binding to various hormone receptors mediating adenylate cyclase inhibition is decreased by sodium ions. We studied the influence of Na⁺ on agonist and antagonist binding to -adrenoceptors in membrane preparations of guinea pig lung, S49 lymphoma wild-type cells (WT) and their N_s-deficient cyc^– variants by measuring binding of the antagonist, [¹²⁵I]iodocyanopindolol ([¹²⁵I]CYP). At 37° C, sodium decreased the receptor affinity for the agonist, isoproterenol, in all three membrane preparations. In lung and WT membranes, Na⁺ steepened the shallow agonist competition curves in a manner similar to and synergistic with guanine nucleotides. When binding was performend at 4° C, sodium regulation but not guanine nucleotide regulation of agonist binding was preserved. At the low temperature, [¹²⁵I]CYP affinity was reduced, and sodium increased [¹²⁵I]CYP binding in both N_s-containing and N_s-deficient membranes by increasing the antagonist affinity without significant change in total receptor number. Compared to Na⁺, Li⁺ and K⁺ were much less potent and efficient in decreasing agonist and increasing antagonist binding. Na⁺ and Mg²⁺ had opposite effects on agonist binding in the N_s-containing lung and WT membranes but not in the N_s-deficient cyc^– membranes. The data indicate that sodium not only regulates binding of inhibitory hormone receptors but also agonist and antagonist binding to the adenylate cyclase stimulatory -adrenoceptor. The finding that sodium regulation of -adrenoceptor binding is also observed in the N_{s 2} cyc^– membranes, furthermore, indicates that the target of sodium is not the -subunit of N_s but possibly a component common to both types of receptor systems regulating adenylate cyclase activity.     

Rapid hydroxylation of methtryptoline (1-methyltetrahydro-β-carboline) in rat: Identification of metabolites by chiral gas chromatography-mass spectrometry

Summary Racemic methtryptoline (1-methyltetrahydro--carboline) and 5-hydroxymethtryptoline-9-carboxylic acid (6-hydroxy-1-methyltetrahydro--carboline-1-carboxylic acid) were administered intraperitoneally to rats and the components of their urine was subsequently investigated by chiral gas chromatography-mass spectrometry. Methtryptoline rapidly became hydroxylated in the 5- and 6-position and excreted in urine. There was about a ninefold predominance of the S(–) enantiomer over the other in the 5-hydroxylated species, while the 6-hydroxylation produced a small excess of the R(+) enantiomer. About 75% of the injected dose of methtryptoline was recovered in the urine as 5- and 6-hydroxylated compounds during the first 24 h period, demonstrating that hydroxylation represents the major metabolic pathway. Treatment with 6-hydroxymethtryptoline-9-carboxylic acid led to a fivefold increase in the urinary excretion of 5-hydroxymethtryptoline during the first 24 h period with a predominance of the S(–)-enantiomer, indicating a much smaller conversion rate than from methtryptoline. It was concluded that hydroxylation of methtryptoline is a likely pathway for the natural formation of 5-hydroxymethtryptoline.     

Autocrine and paracrine growth regulation of human breast cancer

Summary We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF, TGF, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or byras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.     

An “all-season” mammoplasty

A reduction mammoplasty must produce a reduction in volume, a natural lasting shape, and minimal residual scarring. Many attempts to achieve this goal have been developed in recent years. The author described, in 1970, a vertical technique achieving an important reduction and a good shape but with the appearance of the end of the vertical scar below the brassiere line. In 1977, the author [3] modified the technique by the adjunction of a small horizontal scar to eliminate the inconvenience of the visible part of the vertical scar. In this article the author describes his technique which appears to be suitable for most types of breast deformities.     

Anastomotic insufficiency in small bowel surgery —incidence and treatment

Summary In the period 1977–1981 234 small bowel anastomoses were constructed in 143 patients. Eight anastomoses showed leakage (3.4%) and from nine anastomoses a fistula developed (3.8%): a total rate of disturbed healing of small bowel anastomoses (7.3%). In the presence of intra-abdominal infection this rate was 14.8%, in the absence of infection 0.8%. The results of treatment with oversewing and with resection and immediate anastomosis were disappointing. Better results were obtained by dismantling of the anastomosis, establishment of a split-enterostomy and reestablishment of continuity in a second stage. Mortality was 3/17 (18%). The literature is reviewed.

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Insuffizienz von Dünndarmanastomosen — Ineidenz und Therapie

Zusammenfassung In dem Zeitraum 1977–1981 wurden bei 143 Patienten 234 Dünndarmanastomosen angelegt. Acht Anastomosen zeigten eine Nahtleckage (3,4%), bei neun entwickelte sich eine Fistel (3,8%): die Gesamthäufigkeit von Wundheilungsstörungen bei Dünndarmanastomosen war 7,3%. Bei gleichzeitigem Vorliegen intraabdominaler Infektionen betrug die Häufigkeit 14,8%, ohne diese 0,8%. Die Resultate einer Therapie durch Übernähung oder Resektion mit sofort anschließender Reanastomosierung waren enttäuschend. Befriedigendere Ergebnisse wurden durch Aufheben der Anastomosen, Anlage einer split enterostomy unter Wiederherstellung der Kontinuität in einer zweiten Sitzung erzielt. Die Mortalität betrug 3/17 (18%). Ein Literaturüberblick wird gegeben.

     

Species differences in the relative analgesic potencies of some classical opiates and opioid peptides

The analgesic ED₅₀ values of some classical morphine congeners (morphine, methadone, fentanyl, azidomorphine) in the rat and mouse tail-flick tests were found to be similar. However, several synthetic derivatives of the natural enkephalins were more potent in mice than in rats. (These analogs contain d-amino acid in position 2 and d- or l-sulfonic (or phosphonic) acid residue in position 5). -Endorpin, d-Met², Pro⁵-enkephalinamide and two partial agonists showed intermediate interspecies relative potencies. According to the data obtained, similar opiate receptors might mediate the analgesic action of classical opiates in rats and in mice. However, the opiate receptors responsible for the antinociceptive effects of the above mentioned enkephalin analogues must be dissimilar in the two species examined. The results are discussed in terms of the role of - and -receptors in mediation of the analgesic effect induced by different types of opioids.     

ZK 91296, a partial agonist at benzodiazepine receptors

ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl--carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedatiye effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.     

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants onβ-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Summary The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of-adrenoceptors and 5-HT₂ binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the-adrenoceptor produced by these compounds.Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT₂ binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT₂ binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.     

The effect of neuroleptic treatment and of high dosage diazepam therapy onβ-endorphin immunoreactivity in plasma of schizophrenic patients

Summary Synapsin I (Protein I), a neuron-specific phosphoprotein enriched in presynaptic nerve terminals, has been used as a quantitative marker for the density of nerve terminals in five brain regions (caudate nucleus, cingulate gyrus, hippocampus, mesencephalon and putamen) from patients who had suffered from Alzheimer disease/senile dementia of Alzheimer type (AD/ SDAT), from patients with multi-infarct dementia (MID), and from agematched controls. Samples were obtained at autopsy. Lower levels of Synapsin I were observed in the hippocampus of patients with AD/SDAT but not with MID. There were no significant differences in Synapsin I levels between patients and controls in any of the other four brain regions examined.     

Caffeine actions on currents induced by calcium-overload in Purkinje fibers

The ionic events underlying the changes induced by caffeine in calcium-overloaded Purkinje fibers were studied by means of a voltage-clamp technique. The following results were obtained. In fibers exposed to strophanthidin (5 X 10(-7) M), a depolarizing clamp of suitable magnitude or duration is followed by an oscillatory current (Ios) often superimposed on a decaying inward tail current (the "tail current"). Caffeine (9 mM) abolishes Ios and increases the tail current. Caffeine has similar actions when calcium overload is induced by increasing [Ca]0 or decreasing [Na]0. The magnitude of the tail current is reduced by decreasing [Ca]0. The tail current appears with repolarizations to -40 mV or more negative values as Ios appears in the absence of caffeine. As with Ios the tail current can be triggered twice (during and after a test clamp of suitable characteristics), becomes more inward with repeated clamps and becomes larger with larger or longer conditioning clamps. During the recovery from caffeine exposure, the tail current decreases gradually as Ios returns progressively. It is concluded that both Ios and tail current are caused by calcium overload but are affected in opposite direction by caffeine, apparently because caffeine decreases the calcium overload in the sarcoplasmic reticulum (abolition of Ios) and increases the calcium to be extruded from the sarcoplasm (increase in the tail current).