Prostaglandin-induced serotonin release

Zusammenfassung Bei Ratten wurde die Gesamtmenge von Serotonin in der Fundus- und Atriumschleimhaut sowie im mittleren Jejunum bestimmt. Prostaglandin E₁ (200 g/kg, s.c. oder i.v.) reduzierte den Serotoninspiegel weder in den Kontrolltieren noch in mitp-Chlorophenylalanin (150 oder 300 mg/kg) oder mit Reserpin (5 mg/kg) vorbehandelten Tieren.     

Serotoninantagonismus an der Placenta

Summary The placentae of 17 to 19 days pregnant mice respond to subcutaneous serotonin (15 mg/kg) with vascular changes which lead to the death of the fetuses in 3–4 h. Pretreatment of the females withd-lysergic acid derivatives preserves the life of the young. Thus, LSD showed an ED₅₀ of only 30 g/kg, while UML (Deseril®) gave an ED₅₀ of 3.7 g/kg. PML takes an intermediate position. At a 50% efficiency level, UML (Deseril®) antagonises the effect of a 4000 times higher dose of serotonin.     

Laktationshemmende Wirkung von N-[d-6-Methyl-8-isoergolin-I-yl]-N′, N′-diäthylharnstoff (VÚFB-6638)

Summary The inhibiting effect of orally administered N-[d-6-methyl-8-isoergolin-I-yl], N, N-diethylurea (VÚFB-6638) on the production of milk was found in rats. The inhibition of lactation was ascertained through the observation of the daily weightgains of the suckled puppies (ED₅₀=0.112 mg/kg/day) and through the observation of the presence of milk in the stomach of these puppies, as seen through their abdomen wall (0.084 mg/kg/day). This inhibition could be abolished with exogenous prolactin, which gives evidence that the drug studied acts via the endocrine system.

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Für die technische Assistenz danken wir FrauM. Kommersová und FrauV. Maitová.     

Effect of aflatoxin B1 on the incorporation of14C-acetate into cholesterol by rat liver

Résumé L'administration d'aflatoxine B₁ (2 et 5 mg/kg, i.p., 24 h avant le sacrifice) a résulté en un abaissement de 80% de l'incorporation du l-¹⁴C-acétate en cholestérol par des coupes de tissu de foie. Le même traitement n'a pas altéré l'activité des drug metabolizing enzymes au niveau des microsomes du foie.     

Influence of repeated prazosin administration on cardiovascular responses in rats and rabbits

Prazosin was injected i.v. at a dose of 50 g/kg every 2 h for 8 h in conscious rats. Its hypotensive action significantly declined. A similar effect was also observed in rabbits pretreated with prazosin (40 g/kg, i.v.) every 1 h for 4 h. In prazosin-treated rabbits, the total peripheral resistance became less responsive to phentolamine stimulation. Repeated prazosin administration abolished its ability to block receptors in a model of anococcygue muscle contraction after noradrenaline (NA) stimulation. The -adrenoceptors in anococcygue muscle exhibited lower pD₂ to NA and lower pA₂ to prazosin in prazosin-treated rats. The results demonstrate that repeated prazosin administration reduces the effectiveness of -adrenoceptors blockers.     

The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP+-lesioned mice

Orally administered Madopar (levodopa/benserazide 41) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP⁺-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.     

The influence of peripheral or central administration of ondansetron on stress-induced gastric ulceration in rats

Ondansetron (0.08, 0.15 or 0.3 mg/kg) injected s.c., every 12h with the fourth dose given 0.5 h before experiments, dose-dependently lessened gastric glandular mucosal ulceration produced by cold-restraint stress for 2h. When given intracerebrally (i.c.) (0.1, 0.5 or 1g), using the same treatment regimen, infusion of ondansetron 1 g into the nucleus amygdaloideus centralis decreased stress-evoked ulcers; in contrast, injection of the same dose into the nucleus accumbens intensified these lesions. The associated stress-induced stomach wall mast cell degranulation was unaffected by all s.c. or i.c. doses of ondansetron. Pretreatment with disodium cromoglycate i.p. alone, or concurrently with ondansetron s.c., prevented not only ulceration but also mast cell degranulation. 5-Hydroxytryptamine₃ receptor antagonism appears to inhibit stress-evoked ulcers mainly by blocking the peripheral effects of the amine after its release from the gastric mucosal mast cells.     

Influence of adrenergic blocking agents upon morphine and catecholamine analgesic effect

Resumen Las catecolaminas adrenalina (0,25 y 0,5 mg/kg) noradrenalina (0,5 y 1 mg/kg) e isoproterenol (4 y 8 mg/kg) producen efecto analgésico significativo en lauchas. También aumentan (adrenalina 0,25 mg/kg, noradrenalina 0,5 mg/kg e isoproterenol 4 mg/kg) el efecto analgésico de pequeñas dosis de morfina (1 mg/kg). El bloqueador -adrenérgico dihidroergotamina (4 mg/kg) no influencia substancialmente estas acciones, pero el bloquente-adrenérgico propranolol (1 mg/kg) bloquea los efectos analgésicos de la morfina, adrenalina e isoproterenol, no siendo tan efectivo contra la noradrenalina. Se deduce que debe existir un compromiso de receptores-adrenérgicos en el mecanismo de los efectos analgésicos de las catecolaminas y también de la morfina.

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Fellow of the Consejo de Investigaciones Cientificas y Técnicas.     

Metallothionein induction by cadmium and zinc in rat secretory organs

Summary Metallothionein (MT) levels were determined in four secretory organs of the rat following administration of zinc (Zn) and cadmium (Cd). The concentrations of MT in the lacrimal, parotid and adrenal glands of untreated rats were in the range of 2.2–4.9 g/g wet weight tissue while in the pancreas it was shown to be 15.2 g/g. Injection of zinc at total doses of 16, 32 and 80 mg/kg resulted in a 1.8-, 3.2- and 5.9-fold increase in lacrimal MT content, respectively, while a 10.2- and 13.1-fold elevation was observed following treatment with 4 and 8 mg/kg of Cd, respectively. Similar findings were found in the adrenal gland. The parotid MT was elevated 5.9 and 17 times following Zn treatment at doses of 16 and 80 mg/kg respectively, whereas 4 mg/kg of Cd increased MT 14.4 times in this gland. Pancreatic MT was elevated by 39- and 40-fold after injection of Zn at doses of 16 and 32 mg/kg respectively, whereas 4 and 8 mg/kg of Cd caused a 9.8- and 17.9-fold induction, respectively. These results may indicate that secretory organs participate in metabolism of heavy metals in the mammalian body.     

Stimulation of gastric secretion by prostaglandin F2 α in rats

Summary In rats with chronic gastric fistulas, prostaglandin F₂ stimulated the gastric acid secretion in graded doses of 50. 100, 200 and 400 g/kg b. wt, while higher doses above 1 mg/kg b. wt tended to inhibit significantly. The gastric antisecretory effect of prostaglandin E₁ could not be altered or modified by subsequent treatment of prostaglandin F₂ , while the latter alone without any prior treatment of the former, stimulated output of gastric juice, HCl and pepsin without significantly affecting the concentration of these components.Acknowledgement. The gift of the prostaglandin E₁ and prostaglandin F₂ is acknowledged to Dr J.E. Pike, Upjohn, USA. This paper was read at the IXth Annual Conference of the Indian Pharmacological Society held at Benares (1976) and abstracted in the Indian J. Pharmac.9, 73 (1977).     

Feeding induced by blockade of histamine H1-receptor in rat brain

Summary Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H₁-, but none of the H₂-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by -fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H₁-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels.     

Cyclophosphamide-impaired regulation of hepatic heme metabolism

Summary Im male rats hepatic cytochromes b₅ and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a non-cytochromal form. Parallel to the above changes the heme metabolism showed derangement: -aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.     

Effect of desipramine on the contents of some free amino acids of mouse brain

Summary I.p. injections of desipramine-HCL (100 mg/kg) produced decreases in the contents of several amino acids of mouse brain after 1 h. Using a 10–100 mg/kg range of doses, these effects appeared to be dose-dependent for -alanine and aspartate. These changes may be due, in part, to a decrease in cerebral oxidative metabolism (Krebs cycle activity) which occurs secondarily to desipramine-induced hypothermia.This study was supported by Centro Ramón y Cajal and Fundacion Juan March.     

Evaluation of monoaminergic receptors in the genetically epilepsy prone rat

Summary The intensity of sound-induced convulsions in the genetically epilepsy-prone rat (GEPR) was reduced in a dose related fashion by intracerebroventricular administration of dobutamine, (₁ agonist), terbutaline (₂ agonist) or phenylephrine (₁ agonist). BHT-920 (₂ agonist) did not cause a dose-related decrease in sound-induced convulsion intensity. Binding studies showed that whole brain and receptor densities (B_max) were normal while the K_d was increased for the ligand in GEPR brain.Acknowledgment. We are most grateful to Boehringer Ingelheim for generously supplying BHT 920. We are also indebted to Ciba-Geigy Corporation for the gift of terbutaline hydrochloride and phentolamine hydrochloride. The work was supported in part by NIH grant NS 16829.     

The chemistry of the polymyxin antibiotics

Zusammenfassung Die Chemie der Polymyxine, einer Klasse von basischen Polypeptid-Antibiotika, begann 1954, als durch Gegenstromverteilung erstmals ein definierter Vertreter, das Polymyxin B₁ in reiner Form isoliert werden konnte (L. C.Craig). Partialhydrolyse mit Mineralsäuren führte zum Schluss, dass es sich um Cyclohepta- oder Cyclooctapeptide mit Seitenketten handelt, die, -Diaminobuttersäure (Dab) enthalten (W.Hausmann).Amidartige Verknüpfung der Seitenkette mit einer Fettsäure [(+)-6-Methyloctansäure (MOA) oder 6-Methylheptansäure (IOA)] (S.Wilkinson) verleiht diesen Antibiotika den Charakter von Invertseifen. Sie sind besonders gegen gramnegative Erreger wirksam. Schwierigkeiten bereiteten die Aufklärung der Verknüpfungsweise der Seitenkette (- oder-) und die Beantwortung der Frage, ob das Molekül nebend-Phenylalanin in der Ringsequenz noch einend-, -Diaminobuttersäurerest in Nachbarschaft zur Fettsäure in der Seitenkette enthält. Synthetische Versuche mitd-, -Diaminobuttersäure an dieser Stelle führten zu hochaktiven Produkten, die aber mit natürlichem Polymyxin B₁ nicht identisch waren. Entscheidende Fortschritte wurden mit dem bakteriellen Enzym Nagarse (T.Suzuki) erzielt, das schrittweise die Seitenkette bis zum Ringpeptid abbaut. Dabei ergab sich, dass den Polymyxinen die allgemeine Struktur eines Cycloheptapeptides mit-verknüpfter Seitenkette zukommt (Figur 4).Die Polymyxine B₁ E₁ (Colistin A) sowie Circulin A unterscheiden sich voneinander nur durch eine Variation in der gleichen Dipeptidsequenz des 7-gliedrigen Ringes. Die im Polymyxin B₁ vorhandene Dipeptidsequenzd-Phe-l-Leu ist in Polymyxin E₁ (Colistin A) durchd-Leu-l-Leu und in Circulin A durchd-Leu-Ll-Ile ersetzt. Im Polymyxin D₁ ist neben dem Ersatz der entsprechenden Sequenz durchl-Leu-l-Thr noch ein, -Diaminobuttersäurerest der Seitenkette durch eind-Serin ausgetauscht. Die entsprechenden Verbindungen mit dem Index 2 unterscheiden sich von denjenigen mit dem Index 1 durch einen Austausch der (+)-6-Methyloctansäure durch 6-Methylheptansäure.Die Struktur von Polymyxin B₁ E₁ und Circulin A konnte durch Totalsynthese gesichert werden (K.Vogler). Weitere Fortschritte in der Erforschung der Natur der noch unbekannten Vertreter sind in Kürze zu erwarten.     

Centrally acting hypotensive fraction in the venom ofDendroaspis angusticeps

Summary I.v. administration of 100 g/kg ofDendroaspis angusticeps venom produced a biphasic vasodepressor response. The first fall in blood pressure is due to a cholinergic component, whereas the second fall may be due to central depressant effect.The work reported here was undertaken in partial fulfilment of the requirements for the degree of PhD of the University of Nairobi.Acknowledgment. We are grateful to the University of Nairobi for the research grant (No. 670-052) which supported this work. We also thank Merck, Sharp & Dohme Ltd for a liberal supply of cyproheptadine and Mr E. Njogu (chief technician, Dept of Veterinary Anatomy) for photographic assistance.     

Activité antifibrillante chez l'animal d'un nouveau dérivé de la phényl-éthylamine

Summary A new synthetic phenyl-ethyl-amine derivative, the 2-[N- (3, 4-methylen-dioxyphenylethyl)-methylaminomethyl]-tetrahydrofuran, No. 11 081, exhibits a strong protective effect against cardiac fibrillation and arrhythmias produced by various experimental methods: against fibrillation due to aconitine 3 × 10^–8 on the isolated cat's heart, it is active in a concentration of 10^–6–2 × 10^–6. Against cardiac arrhythmias produced in the cat by adrenaline + CHCl₃ or cyclopropane, it shows a protective effect by 5–10 mg/kg i.v. and even perorally by 50 mg/kg. In these tests, the antifibrillatory activity of the new compound seems to be roughly the same as that of -fagarine, and higher than that of procaine.

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9^e communication sur les dérivés des alcoylène-imines; 8^e communication, cf. Exper.10, 261 (1954).     

DDT: The degradation of ring-labeled14C-DDT to14CO2 in the rat

Summary Ring fission ofp, p-DDT was studied in the rat following a single oral dose of 0.74 mg/kg (1.04 Ci) of uniformly ring-labeled¹⁴C-DDT. Expired air was passed through a solution of ethanolamine-ethylene glycol monomethyl ether (12) to trap¹⁴CO₂. A total of 1.6% of the radioactivity administered was recovered in the expired air collected continually for 10 days, indicating that while degradation of the phenyl moiety is not a major route pfp, p-DDT metabolism in the rat, it is equal to the urinary excretion. Nevertheless, these results represent the most radical change accomplished in vivo of a residual insecticide yet reported in mammals.Acknowledgment. We acknowledge the secretarial work of Ms.Elaine Smolko. This study was supported by NIH fellowship No. 1 F22 ES01723-01 and No. HL16264.     

Occurrence of mitochondrial monoamine oxidase in human semen

Summary Mitochondrial monoamine oxidase (MAO) was found in human semen, showing its K_m and V_max values of 91.7 M and 290 pmoles/mg of protein/60 min, respectively, with kynuramine as substrate. A major part of the activity was due to type A MAO.