Library

Notes: Abstract Histamine concentrations in canine whole blood and plasma were determined under several pharmacological, pathophysiological, and clinical conditions, using fluorometric methods. The specificity of the assay for whole-blood histamine was investigated by comparing 3 purification procedures for the isolation of histamine from whole blood including butanol extraction (Shore), ion-exchange chromatography on Dowex 50 W-X 8, and the combination of these 2 methods (Lorenz). Histamine in whole blood was identified in analytical and preparative samples by fluorescence spectra, thin-layer chromatography, degradation by diamine oxidase from pig kidney and inactivation by histamine methyltransferase from guinea-pig brain as well as by biological tests on the isolated guinea-pig ileum. Since butanol extraction resulted in significantly higher ‘histamine’ values than the other two purification procedures, ion-exchange chromatography on Dowex 50 was recommended as the method of choice for the specific determination of histamine in dog's whole blood. Normal values of histamine concentrations in canine plasma were tentatively estimated. They depended on the time between pretreatment of the animals (anaesthesia, operation) and the collection of blood and showed an approximately logarithmic normal distribution. The median, the lower/upper quartiles and the range of the plasma histamine levels obtained 30 minutes after the end of pretreatment were 0.2, 0–0.4 and 0–1.2 ng/ml, respectively. Nearly 50% of the values were zero (below 0.1 ng according to the sensitivity of the method), only 1% of them exceeded slightly 1 ng/ml. Thus histamine release by drugs or by other medical treatments was only stated, when plasma histamine levels exceeded 1 ng/ml and decreased in a way to give an elimination curve of approximately first-order kinetics (Bateman function). Histamine concentrations in dog's whole blood showed approximately a logarithmic normal distribution. The median, lower/upper quartiles and range were 47, 34/75 and 13–209 ng/ml respectively. The histamine levels in the whole blood of four circulatory regions did not show any significant differences. The plasma histamine concentrations in the portal vein were slightly higher than in the hepatic veins. The injection of exogenous histamine and the concomitant determination of plasma and whole-blood histamine levels in four circulatory regions showed that the plasma histamine determination was the more sensitive method for measuring histamine elimination curves than the whole-blood histamine assay. The elimination of exogenous histamine administered intravenously was influenced by several drugs including inhibitors of histamine inactivation and histamine receptor antagonists. Aminoguanidine and the H2-receptor antagonist burimamide slowed down the disappearance of histamine from the plasma, the H1-receptor antagonist dimethpyrindene enhanced it, but amodiaquine had no significant effects. Dimethpyrindene and burimamide were capable of releasing histamine in dogs, in some cases to a considerable extent. The plasma substitute Haemaccel®, a chemically modified gelatin, released histamine in dogs. Using batch 3000, from 27 animals investigated, 15 animals showed elevated plasma histamine levels and a hypotensive blood pressure response, whereas in 12 of the dogs it did not show an effect on these parameters. The plasma histamine levels at the time of maximum hypotension showed an approximately logarithmic normal distribution. This frequency distribution in combination with the varying incidence of anaphylactoid reactions depending on the batches used seemed very important for the interpretation of clinical reactions to Haemaccel in human test persons and patients. By histamine determinations in plasma and whole blood of several circulatory regions and in various tissues before and after infusion of Haemaccel it could be demonstrated that the sites of histamine release by Haemaccel in dogs were especially the skin of the upper hemisphere of the body and the liver, whereas the gastro-intestinal tract took up histamine from the circulation. These numerous results under various experimental conditions may be considered as an evidence for the high quality and reliability of the method to study histamine release in the whole animal or in human subjects by evaluating histamine elimination curves in plasma.

Notes: Zusammenfassung Zur Bestimmung der Halbwertszeit des Secretins wurde eine indirekte Methode gewählt, da die Secretinkonzentration im Blut zur Zeit noch nicht direkt bestimmt werden kann. Die Versuche wurden an Hunden vorgenommen. Die „indirekte Secretinhalbwertszeit“ entspricht dabei per definitionem der Zeitspanne, in der die Aktivität des Secretins, gemessen am Parameter der Pankreassekretion und transformiert über die Dosiswirkungskurve, um die Hälfte abnimmt. Der einer exponentiellen Funktion folgende Sekretionsabfall wurde über die Dosiswirkungskurve in eine Dosiszeitkurve übertragen, aus der die indirekte Halbwertszeit des Secretins abgelesen werden kann. Die indirekte Secretinhalbwertszeit ist dabei nicht konstant, sondern ändert sich wegen des doppelt logarithmischen Aktivitätsabfalls stetig. Bei mittlerer Dosierung (1 E/kg) wurde eine Halbwertszeit von ungefähr 2,9 min gefunden. Bei Verdoppelung der Dosis resultiert aus der Aktivitätsverlaufskurve eine Halbwertszeit von rund 2,2 min, während sie bei halber Dosierung (1/2 E/kg) bei ungefähr 4,4 min liegt. Die mittlere Halbwertszeit, ein Durchschnittswert aus diesen Zeitspannen, liegt bei 3,2 min.

Notes: Zusammenfassung In der beim maximalen Histalogtest üblichen Dosis von 2 mg/kg, zeigt Histalog bei verschiedenen Tierspezies neben dirketen histaminartigen Wirkungen auch noch eine Steigerung der Serotonin- und Kininwirkung. Wahrscheinlich sind deshalb Antihistaminica ohne Antikinin- und Antiserotoninwirkung gegenüber Nebenerscheinungen des maximalen Histalogtestes wirkungslos. 13fach höhere Histaminspiegel im Magensaft als im Blutplasma des Menschen sprechen für eine Histaminliberierung durch Histalog.

Notes: Summary In a series of 133 dogs, 10–20 ml/kg arterial blood were removed and replaced by rapid intravenous infusion of an equivalent volume of various plasma substitutes. Following the infusion of gelatine solutions, an acute fall in arterial blood pressure was observed, but not following the infusion of equal quantities of Dextran 60 or of 0.9% NaCl solution. Measurement of the blood histamine levels as well as the fact that the circulatory effects could be modified by the previous administration of anti-histaminic drugs indicate that the hypotension observed following the rapid infusion of gelatine solutions is due to the release of histamine. Since histamine liberation has also been shown in preliminary studies in man, rapid infusions of gelatine solutions should be avoided in clinical practice, or patients receiving them should be pre-treated with anti-histaminic drugs.

Notes: Summary 1. Some parameters of salivary secretion (latency, volume of saliva, duration of salivation and concentration and amount of histamine in the submaxillary gland and saliva) were determined after i.a. administration of pilocarpine, physostigmine, carbachol, acetylcholine, histamine and mepyramine to dogs. Dose-response relationships after i.a. and i.v. administration are presented. 2. After the injection of pilocarpine the volume of saliva is directly proportional to the amount of histamine in the submaxillary gland and, in the same dog, to the amount of histamine in the saliva. A correlation was found between the amount of histamine in saliva and the increase of activity of the specific histidine decarboxylase in the gland (adaptative formation of histamine). 3. In experiments in which attempts were made to exhaust the gland by numerous injections of pilocarpine the initial intensity of the response was diminished by only 13% after many hours, whereas the time of latency was prolonged and the duration of response was, in parallel with the histamine amount of the saliva, strongly diminished. 4. After the injections of physostigmine, the volume of saliva is directly proportional to the amount of histamine in the saliva, not only in the same dog, but also between different dogs. The latency of the response and the secretion curve contradict a direct action of physostigmine at the secreting cell. 5. In contrast to other antihistamine drugs which inhibit the salivation induced by parasympathetic drugs and histamine, mepyramine causes a large release of histamine and stimulation of salivary secretion, which could be inhibited by the former antihistamine drugs. 6. Histamine induced salivation is strongly augmented by prestimulation of the submaxillary gland with pilocarpine, carbachol, physostigmine, nicotine, and by treatment with aminoguanidine. Aminoguanidine (5 mg/kg) itself stimulates salivation. After i.a., but not after i.v. administration of histamine, the release of histamine into the saliva is increased. Injected histamine is partly stored by “glandotrop” histamine pools (pools, from which histamine is released in order to stimulate directly elements in the same gland) and can be released by pilocarpine, acetylcholine, and physostigmine. Only histamine which is released from stores is involved in the stimulation of secretion. 7. The pancreatic juice obtained by stimulation by secretin and pilocarpine, but not by pancreocymine, contains histamine in a high concentration which is constant during the whole secretion period. Histamine itself stimulates pancreatic secretion. 8. A model showing how histamine mediates parasympathetic stimulation of the submaxillary gland is discussed: acetylcholine from parasympathetic nerve endings releases histamine from the “glandotrop” histamine stores. Histamine then stimulates glandular elements.

Notes: Zusammenfassung Verschiedene Isolierungsverfahren für Histamin zur fluorimetrischen Bestimmung wurden geprüft. Für Histamingehalte von mehr als 1 μg/g Gewebe oder Milliliter Vollblut eignet sich sowohl die Butanolextraktion als auch die Ionenaustausch-Chromatographie an Dowex 50W-X8, für Vollblut des Hundes nur das letztere Verfahren, für Plasma und Magensaft des Menschen nur die Kombination der beiden Isolierungsmethoden. Histamin wurde identifiziert durch Dünnschicht-Chromatographie auf Cellulose, Umsatz durch angereicherte Diaminoxydase und Histaminmethyltransferase, durch die Fluorescenzspektren nach Kondensation mit o-Phthaldialdehyd und durch seine biologische Aktivität. Die Histamingehalte in Geweben und Körperflüssigkeiten des Menschen und einiger Versuchstiere werden mitgeteilt.