P. A. van Zwieten

Acute hypotensive action of 2-(2,6-dichlorophenylamino)- 2-imidazoline hydrochloride (St 155) after infusion into the cat's vertebral artery

Abstract Low doses (0.25–2.0 μg/kg) of 2-(2, 6-dichlorophenylamino)-2-imidazoline-hydrochloride were infused into the vertebral artery of anesthetized cats. A considerable, dose-dependent decrease in blood pressure developed suddenly towards the end of the infusion. The same low doses hardly affected blood pressure when given intravenously. The hypotensive effect, observed after infusion into the vertebral artery is in agreement with the presumed central mechanism of action of the drug. In most animals the infusion of 1 μg/kg 2-(2, 6-dichlorophenylamino)-2-imidazoline-hydrochloride into the verterbral artery reduced the carotid occlusion reflex considerably, probably also via a central mechanism. The chemo-receptor component of the reflex seemed to be affected more by the drug than the baroreceptor component.

The central hyperglycaemic effect of clonidine.

Abstract Clonidine, 10 μg/kg, infused into the left vertebral artery of anaesthetized cats caused a pronounced though transient hyperglycaemia. After i.v. injection the same dose did not change the concentration of blood glucose. Therefore, the hyperglycaemia must be of central origin. The most likely site of action in the CNS is the hypothalamic region which in its turn may activate the anterior pituitary gland. The increased production of somatotropine might then explain the hyperglycaemia. The central hyperglycaemic effect was diminished by phentolamine, propranolol and atropine. The reduction of the hyperglycaemic effect by sympatholytic agents and atropine might be of primarily central origin. The influence of haloperidol pretreatment or bilateral adrenolectomy did not allow definite conclusions concerning the mechanism of the central effect. The sites of action in the CNS for the hyperglycaemic and hypotensive effects are probably different. The present studies present pharmacological evidence for a central component in the regulation of carbohydrate mechanism.

The influence of 2-(2,6-dichlorphenylamino)-2-imidazoline hydrichloride (clonidine) and some related compounds on gastric secretion in the anaesthetized rat

Abstract Drugs tested on the anesthetized rat were: clonidine, naphazoline, xylometazoline, tolazoline, and phentolamine. Clonidine, naphazoline, xylometazoline and tolazoline produced a dose dependent stimulation of gastric acid secretion. The effect was probably not related to the influence of these drugs on haemodynamics. Phentolamine did not increase gastric acid secretion. The increased production of gastric acid was hardly affected by atropine but was considerably reduced after pretreatment with hexamethonium. Only the effect of tolazoline was completely blocked by atropine. Clonidine was less effective in the anaesthetized guinea pig than in the rat. Clinidine did not affect gastric secretion in the despinalized (pithed rat). The response to histamine was also markedly reduced. The stimulatory effect of clonidine and related drugs in the anaesthetized rats is possibly caused by a histamine-like action or by the liberation of histamine. Ganglionic stimulation may also contribute. In conscious animals the decreased gastric secretion resulting from treatment with clonidine is probably of central origin.

Decrease in ionic permeability of the cell membrane in guinea‐pig atrial tissue by treatment with antifibrillatory agents and hexobarbitone, determined by means of 86Rb

1 The influence of antifibrillatory agents on the release of previously accumulated 86Rb+ ions was studied in guinea‐pig isolated left auricles, incubated in a K+‐free Tyrode solution that contained an equivalent concentration (2.7 mm) of Rb+. The auricles were stimulated electrically at a frequency of 100/min and showed entirely “normal” mechanical behaviour in the incubation medium. 2 Quinidine, tetracaine, hexobarbitone‐Na and propranolol caused a dose‐dependent negative inotropic effect. The frequency of beating (100/min) was usually not affected by these drugs. 3 The reduction in contractile force was accompanied by a dose‐dependent inhibition of 86Rb release. The concentration‐response curves for both the mechanical effect and the influence on 86Rb release almost coincided for quinidine, although these curves diverged for the other drugs studied. 4 It is suggested that all the four different antifibrillatory drugs cause a general reduction of the membrane permeability to inorganic ions. The mechanism of this membrane stabilization remains unknown.

Serumkonzentration und Ausscheidung von3H-Digitoxin beim Menschen unter normalen und pathologischen Bedingungen

Zusammenfassung3H-Digitoxin (1 µC/kg Körpergewicht) wurde 3 Patientengruppen intravenös verabreicht, nämlich:a)Patienten mit normaler Nieren-, Leber- und Herzfunktion.b)Leberkranken, bei denen entweder ein Verschlußikterus oder Leberparenchymschaden nachgewiesen werden konnte.c)Patienten mit einer Niereninsuffizienz. Die Gesamtradioaktivität wurde mindestens bis 72 Std p.i. in Serum, Urin und Stuhl quantitativ bestimmt. Bei den Kontrollpatienten folgte die zeitliche Abnahme der Serumradioaktivität zwei Exponential-Funktionen mit Halbwertzeiten von 20 min bzw. 120 Std. In 72 Std wurde etwa 11% der injizierten Menge an radioaktivem Material mit dem Urin und etwa 5% mit dem Stuhl ausgeschieden. Bei den nieren-insuffizienten Patienten war die Ausscheidung mit dem Urin nur dann vermindert, wenn die BUN- und Kreatinin-Werte stark erhöht waren. In diesen Fällen fiel die Serumradioaktivität entsprechend langsamer ab. Die Leberkranken schieden mit Urin und Stuhl die gleiche Menge an radioaktivem Material wie die Kontrollpatienten aus. Auch während einer deutlichen Abflußbehinderung der Galle nahm die Serumradioaktivität ab wie bei den normalen Patienten. Es wurde daraus geschlossen, daß3H-Digitoxin (bzw. seine Metaboliten) vorwiegend über die Niere ausgeschieden werden. Die Ausscheidung über die Leber spielt offenbar für dieses Glykosid keine wesentliche Rolle.Summary3H-Digitoxin in subthreshold doses (1 µC/kg body weight) was administered intravenously to patients that were divided into the following three categories:a)Patients with normal renal, hepatic and cardiac functions.b)Patients suffering from liver disease, accompanied by biliary obstruction or parenchyme damage.c)Patients suffering from renal failure. Total radioactivity was determined in serum, urine and stool during at least 72 hrs following drug administration. In the control patients the3H-digitoxin disappeared from the serum by means of two exponentials with half-lives of about 20 min and 120 hrs, respectively. During 72 hrs about 11% of the injected radioactive material was excreted with the urine and approximately 5% with the stool. During renal failure the urinary excretion was inhibited only in case of high BUN and creatinine levels. In the same patients the decline in serum radioactivity was retarded. In patients suffering from liver disease the same relative amount of radioactive material was excreted with both stool and urine as in control patients. During biliary obstruction the elimination remained also the same as under normal circumstances. It was concluded that3H-digitoxin (and its possible metabolites) is mainly excreted via the kidneys. In man, the excretion via the liver is obviously of minor importance.

Calcium metabolism in atrial tissue during frequency potentiation and paired stimulation

SummaryIn order to study whether the application of paired stimuli and also the occurrence of frequency potentiation were accompanied by changes in calcium metabolism, the uptake and release of45Ca and also the total tissue Ca were studied in guinea pig isolated left auricles, subjected to either single or paired stimulation at different basic frequencies. 1.The uptake of45Ca reached equilibrium after approximately 90 min when single stimuli were applied at frequencies in the range 20–320/min. About 80–90% of the cellular Ca exchanged against extracellular45Ca. At a low frequency (20/min) this figure amounted to 61%. After particularly prolonged times of incubation the exchange still increased a little but complete exchange was nerver observed. Total calcium remained unchanged throughout the experiments.2.There was no difference in45Ca uptake during eithersingle orpaired stimulation at all frequencies studied. Paired stimulation did not affect the total calcium content of the tissue either. The release of previously accumulated45Ca also proved the same during single or paired stimulation.3.The amount of calcium entering the cell per single excitation significantly decreased at rising frequencies. The tentatively estimated amount of calcium penetrating into the cells as a result of one action potential increased the already existing Ca-ion-concentration by the following values:Frequency 20/min: 2.5×10−7 M, frequency 160/min: 7×10−8 M, frequency 320/min: 6×10−8 M.4.Consequently, both frequency potentiation and the response to paired stimulation cannot be explained by changes in calcium fluxes per stimulus. It should rather be considered that the enddiastolic concentration of Ca2+-ions within the cell is a function of the frequency of stimulation. The higher the frequency, the higher the remaining Ca2+-ion-concentration will be. This phenomenon is particularly obvious during the application of paired stimuli. In this case the second excitation occurs at a moment where the Ca2+-ion concentration is so high that actomyosin is still completely activated. The level of the Ca2+ concentration at the end of the diastole may be caused by the relation between inactivation or outward transport of Ca2+ and the amount Ca2+ entering the cell per excitation.

The influence of iproveratril on calcium movements in isolated heart muscle

Abstract The influence of iproveratril on Ca-metabolism was studied in electrically driven, isolated atria of the guinea pig and also in resting left auricles. Iproveratril (5 × 10 -7 M) did not afffct the Ca influx in spite of its strong negative inotropic action. At 5 × 10 -5 M all mechanical activity ceased. This drug concentration reduced the passive Ca permeability in resting auricles. The results suggest that iproveratril cannot be considered as a specific calcium antagonist.

Effect of hydrazinophthalazines on catecholamines in rats.

Abstract The actions of hydralazine and dihydralazine on the noradrenaline content of the heart, adrenals and brain were investigated in rats. Both drugs decreased the concentration of bound dl-7-3H-noradrenaline in the rat heart. The only significant change in the endogenous catecholamine content of tissues after the drugs were given twice daily for two days was observed in the hearts of rats treated with dihydralazine. After a single injection of dihydralazine, the endogenous noradrenaline content of the heart decreased, the lowest concentration being reached after 4 hours, and then returned rapidly to normal levels 6 hours after the administration of the drug. The repeated administration of dihydralazine to rats which had received tritium-labelled noradrenaline, led to a decrease in the specific activity of the cardiac noradrenaline in the treated groups as compared with the controls. the depletion of cardiac noradrenaline is interpreted as the consequence of an increased activity of the sympathetic cardiac nerves, triggered off by the decrease in the peripheral vascular resistance.

Mechanical performance and calcium metabolism in rat isolated heart muscle after adrenalectomy

ZusammenfassungDas mechanische Verhalten und der Calcium-Stoffwechsel wurden in isoliertem Vorhofgewebe adrenalektomierter Ratten bestimmt. Eine beidseitige Adrenalektomie erfolgte 1 Woche vor Versuchsbeginn.1.Im Laufe einer 3stündigen Inkubation in normaler Tyrode-Lösung nahm die Kontraktionskraft der Vorhöfe adrenalektomierter Tiere signifikant schneller ab als die der Kontrollorgane. Der Effekt war der gleiche bei spontan kontrahierenden und bei elektrisch gereizten Vorhöfen (Frequenz 300/min).2.Zusatz von Corticosteron (10−5 g/ml) zur Tyrode-Lösung verhinderte die mechanische Insuffizienz der Vorhöfe adrenalektomierter Tiere.3.Etwa 1 Woche nach der Adrenalektomie war die Calciumkonzentration im Serum signifikant niedriger als im Serum von Kontrolltieren, die Gesamtcalciumkonzentration im Herzmuskel blieb jedoch unverändert.4.Nach Adrenalektomie der Spendertiere war der Ca-Influx in den Vorhöfen signifikant niedriger als bei den Kontrollen. Jedoch war in beiden Versuchsgruppen das gesamte celluläre Calcium austauschbar.5.Der reduzierte Influx von45Ca wurde in Anwesenheit von Corticosteron in der Badflüssigkeit (10−5 g/ml) wieder normalisiert.6.Die schnelle mechanische Ermüdbarkeit und die reduzierte Calcium-Austauschgeschwindigkeit des Vorhofgewebes von adrenalektomierten Ratten werden möglicherweise durch eine herabgesetzte Membranpermeabilität für Calcium verursacht. Corticosteron normalisiert die Beeinträchtigung der Membraneigenschaften auch in vitro.SummaryMechanical performance and calcium metabolism were studied in isolated atria, obtained from adrenalectomized rats. Bilateral adrenalectomy was carried out one week before dissection of the atria.1.Upon incubation in normal Tyrode solution for 3 h the contractile force of isolated atria obtained from adrenalectomized rats diminished significantly more rapidly than that of control atria. The effect was the same in spontaneously beating and in electrically driven atria (frequency 300/min).2.Corticosterone (10−5 g/ml) dissolved in the medium completely prevented the accelerated decline in contraction amplitude, observed in isolated atria from adrenalectomized rats.3.Approximately one week after bilateral adrenalectomy, the serum calcium content was significantly lower than that of control animals, although the calcium concentration in heart muscle remained unchanged.4.The uptake of45Ca from the medium by isolated atria proved significantly slower after adrenalectomy. However, in both cases (control atria and organs from adrenalectomized rats) all of the cellular Ca was exchangeable.5.Corticosterone (10−5 g/ml) in the medium restored the retarded uptake of45Ca after adrenalectomy to control values.6.The changes in mechanical performance and in calcium metabolism, observed in isolated atrial tissue from adrenalectomized rats migh be caused by a reduced permeability of the cell membrane towards Ca. Also in vitro, corticosterone restored the membrane permeability to normal values.

The use of86Rubidium for the determination of changes in membrane permeability in guinea pig atrial tissue

SummaryInvestigations were performed in order to establish whether86Rb may be used as a tool for the determination of changes in K-efflux, in guinea pig atrial tissue (isolated atria or left auricles). The isolated organs were incubated in K-free, Rb-containing Tyrode solution that contained 2.7 mM RbCl/l instead of KCl. An experimental, method was developed for the continuous recording of the mechanogram and of86Rb loss from isolated organs that had been loaded previously with86Rb.1.Even after incubation in Rb-Tyrode solution for 4–5 hrs the atria or left auricles showed entirely “normal” contractile activity and also a “normal” response towards electrical stimulation and towards various cardioactive drugs.2.Upon incubation in Rb-Tyrode solution the Rb concentration in atrial tissue reached a maximum of 53 mMol Rb+/l fibre water. At equilibrium the tissues still contained 22 mMol K+/l fibre water and also about 70 mMol Na+/l fibre water. The Na+ simultaneously taken up is probably a compensation for the cation deficit and not necessarily the expression of damage to the cells, since the mechanical activity remained unimpaired.3.The exchange of86Rb+ ions occurred with two different rate constants. For beating atria (180/min) these constants were 22.4×10−4 and 2.0×10−4 sec−1, for resting left atria 17.8×10−4 and 0.8×10−4 sec−1, respectively. The Rb efflux for beating atria and resting left atria amounted to 3.2 and 1.3pMol Rb+ cm−2 sec−1, respectively (slower phase).4.The Rb efflux proved directly related to the number of contractions but independent on the contractile force. The extra efflux per beat was approximately 0.6pMol Rb+ cm−2.5.2.4-dinitrophenol provoked a strong, dose-dependent increase of86Rb efflux.6.From the results it is concluded that86Rb is a suitable isotope for the estimation of changes in membrane permeability for ions in atrial tissue, especially in pharmacological experiments.ZusammenfassungEs wurde untersucht, inwiefern86Rb für die Bestimmung von Veränderungen des K-efflux in isoliertem Vorhofgewebe des Meerschweinchens verwendet werden kann (isol. Vorhöfe bzw. linke Herzohren). Die isolierten Organe wurden in einer K-freien, Rb-haltigen Tyrode-Lösung inkubiert, die pro Liter 2,7 mMol RbCl statt KCl enthielt. Es wurde eine experimentelle Methode entwickelt die es ermöglichte, sowohl das Mechanogramm als auch die Abgabe von vorher aufgenommenen86Rb kontinuierlich zu registrieren.1.Nach einer vier-bis fünfstündigen Inkubation in Rb-haltiger Tyrode-Lösung blieben die Vorhöfe und Herzohren noch voll funktionstüchtig. Die Organe reagierten „normal” auf elektrische Reizung und auf verschiedene herzwirksame Pharmaka.2.Während der Inkubation in Rb-Tyrode-Lösung erreichte die Rb-Konzentration im Gewebe ein Maximum von 53 mMol/1 Faserwasser. Im Gleichgewicht enthielt das Gewebe noch 22 mMol K+/l Faserwasser und 70 mMol Na+/l Faserwasser. Das gleichzeitig aufgenommene Natrium kompensiert das Kationendefizit und muß nicht unbedingt auf eine Zellschädigung hinweisen.3.Der Austausch von86Rb+-Ionen verlief mit zwei verschiedenen Zeitkonstanten. Für kontrahierende Vorhöfe betrugen diese Konstanten 22,4·10−4 und 2,0·10−4 sec−1, für ruhende linke Herzohren 17,8·10−4 und 0,8·104 sec−1. Der Rb+-Efflux in der langsamen Phase betrug für kontrahierende Vorhöfe und für ruhende linke Herzohren 3,2 bzw. 1,3pMol Rb+ cm−2 sec−1.4.Die Größe des Rb+-Efflux ist direkt abhängig von der Anzahl Kontraktionen des Vorhofgewebes, jedoch nicht von der Kontraktionskraft. Pro Kontraktion werden zusätzlich zum Ruhe-Efflux etwa 0,6pMol Rb+ cm−2 freigesetzt.5.Der Stoffwechselhemmstoff 2,4-Dinitrophenol verursacht eine beträchtliche, dosisabhängige Zunahme der86Rb-Abgabe.6.Die Ergebnisse legen den Schluß nahe, das Isotop86Rb sei vor allem im pharmakologischen Experiment zur Bestimmung von Änderungen der Membranpermeabilität für Ionen geeignet.