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A quantitative study of antagonists of adrenaline on the vessels of the rabbit's ear
... Strychnine was also tested as a histamine antagonist. The ability of this compound to abolish post-synaptic inhibition of spinal cord motoneurones is well known (Eccles, 1957) and it has recently been shown that it depresses some synaptic inhibitions as well as the inhibitory effects of ACh, noradrenaline and 5-hydroxytryptamine on cortical neurones (Phillis & York, 1967b). A similar effect was observed on the histamine depression of cortical neurones (Fig. 4C ). ...
... Evidence for a synaptic transmitter role of histamine will, however, have to await the availability of more specific antagonists. The non-specificity of action by histamine antagonists on cortical neurones may possibly be explained by the so-called " local anaesthetic," anti-ACh and anti-catecholamine actions of some of these compounds (Reuse, 1948; Lands et al., 1949; Fleckenstein, 1952; Sethi, Gulati, Gokhale & Joseph, 1967). The iontophoretic method of application of drugs seems to discriminate between the specificity of various types of antagonist compound. ...
... Indeed, 'adrenaline receptor' was employed by many distinguished pharmacologists up until the early 1960s (e.g. Dale, 1943;Ing, 1943;Tickner, 1951;Fleckenstein, 1952;McDougal and West, 1953;Stafford, 1963). So, how did it all get so confused that three alternative names (adrenoceptor, adrenoreceptor, adrenergic receptor) are now used, none of them corresponding to these logical names? ...
Unlabelled:
This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2011 by J.C. McGrath. A recording of the lecture is included as supporting information. It covers his laboratory's work from 1990 to 2010 on the localization of vascular α1 -adrenoceptors in native tissues, mainly arteries.
Main points:
(i) α1 -adrenoceptors are present on several cell types in arteries, not only on medial smooth muscle, but also on adventitial, endothelial and nerve cells; (ii) all three receptor subtypes (α1 A , α1 B , α1 D ) are capable of binding ligands at the cell surface, strongly indicating that they are capable of function and not merely expressed. (iii) all of these cell types can take up an antagonist ligand into the intracellular compartments to which endocytosing receptors move; (iv) each individual subtype can exist at the cell surface and intracellularly in the absence of the other subtypes. As functional pharmacological experiments show variations in the involvement of the different subtypes in contractions of different arteries, it is concluded that the presence and disposition of α1 -adrenoceptors in arteries is not a simple guide to their involvement in function. Similar locations of the subtypes, even in different cell types, suggest that differences between the distribution of subtypes in model systems do not directly correlate with those in native tissues. This review includes a historical summary of the alternative terms used for adrenoceptors (adrenergic receptors, adrenoreceptors) and the author's views on the use of colours to illustrate different items, given his partial colour-blindness.
... Similar effects of lignocaine have been reported on isolated peripheral vessels (Gerke, Frewin and Frost, 1976) and aortic strips (Astrom, 1964;Fleisch and Titus, 1973) suggesting considerable catecholamine-lignocaine antagonism in vascular smooth muscle. Such antagonism probably holds true for most local anaesthetics in vitro (Fleckenstein, 1952;Astrom, 1964). Our preliminary in vivo investigations on two other common amide local anaesthetics, prilocaine and mepivacaine, produced results similar to those obtained with lignocaine. ...
The effects of i.a. administered lignocaine on the in vivo response of the vascular bed supplied by the lingual, external
maxillary and posterior auricular branches of the common carotid artery were studied in the rat. Infusions of lignocaine in
concentrations of 10–1000 μg ml−1 administered at the rate of 0.05 ml min−1 for 10 min did not affect vascular resistance or arterial pressure in the common carotid artery. However, following such
infusions, the increase of vascular resistance caused by bolus doses of adrenaline (20–120 ng in 0.1 ml) was inhibited, indicating
lignocaine-adrenaline antagonism. Responses to adrenaline remained significantly depressed 60 min after the termination of
a 100-μg ml−1 or higher lignocaine infusion.
The complexity of the effects of histamine upon the circulatory apparatus might explain what was called, in earlier times, the “histamine paradox”. When injected intravenously in cats and dogs, histamine produced a sharp fall in arterial blood pressure, though when perfused through isolated tissues or organs, not infrequently, a pure vaso-constrictor effect with decline in outflow was observed. This constrictor effect upon isolated perfused organs was particularly seen in cats (Dale and Richards, 1918). With improvement in the conditions of the perfusion experiments, and especially when dogs or monkeys were utilized as donors of the biological structure to be perfused, a vasodilation with increase in volume of the perfused limb and its venous outflow was observed (Burn and Dale, 1926). However, in rabbits and rats the main effect of histamine, when injected into the perfusing cannula, was a sharp decrease in outflow, in spite of the fact that when the amine was injected intravenously in the intact rat, a consistent fall in blood pressure could be observed. Even in the rabbit, under special conditions of anesthesia, histamine produced a fall of arterial blood pressure (Feldberg, 1927). Therefore, the paradox persists and can be understood only through an extensive analysis of the mode of action of histamine upon the cardio-vascular system.
This chapter provides an overview of hypotensive Agents. Hypotensive agents are grouped into (1) ganglion-blocking compounds, (2) RauwolJia alkaloids, (3) Veratrum alkaloids, (4) hydrallazine, and (5) bretylium and guanethidine that selectively inhibit sympathetic impulses at nerve-endings. The diuretic compound, chlorothiazide, and its congeners, given in conjunction with hypotensive agents, enhance their effects. Ganglion-blocking compounds may be sub-divided into quaternary ammonium compounds and amines. The former are not well absorbed on oral administration as the latter, and their distribution in the body is confined to the extracellular body fluids. Hexamethonium, pentolinium, and chlorisondamine block transmission in both sympathetic and parasympathetic ganglia, their side effects consisting mainly of parasympathetic block. The fall in blood pressure resulting from the administration of reserpine has been attributed partly to a central action and partly to a peripheral effect on the sympathetic system. Hydrallazine has the property of dilating the renal vessels as well as lowering the blood pressure, but it has side effects that limit its usefulness.
Marked nicotine-like stimulant properties are possessed by choline phenyl ether and choline o-tolyl ether, and to a decreasing extent by choline 2:6-xylyl ether and choline 2:4:6-mesityl ether. The compounds all show neuromuscular blocking properties, which are of short duration and pass from mainly decamethonium-like to mainly curare-like as more methyl groups are added to the phenyl nucleus. This series of compounds also possesses muscarinic, weak anti-adrenaline and vasodilator properties, as well as long-lasting local anaesthetic effects in the two compounds tested by intradermal injection.
The hypotensive action of various antimuscarinic compounds structurally related to atropine was studied in conscious, unanesthetized rats. The alpha-adrenolytic activity of these agents was assessed both in vivo (blockade of norepinephrine-induced pressor response) and in vitro (displacement of [3H]WB-4101 binding). Benztropine, homatropine and hyoscyamine caused hypotension and produced alpha-adrenergic receptor blockade similar to atropine. Other analogues were either inactive (atroscine, scopolamine, tropic acid and tropine) or evoked nonspecific changes in blood pressure and lacked alpha-adrenolytic activity (benactyzine, eucatropine, methylatropine, methylhomatropine and methylscopolamine). Based on these data, we propose the following structure-activity relationship for hypotension and alpha-adrenolytic activity: (a) the tropine moiety is inactive unless it is attached to another group by an ester linkage, (b) chemical modification of the tropine moiety, including quaternization, decreases potency, (c) the d-stereoisomer appears to be more potent than the corresponding 1-form.
1. The rat isolated anterior mesenteric artery was perfused at a constant rate with a calcium-free depolarizing solution. Injection close to the cannula of 0.05-0.1 ml. of solutions of CaCl(2) (117 mM) or BaCl(2) (100 mM) caused a rise in perfusion pressure.2. The responses to injected CaCl(2) solution could be obtained repeatedly but those to successive injections of BaCl(2) solution slowly declined. When the responsiveness to barium had almost disappeared, it could be restored by the addition to the perfusing fluid of a small amount of calcium (0.05 mM).3. The contractile effects of calcium or barium were antagonized by the addition to the perfusing fluid of several anti-inflammatory substances, certain local anaesthetics and certain spasmolytic drugs.4. Perfusion of the mesenteric artery with a depolarizing solution containing 0.2 mM-CaCl(2) caused a persistent rise of the perfusion pressure. This was rapidly and completely reversed by the addition of indomethacin (4 mg/100 ml.) or cinchocaine hydrochloride (2 mg/100 ml.) to the perfusing fluid.5. The uptake of (45)Ca by rat aorta depleted of calcium was reduced by amethocaine hydrochloride (10 mg/100 ml.) or cinchocaine hydrochloride (2 mg/100 ml.) but not by indomethacin (10 mg/100 ml.) or desipramine hydrochloride (1 mg/100 ml.).
Xylocaine (lidocaine) and procaine but not nupercaine caused contractions of the rat vas deferens. Xylocaine produced a persistant type of contraction whereas procaine produced phasic contractions with marked spontaneous activity. An analysis of their contractions suggests that both agents act directly on the smooth muscle cells. The contractions were found to be modified by various experimental procedures. They were reduced or abolished by lowering the temperature of the bathing media to 25°C. The contractions to both agents were highly dependent of the glucose concentration of the medium. Inhibitors of both glycolysis and oxidative phosphorylation abolished their contractile responses suggesting that glucose is essential for providing metabolic energy for the actions of xylocaine and procaine. Contractions to these two local anesthetics were highly dependent of the pH of the physiological solution. An increase in the pH increased their contractions and vice versa. Though studies of the pH effect indicate that the unionized forms of the local anesthetics are necessary for their action, the molecular species responsible for inducing contractions still remains unsolved.
1 A modification of the Folkow Technique for simultaneous measurement of blood flow and capillary filtration coefficient (CFC) in the cat jejunum is described. The modification retained the sympathetic innervation of the preparation, and in the present experiments, drugs were administered intravenously.2 There is evidence that CFC is a cardiovascular quantity independent of blood flow or regional vascular resistance in these preparations. Low doses of drugs may affect CFC without altering the blood pressure, blood flow, or heart rate.3 Under control conditions the CFC, a measure of functional exchange vessel area, was lower than previously reported for similar, but denervated preparations.4 alpha-Adrenoceptor stimulation with phenylephrine (1.0 mug kg(-1) min(-1), i.v.) caused a fall of 75-85% from control values of CFC with concomitant rises in blood pressure of 0-15% and falls in blood flow of 10-40%. The heart rate rose by 0-15%. Phentolamine (0.5-2.0 mg/kg, i.v.) caused a rise in CFC and a slight fall in vascular resistance, and blocked the effects of phenylephrine on this tissue.5 beta-Adrenoceptor stimulation with isoprenaline (0.2 mug kg(-1) min(-1), i.v.) caused a rise in CFC of 75-110%, a fall in blood pressure of 0-10%, a rise in blood flow of 10-60% and a rise in heart rate of up to 35%. Propranolol caused a transient rise in CFC when injected i.v. in a dose of 0.1 mg/kg, which was adequate to block the effects of isoprenaline.6 Angiotensin (25-100 ng kg(-1) min(-1), i.v.) caused falls in CFC of up to 100% and rises in vascular resistance. Aminophylline (0.2-0.4 mg kg(-1) min(-1), i.v.) caused rises in CFC of up to 200% with falls in vascular resistance.7 Histamine (0.01 to 1.0 mug kg(-1) min(-1), i.v.) had little effect on vascular resistance, but 10 and 40 mug kg(-1) min(-1) caused falls in vascular resistance. Doses up to and including 10 mug kg(-1) min(-1) caused falls in CFC, but the higher doses, or smaller doses after histaminase inhibition caused rises in CFC. alpha-Adrenoceptor blockade reversed the fall in CFC caused by small doses of histamine, to a rise. Mepyramine completely blocked the effects of histamine on these preparations.8 5-Hydroxytryptamine (33-100 mug kg(-1) min(-1), i.v.) caused a rise in vascular resistance and a fall in CFC of up to 85%. These effects were blocked by methysergide (250 mug/kg, i.v.).9 Rises in CFC indicate an increase in functional exchange vessel area in the tissue, and falls in CFC a decrease in the area available for vascular exchange. These changes are examined against the possibility of the drugs causing reflex adjustments in sympathetic tone, of systemic deactivation of intravenously administered drugs, and of drug effects on vascular permeability.
Rabbit aortic strips were used to investigate and compare the interactions of epinephrine and norepinephrine with cocaine, procaine, and lidocaine. Cocaine potentiated responses to epinephrine and norepinephrine. Responses to epinephrine were antagonized by procaine and lidocaine and responses to norepinephrine were potentiated. Lidocaine possessed some intrinsic activity.
This chapter intends to portray the present knowledge on site and mechanism of action of the ergot alkaloids. The presentation is based chietly on selected work performed in defined isolated systems in which the interference with specific substrates usually called receptors has been sufficiently proven. We hope that this presentation will contribute to the understanding of the complexity of ergot pharmacology as presented in the following chapters.
The cholinoceptor antagonists anisodamine and anisodine are widely used in the People's Republic of China for the management of acute circulatory shock but the mechanism of their beneficial effects is not fully known; we therefore investigated if these agents possessed adrenoceptor blocking properties. The antagonistic effect of anisodamine and anisodine against the specific binding of the alpha 1-adrenoceptor ligand [3H]-WB-4101 to cardiac and brain tissue membrane preparations and against the effects of phenylephrine on isolated aortic strips and left atria of rats were compared with classical muscarinic receptor and adrenoceptor blocking agents. Both anisodamine and anisodine possessed alpha 1-adrenoceptor blocking properties; the order of potency of various agents in displacing the binding of [3H]-WB-4101 to receptors and in antagonizing the effects of phenylephrine on aortic strips and left atria was: prazosin greater than atropine greater than anisodamine greater than scopolamine greater than anisodine. It is concluded that both anisodamine and to a lesser extent anisodine possess alpha 1-adrenoceptor blocking properties; this antagonistic activity of anisodamine may contribute to its salutary effects on the microcirculation. However, it is unlikely that anisodine produces a significant adrenoceptor blockade in the clinically used dose-range.
Atropine sulfate elicited a dose-dependent decrease in blood pressure in normotensive rats at doses higher than needed to cause muscarinic blockade. This hypotensive effect was not altered by pretreatment with ganglionic or β-adrenergic blockers, but was fully abolished by α-adrenergic blockers. In addition, atropine inhibited the pressor response to α-agonists in a dose-dependent manner. The time course for hypotension and α-blockade were the same (onset < 1 minute; duration < 20 minutes). , atropine was found to be 200 times more potent in displacing the α1-adrenergic receptor ligand ([3H] WB-4101) than the α2-ligand ([3H] clonidine). Thus the observed hypotensive effect is apparently due to α-blockade as demonstrated and .
Symptomatologie, Diagnostik, Methoden zur Lokalisation, properative Behandlung, Anaesthesie, operatives Vorgehen, postoperative Behandlung, pathophysiologische Grundlagen der Therapie mit zustzlicher Blutinfusion und Morphologie unterschiedlicher Phaeochromocytomtypen werden an Hand je eines rein ausgeprgten Falles vom Adrenalin- und Noradrenalintyp besprochen. Das gegenstzliche histochemische Verhalten der beiden Phaeochromocytome steht mit ihrem eindeutigen klinischen Bild in guter bereinstimmung.
An Katzen in Urethan-Chloralose-Narkose wurde — im Vergleich zu DHE und Antistin — die Wirkung einiger Phenothiazinkrper auf die Nierenischmie bei elektrischer Reizung des Plexus renalis untersucht. Die Wirkungsstrken von Megaphen, Pacatal, Padisal, Antistin, Atosil und Latibon verhielten sich dabei etwa wie 1:1/16:1/20:1/20:1/20:1/40. Auch die Wirkungsdauer von Megaphen berragte die der anderen Phenothiazine bei weitem. hnliche Ergebnisse wurden bei postganglionrer elektrischer Reizung des Halssympathicus und — mit allgemein geringerer Dosierung — bei i.v. Injektion von Adrenalin und Noradrenalin an der denervierten Nickhaut dekapitierter Katzen erzielt.
Several local anesthetic agents have been tested for their ability to counteract adrenaline-and noradrenaline-induced contractions of the spirally cut strip of rabbit aorta. The method used includes a calibrated spiral spring arrangement attached to a conventional strain gauge transducer. This device which is very useful also for several other isolated organs, is described in detail. All the local anesthetics tested possess anti-adrenaline activity in appropropiate concentrations (1–3 mM), but procaine, mepivacaine and o-methyl-α-propylamino-propionanilide (L 67) are about 5 times more active than lidocaine and cocaine in this respect. The antagonism is non-specific in nature and contractions induced by histamine are counteracted in a similar manner. The results are discussed in relation to the known anesthetic properties of the agents. The conclusion is drawn that the non-specific anti-adrenaline action varies independently of the local anesthetic effect as measured in vitro on the isolated nerve preparation.
Zusammenfassung 1.Es wird eine Methode zur Herstellung einer positiv geladenen, elektiv anionendurchlässigen Membran beschrieben, die darauf beruht, daß der basische Farbstoff Rhodamin B in die Porenwandungen von Kollodiummembranen eingelagert wird.2.Der Nachweis der elektiven Anionenpermeabilität dieser Membranen wird sowohl auf analytischem Wege durch Nachweis des Anionenaustausches in Dialyseversuchen wie auch durch Messung der Membranpotentiale geführt.3.Die elektrometrischen Werte zeigen, daß elektromotorisch wirksam nur Anionen sind, Kationen dagegen keinen Effekt haben. Es verhalten sich daher diese Membranen gegensätzlich zu den getrockneten, negativ geladenen Michaelisschen Kollodiummembranen.4.Werden die Anionen nach ihrer elektromotorischen Wirksamkeit geordnet, so erhält man die lyotrope Reihe: + SCN, NO3, J, Br, Cl, Acetat, SO4. Bei der Messung der Konzentrationseffekte wurde die verdünntere Lösung gegenüber der konzentrierteren negativ gefunden. Weiterhin zeigte sich, daß mit Abnahme der absoluten Konzentrationen bei gleichbleibendem Konzentrationsverhältnis die Größe der Potentialdifferenzen sinkt.
The attempt is made to reconcile the two existing theories on the mechanism of selective ion permeability of the cell membrane by taking into account the molecular arrangement in the substance of the membrane. It is shown that the pore theory and the solubility theory are not contradictory, but two aspects of the same problem, one from the thermodynamic point of view, the other from the point of view of molecular theory. The dried collodion membrane is used as a model in these studies. Its different behavior towards anions and cations is explained on the ground of a quasi-crystalline structure of collodion, the NO(3)-groups acting as dipoles with the negative charge directed towards the intermolecular spaces, no matter whether these pores are of molecular dimensions or larger. In this way a continuity in the behavior of the ordinary large pored collodion membrane and the dried membrane is established, both theoretically and experimentally. Experiments, with membranes of other cellulose derivatives agree with the mechanism suggested. Membranes of cellophane and ethyl cellulose are negatively charged, membranes of cellulose acetate positively. From solutions of collodion mixed with basic dyestuffs or alkaloids membranes can be obtained more permeable to anions than to cations in contrast to the ordinary collodion membrane. Membranes can be built which give high potential differences even between two identical electrolyte solutions. The asymmetry lies here within the membrane and is artificially produced by gluing together an ordinary collodion membrane with one previously impregnated with a basic dyestuff or an alkaloid.
Some antihistamine compounds The action of dibenamine is almost irreversible. Tolazoline Antihistamine compounds Anti-This preference may be obvious Brit
- H Haas
- R Mond
- F Hoffmann
- T Sollmann
- R P Stephenson
Haas,H.(1951). Mond, R., and Hoffmann, F. (1928). Pflug. Arch. ges. Physiol., 220, 194. Sollmann,T.(1945). Stephenson, R. P. (1948). Wilbrandt, W. (1935).J. gen. Physiol., 18, 933. Some antihistamine compounds The action of dibenamine is almost irreversible. Tolazoline Antihistamine compounds Anti-This preference may be obvious Brit. J. Pharmacol., 6, 110. Arch. exp. Path. Pharmak., 214, 38
The anti-adrenaline potencies of various substances, including anti-adrenaline and antihistamine compounds, simple local anaesthetics, and substances like atropine, pethidine, quinine, quinidine, tolazoline (Priscol), and strychnine, have been REFERENCES Burn
The anti-adrenaline potencies of various substances, including anti-adrenaline
and antihistamine compounds, simple local anaesthetics, and substances like atropine,
pethidine, quinine, quinidine, tolazoline (Priscol), and strychnine, have been
REFERENCES
Burn, J. H., and Dutta, N. K. (1948). Brit. J. Pharmacol., 3, 354.
- L J Bussell
- R P Cook
Bussell, L. J. (1940). J. Pharmacol., 69, 128.
Cook, R. P. (1926). J. Physiol., 62, 160.
- J H Burn
Burn, J. H., and Robinson, J. (1951). Brit. J. Pharmacol., 6, 110.
Histamin und Antihistamine
- H Haas
Haas, H. (1951). Histamin und Antihistamine, Editio Cantor, Aulendorf (Germany).
Manual ofPharmacology
- T Sollmann
Sollmann, T. (1945). Manual ofPharmacology, 6th ed. Philadelphia: Saunders.
Stephenson, R. P. (1948). J. Physiol., 107, 162.