The Inhibition by Sodium Salicylate of Oedema of the Hind‐paw of the Rat Induced by 5‐hydroxytryptamine

The swelling and capillary hyperpermeability of the mouse foot in response to an injection of formaldehyde, and the increased capillary permeability to an intradermal injection of histamine, have been investigated. Cortisone, mepyramine and sodium salicylate were effective in reducing histamine-induced inflammation, sodium salicylate being less active in the adrenalectomized animal. In formaldehyde-induced inflammation, however, cortisone was ineffective whereas sodium salicylate was effective in the intact mouse, but not in the adrenalectomized animal. Certain aryloxypropionates and anti-esterases were also active in reducing the severity of the formaldehydeinduced inflammation.Formaldehyde will induce an inflammatory reaction at the site of injection, and this has been used by Parratt & West (1957) for studying inflammation quantitatively in the rat foot. Selye (1949) first described the effect of injected formaldehyde in the rat foot as an "arthritic " reaction, but this has been criticized by Bourne (1951) as inaccurate. Various authors are agreed, however, upon the main point, that formaldehyde produces a local inflammation.

Section: Resultsmentioning

confidence: 96%

Some Inhibitors of Histamine‐induced and Formaldehyde‐induced Inflammation in Mice

Northover

Subramanian

1961

“…It has long been recognized that sodium salicylate has a cortisone-like effect, but it has been shown that in man this is not due to an increase in the plasma level of adrenal cortical hormone (Bayliss and Steinbeck, 1954). Kelemen (1957) has shown that salicylate antagonizes the oedema of the paw in the rat produced by locally injected 5-HT in the intact but not in the adrenalectomized animal. This suggests that salicylates depend in some way on the adrenal corticoids for some of their actions, and it seems likely that a similar synergism plays a part in the antagonism of the vascular effects of 5-HT in man.…”

Section: Methodsmentioning

confidence: 99%

“…In the present paper a comparison is made of the antagonistic effect on these responses of 2-bromo-( + )-lysergic acid diethylamide bitartrate (BOL 148) with that of sodium salicylate, which has been shown by Kelemen (1957) to diminish the oedema of the paw of the rat produced by locally injected 5-HT.…”

mentioning

confidence: 99%

The Antagonism of the Vascular Effects of 5‐hydroxytryptamine by Bol 148 and Sodium Salicylate in the Human Subject

Glover

Marshall

Whelan

1957

2-Bromo-(+)-lysergic acid diethylarmide kBOL 148) is a specific antagonist of the constrictor response of the forearm and hand blood vessels to intra-arterial infusions of 5-hydroxytryptamine. This has been shown to be a direct action in the tissue concerned, since the antagonism was as effective when the drug was given by local arterial injection as when given intravenously. Sodium salicylate is also a specific antagonist oi 5-hydroxytryptamine, but its action is indirect, occurring only when the general serum level was raised above 10 or 20 mg.%,!; local limb concentrations of 30 to 40 mg.% had no antagonistic effect. The mechanism of the antagonistic effect of salicylate is not known. It is not related to the associated hyperventilation but is possibly due to the secondary release of, or synergism with, some other substance, probably a hormone.A number of substances including lysergic acid derivatives have been shown by Gaddum and Hameed (1954) and other workers to antagonize the action of 5-hydroxytryptamine (5-HT) on isolated smooth muscle preparations. The effect of some of these substances on the response of the blood pressure to intravenous 5-HT has also been studied in animals (Page and McCubbin, 1953;Salmoiraghi, McCubbin, and Page, 1957) and in man (Spies and Stone, 1952).The vascular responses in the upper limbs of normal human subjects to intra-arterial injections of 5-HT have been described (Roddie, Shepherd, and Whelan, 1955). In the present paper a comparison is made of the antagonistic effect on these responses of 2-bromo-( + )-lysergic acid diethylamide bitartrate (BOL 148) with that of sodium salicylate, which has been shown by Kelemen (1957) to diminish the oedema of the paw of the rat produced by locally injected 5-HT. MATERIALS AND METHODSThe investigations were carried out on ourselves, our colleagues, and medical students. The subject rested on a couch for at least 30 min. before the first observation was made. The room temperature was kept at a constant level in the range 22 to 25'. An indwelling needle was inserted into the left brachial artery in the antecubital fossa and through it either 0.9% saline or a solution of the drug was infused at *Present address: Department of Human Physiology and Pharmacology, University of Adelaide, S. Australia. a rate of 4 ml. /min. using a mechanically driven syringe and a length of polythene tubing. Measurements of forearm blood flow were made by venous occlusion plethysmography using the water-filled, mechanically stirred plethysmographs described by Greenfield (1954), the water temperature being 34 to 350.Changes in the circulation through the skin of the finger were followed using the heat flow discs described by Hatfield (1950). These were applied to the finger pulp using Nobecutane (Evans) and the whole hand inserted into a plethysmograph, the temperature of which was carefully maintained at 29'. In most experiments control observations were made on the opposite limb.5-Hydroxytryptamine creatinine sulphate (Sandoz) was infused intra-arterially f...

“…In the doses which were active against formaldehyde none of these compounds showed any activity against 5-hydroxytryptamine. Keleman (1957) found that salicylate in doses of 600 mg/kg reduces 5-hydroxytryptamine-induced inflammation in the rat foot, but the doses which he used were considerably greater than those used by us.…”

Section: Resultsmentioning

confidence: 99%

A Study of Possible Mediators of Inflammatory Reactions in the Mouse Foot

Northover

Subramanian

1962

A number of compounds have been studied for their ability to antagonize the inflammatory reaction produced by injections of formaldehyde and 5-hydroxytryptamine in the mouse foot. An attempt has been made to elucidate the ways in which certain hydroxybenzoates, pyrazolones, sympathomimetic amines, flavone and flavanone glycosides, local anaesthetics, antihistamines and anti-5-hydroxytryptamine substances produce their anti-inflammatory effect.Several substances occur in damaged tissues which have the ability to increase capillary permeability, the subject having been reviewed by Spector (1958). The presence of such substances does not prove their participation in the mediation of the symptoms observed, and it is difficult to differentiate between the causes and the effects of the process in many types of inflammation. Since Lewis (1927) demonstrated that part of the response of tissues to trauma is mediated by an axon-reflex there has been little work done to discover to what extent this process operates in different types of inflammation. Chambers & Zweifach (1947) have emphasized that little is known about the effect which local changes in blood flow have on the overall inflammatory reaction, and so we have attempted, in the experiments described here, to analyse the anti-inflammatory action of certain drugs which are known to alter blood flow in the skin. METHODSFormaldehyde-induced inflammation in the mouse foot. The details of the method have been described by Northover & Subramanian (1961a). Adult mice of either sex weighing between 25 and 35 g were used in groups of 6 animals. The animals were pretreated with the test substance, given subcutaneously, one injection 24 hr and another 30 min before the injection of formaldehyde. Where variations of this procedure were used they are indicated in the text. All premedicant injections were made in a dose-volume of 0.1 ml., and all compounds were given either as freshly prepared solutions or suspensions, adjusted, where required, to pH 7 with either sodium hydroxide or hydrochloric acid. Each mouse received 0.1 ml. of an aqueous solution containing 0.5% azovan blue and 0.9% sodium chloride through a lateral tail vein, and then immediately afterwards 0.05 ml. of an aqueous solution containing 4% formaldehyde and 0.9% sodium chloride subcutaneously in the dorsum of the right hind foot. The left hind foot received the same volume of saline alone and acted as a control for the formaldehyde-treated foot. The blue-dye accumulation and the swelling in the test foot compared with the control foot were given subjectively assigned scores of from 0 to 3 by