Antimalarial Compounds as Antagonists of Adenosine

Abstract

The possible antagonism of the action of adenosine on some tissues by antimalarial drugs has been studied with the object of obtaining some information on the mode of action of this type of drug. METHODS Antagonism of adenosineThe following techniques were used in these experiments:(1) The isolated hen's caecum.-The action of adenosine on this tissue (Barsoum and Gaddurn, 1935) was studied before and after the addition to the bath -of known concentrations of antimalarials. Although it was possible to demonstrate an antagonism between these compounds and adenosine by this method, satisfactory results were not obtained because ofthe intense relaxation of the caecum produced by the antimalarial substances themselves.(2) The measurement of the duration of the auriculoventricular (a.v.) block produced by intravenous administration of adenosine in the anaesthetized guinea-pig (Drury and Szent-Gybrgyi, 1929 In each experiment a series of doses of adenosine from 0.1 to 0.3 mg./kg. was first administered in order to produce varying degrees of a.v. block. The cannula was then washed with the solution of antimalarial and the drug slowly infused by means of a motor-driven syringe which delivered the solution at the rate of 0.02 ml./min. This infusion was maintained for 30 min. after which the cannula was washed with adenosine solution and a second series of adenosine injections was administered in doses large enough to produce measurable heart blocks.The dose of antimalarial was calculated in mg./kg./min. and adjusted by varying the concentration according to the body-weight of each animal. At least 3 guinea-pigs were used for each dose level of antimalarial.This series was used mainly for the selection ofchemical types able to antagonize the action of adenosine.(b) In the second series the compounds were administered orally in a dosage regime similar to that used by Davey (1946) for the assessment of antimalarial activity against P. gallinaceum in chicks.Batches, usually of 6 guinea-pigs each, were used for each dose level of every compound tested. The animals received two doses daily for -31 days, a total of 7 doses. The drugs were administered in solution in water, or in fine suspensions when insoluble, by means of a stomach tube. After the 7th dose, the guinea-pigs were anaesthetized with pentobarbitone and a series of adenosine injections-was administered as described above.These experiments will be referred to as " chronic" later on.(c) Some experiments were carried out with heart-lung preparations of guinea-pigs. The method was essentially that described by Cruickshank (1945) for the rat; 25 ml. of heparinized guinea-pig's blood were used in the apparatus. The elastic peripheral resistance was adjusted to give a pressure of 80-100 mm. Hg in the aortic cannula; e.c.g. records were taken with leads placed in the superior vena cava and in the apex of the heart. Adenosine was injected into the venous cannula of the preparation.

The birth and postnatal development of purinergic signalling

“…Various antagonists at P2 purinoceptors have been claimed over the years, including: quinidine (Burnstock et al 1970; imidazolines (Madinaveitia & Raventos 1949, Satchell et al 1973); 2-2¢-pyridilisatogen (Spedding et al 1975); ANAPP 3 (Hogaboom et al 1980); apamin ; selective desensitization with a,b-meATP (Kasakov & Burnstock 1982); reactive blue 2 (Kerr & Krantis 1979, Manzini et al 1986, Burnstock & Warland 1987; pyridoxalphosphate-6-azophenyl-2,4¢-disulphonic acid (PPADS) (Lambrecht et al 1992suramin (Dunn & Blakeley 1988, Hoyle et al 1990); 4,4¢diisothiocyanostilbene-2,2¢-disulphonate (Soltoff et al 1993, Bultmann & Starke 1994a). More recently, 2propylthio d-b,c-difluoromethylene ATP (FPL 66092) has been claimed as a P 2T -selective antagonist (Humphries et al 1994) and reactive red 2 as a P 2Y -selective antagonist (Bultmann & Starke 1995).…”

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non‐adrenergic inhibitory nerves in the gut

“…Quinine was reported to antagonize the relaxing effects of adenosine on the fowl rectal caecum (Madinaveitia & Raventos, 1949) but in concentrations up to 10-g/ml quinine had no effect on responses of the taenia coli to ATP or to stimulation of adrenergic or non-adrenergic inhibitory nerves. Similarly, 2,6-xylenol (2 x 10-5 g/ml), a phenol reported to antagonize ATP-induced pulmonary vasoconstriction (Lunde, Waaler & Wall0e, 1968), was without effect on the inhibitory responses of the taenia coli.…”

Purine Antagonists in the Identification of Adenosine‐receptors in Guinea‐pig Trachea and the Role of Purines in Non‐adrenergic Inhibitory Neurotransmission

“…Five compounds with reported purine antagonist activity in a variety of other tissues were tested: they were quinidine (Madinaveitia & Raventos, 1949;Wayne, Goodwin & Stoner, 1949;Bowman & Hall, 1970, Burnstock, Campbell, Satchell & Smythe, 1970, phentolamine (Rikimaru, Fukushi & Suzuki, 1971;Satchell, Burnstock & Dann, 1973) phenoxybenzamine (Nayler, Price & Lowe, 1967), 2-2'-pyridylisatogen tosylate (Spedding, Sweetman & Weetman, 1975) and caffeine (Ther, Muschaweck & Hergott, 1957;Nicholas & Walaszek, 1963;de Gubareff & Sleator, 1965).…”