No abstract

Cats in which the coronary and allied chemoreflexes could not be obtained with small intravenous doses of 5-hydroxytryptamine were insensitive also to phenyldiguanide. In cats which responded to phenyldiguanide with reflex falls of blood pressure and heart rate, abolished by vagotomy, the effects of graded doses (5 to 150 pg./kg.) of phenyldiguanide bore a striking resemblance to those produced initially by 5-hydroxytryptamine in somewhat smaller doses. Differences in the cardiovascular responses to the two drugs are attributed to additional (non-reflex) actions of 5-hydroxytryptamine. The reflex actions of both drugs were blocked reversibly also by 2-naphthylguanidine (500 pxg.). Certain other drugs (bufotenine, procaine, S-decylisothiourea) antagonized the depressor action of phenyldiguanide as well as the reflex depressor action of 5-hydroxytryptamine. Like 5-hydroxytryptamine, phenyldiguanide and certain other amidine derivatives caused pain when applied to the base of blisters in human subjects. Unlike 5-hydroxytryptamine, phenyldiguanide did not constrict perfused rat blood vessels or increase the tone of the rat fundal strip preparation of Vane (1957). Phenyldiguanide did not affect the sensitivity of these smooth muscle preparations to 5-hydroxytryptamine, but other amidine derivatives proved to be moderately strong antagonists of the vasoconstrictor actions of 5-hydroxytryptamine and of adrenaline. Unlike 5-hydroxytryptamine, phenyldiguanide did not produce gastric haemorrhage in the mouse. Phenyldiguanide did not prolong chloral hydrate sleeping time in mice by the same mechanism as did 5-hydroxytryptamine. Phenyldiguanide was not highly toxic to mice (LD50 being 240 mg./kg.). It is concluded that phenyldiguanide and certain other amidine derivatives act on sensory receptors which respond to 5-hydroxytryptamine, but that they show little pharmacological resemblance to 5-hydroxytryptamine in other respects.

Gastric haemorrhage was produced regularly in mice within 6 hours of the subcutaneous injection of a large dose (2 to 10 mg./kg.) of reserpine or of deserpidine. Rescinnamine,, and tetrabenazine (Ro 1-9569) were less active. Gastric haemorrhage was also produced within 6 hours when 5-hydroxytryptamine (10 mg./kg.) was injected every half-hour. Neither reserpine nor 5-hydroxytryptamine produced gastric haemorrbage in mice which had been vagotomized by tying the oesophagus at the cardio-oesophageal junction or which had been pre-treated with iproniazid. Amphetamine was less effective than iproniazid in preventing gastric haemorrhage after reserpine, and the following drugs were ineffective: cocaine, methyl phenidate (Ritalin), amarin, caffeine, nikethamide, lysergic acid diethylamide and its 2-bromo derivative (BOL148). Gastric haemorrhage was not observed in mice which had been given substantial doses of atropine or of hexamethonium before reserpine. The incidence of haemorrhage was substantially reduced by treatment with an antacid mixture. It is concluded that reserpine-like drugs cause gastric haemorrhage by a mechanism which has an important central component and which involves the liberation of 5-hydroxytryptamine.Haverback and have shown that gastric erosion was produced in rats within 18 hr. of the injection of large doses of 5-hydroxytryptophan. Reserpine in large doses had a similar effect (Benditt and Wong, 1957;Haverback and Bogdanski, 1957;Blackman, Campion, and Fastier, 1958). Some of the pharmacological actions of both these drugs appear to be mediated by 5-hydroxytryptamine. Reserpine liberates 5-hydroxytryptamine from platelets and certain other parts of the body, and interferes with the uptake of 5-hydroxytryptamine, while 5-hydroxytryptophan is the natural precursor to 5-hydroxytryptamine (Pletscher, Shore, and Brodie, 1955; Page, 1958). Therefore, when we observed in experiments on mice that large doses of reserpine produced gastric haemorrhage and melaena within a few hours (Blackman et al., 1958), we supposed at first that this was a peripheral effect brought about by an increase in " free " 5-hydroxytryptamine. The possibility that it was a central effect was raised by our observation that reserpine did not produce gastric haemorrhage in mice which had been vagotomized at the cardio-oesophageal junction. Another observation at variance with our original hypothesis was that reserpine did not produce gastric haemorrhage in mice which had been previously treated with iproniazid (Blackman et al., 1958). Since iproniazid is a powerful inhibitor of mono-amine oxidase and is believed to delay the destruction of 5-hydroxytryptamine in the body (Page, 1958), it would be expected to enhance rather than antagonize the harmful effect of reserpine on the gastric mucosa, were the erosion brought about by the local action of 5-hydroxytryptamine. These anomalous findings induced us to carry out the experiments reported here. METHODS Male mice weighing 30 to 40 g. were used. During the 24 hr. period precedi...

Following the discovery of its action on the blood pressure [Smirk, 1941], S-methyl iso-thiourea sulphate has been used clinically by one of us (F. H. S.) as a pressor agent and some of its pharmacological properties have already been described [McGeorge, Sherif & Smirk, 1942]. While these investigations were in progress, a rapid examination of some eighty thiourea and iso-thiourea derivatives was carried out in the hope that other substances of therapeutic value might be obtained. Several iso-thiourea derivatives, especially those without N-substituents, were found to resemble S-methyl iso-thiourea in that their intravenous injection produced one or more of the following effects:(1) a prompt rise of arterial pressure, which with several derivatives remained elevated for periods ranging from five minutes to an hour or more; (2) slowing of the heart beat; (3) increased respiratory movements; (4) an increase in and sometimes prolongation of the pressor action of adrenaline. This paper records our observations on the circulatory properties of those iso-thioureas which were chosen for further study, viz. S-methyl, S-ethyl, S-iso-propyl, S-n-butyl and S-tert.-amyl iso-thioureas, of general formula R. S .