John H. Wyllie

EFFECTS IN MAN OF HISTAMINE H2-RECEPTOR BLOCKADE BY BURIMAMIDE

Abstract Burimamide is a new type of histamine antagonist; it blocks the H 2 -receptors involved not only in histamine-induced stimulation of gastric secretion but in certain other pharmacological responses as well. This paper shows that burimamide can antagonise gastric secretion in man when this is stimulated by intravenous infusion of high doses of either histamine or pentagastrin. Burimamide is far more effective than atropine as an inhibitor of gastric acid secretion and, unlike atropine, it produces no acute side-effects.

TREATMENT OF DUODENAL ULCER WITH CIMETIDINE

In a small open trial nineteen patients with active duodenal ulceration shown by fibreoptic endoscopy were treated with a 6-week course of cimetidine 1.6 g daily. Seventeen had healed ulcers on repeat endoscopy at 6 weeks. Seven of these have relapsed symptomatically within a month of withdrawal of cimetidine. No statistically significant change in the haemoglobin, white-blood-cell count, urea and electrolytes, or liver-function tests was associated with treatment. Plasma-creatinine showed a very small but significant rise but the mean level remained within the normal range. The significance of this is not clear.

Stimulation of mucus output from rat colon in vivo

Sodium chloride (155 mM) and N-acetyl cysteine (6 mM) were recirculated through the colons of anaesthetized rats. Mucus accumulated in the perfusion fluid which was changed at intervals to allow mucus output to be estimated by measurement of hexose. The output of mucus could be stimulated by intravenous administration of the cholinergic drugs carbachol and bethanechol; this effect was inhibited by atropine. Mucus output could also be stimulated by intravenous 5-hydroxytryptamine. This was not a muscarinic cholinergic effect because atropine did not prevent it. Neither did methysergide inhibit it; but chlorpromazine did. Precursors of 5-hydroxytryptamine, 5-hydroxytryptophan and L-tryptophan, also stimulated mucus output if given in high dosage. The results suggest that in this preparation mucus output can be stimulated by two distinct mechanisms, one cholinergic, the other involving 5-hydroxytryptamine and perhaps 5-hydroxytryptophan.

Evidence for purinergic transmission in mouse bladder and for modulation of responses to electrical stimulation by 5-hydroxytryptamine

Electrical stimulation (ES) contracted superfused mouse bladder, and 10(-7) M tetrodotoxin (TTX) abolished the twitches without impairing responses to acetylcholine (ACh) or beta,gamma-methylene ATP. ES acted largely through nerves which were not cholinergic, adrenergic or histaminergic. They may be purinergic because the bladder was contracted by stable analogues of ATP, and after desensitisation by a high concentration of alpha,beta-methylene ATP the response to ES was selectively reduced. 5-Hydroxytryptamine (5-HT) at 0.03-3 X 10(-6) M and tetraethylammonium (TEA) at 0.1-10 X 10(-3) M potentiated responses to ES, on average by 64% and 182%. Pempidine had no effect on responses to ES. The action of TEA was different from that of 5-HT; potentiation of responses was greater than could be produced by 5-HT, and whereas 5-HT did not increase responses to ACh, TEA markedly increased twitch tensions. The mode of action of 5-HT is not clear.

SOME PROPERTIES OF 5‐HYDROXYTRYPTAMINE RECEPTORS IN THE HINDQUARTERS OF THE RAT

1 The rat hindquarter preparation, as described, responds with reproducible vasoconstriction to noradrenaline and tryptamines. 2 The receptors involved in these responses are distinct. 3 Evidence of heterogeneity of tryptamine receptors was not obtained. 4 The 5‐hydroxytryptamine (5‐HT) antagonists, methysergide and cyproheptadine, although very potent, displayed antagonism of a non‐competitive type whereas a series of phenothiazines and phentolamine displayed competitive antagonism against 5‐HT. 5 For the phenothiazines the order of increasing potency was promazine < chlorpromazine < triflupromazine.