(a) Hypotension was produced by quinuronium in rat, guinea pig, chicken, rabbit and sheep. In the rat this hypotension was antagonised by mepyramine; in rabbits only by atropine; in sheep partially by both atropine and mepyramine. In guinea pig and chicken neither antagonist was effective.
(b) Experiments on the blood vessels of the rabbit's ear showed a muscarinic effect of quinuronium, whereas plethysmo- graphic studies on the hind-limb and small intestine of the sheep showed that both histaminic and muscarinic factors were involved in the vascular actions, with the latter predominating.
(c) Quinuronium stimulated both the rate and amplitude of contraction of the isolated heart of guinea pig and rabbit. The effect was not muscarinic, but in the absence of a suitable antagonist it was not possible to determine the extent this might have been due to histamine or to histamine-like activity. The stimulant effect of quinuronium on the isolated heart suggested that such a cardiac action could play little part in inducing hypotension and it was concluded that peripheral vaso-dilatation was probably the more important factor.
(d) The contractions of the smooth muscle of the intestine and bladder by quinuronium appeared to be muscarinic and the
89. specific potentiating effect of this agent on the action of acetylcholine was evidence of anticholinesterase activity. The findings supported clinical evidence of defaecation end urination produced by quinuronium and antagonised by atropine.
(e) Excessive salivation after quinuronium appeared to be attributable to muscarinic effects, whereas the stimulation of gastric secretion by quinuronium was not entirely muscarinic. The potentiating action of quinuronium on acid production induced by acetylcholine was indicative of anticholinesterase activity. It was clear that part of the action of quinuronium on gastric acid secretion in rats was not muscarinic, but in the absence of antagonists of the gastric effects of histamine it was not possible to show whether or not this other action was histaminic.
(f) Small doses of quinuronium potentiated the contraction of supra-maximally stimulated skeletal muscle in chicken and rabbit, whereas larger doses produced a neuromuscular block apparently similar to that produced by d-tubocurarine. The effect of quinuronium in depressing respiration in these species was much greater than that of d-tubocurarine at doses which were equi-potent in producing neuromuscular block. This sugnested that respiratory depression of quinuronium was only partially accounted for by neuromuscular blockade.
(g) Anticholinesterase activity was shown in whole blood in vitro in a wide variety of species and was confirmed in the live sheep. There was evidence of substrate reversal of the action of quinuronium in vitro, whereas in the living sheep the cholinesteras
90, enzyme did not return to completely normal activity for two weeks, which suggested a partial irreversibility. Sheep were hyper- susceptible to a second dose of quinuronium when this was given within two weeks of the first dose. A number of explanations were proposed. Studies with the cholinesterase "reactivator" pyridine 2-aldoxime methiodide indicated that this agent did not protect or alleviate whole blood cholinesterase inhibition by quinuronium.
(h) Quinuronium was shown to liberate histamine from rat skin in vitro and from the skin of rats and mice in vivo. In the rat the evidence for histamina-induced hypotension and gastric acid secretion was substantiated by direct evidence for histamine release; and it seemed that released histamine was at least as important as muscarinic activity in this species. Direct evidence of histamine release from sheep diaphragm in vitro and indirect evidence from increased capillary permeability ("bluedye" test) and from mast cell disruption and degranulation indicate that histamine release is an important part in the overall pharmacodynamic activity of quinuronium in sheep.
(a) Experiments with the isolated rabbit ear showed that amicarbalide antagonised the action of acetylcholine on the blood vessels.
(b) Further evidence of an atropine like action was obtained from studies on the smooth muscle of the bladder and intestine.
c) Amicarbalide stimulated the secretion of gastric acid in the anaesthetised rat and neither atropine nor repyramine antago- nised this. Amicarbalide partially antagonised the action of acetylcholine on gastric acid secretion which was further evidence of an atropine like action.
(d) The anticholinesterase activity of amicarbalide was weak by comparison with quinuronium. This result was probably not clinically significant.
(e) The release of histamine by amicarbalide was most marked in rat tissue, absent in mice and weak in sheep in vitro and in vivo. The evidence suggests that in the rat, histamine release is a major factor in the toxicity of amicarbalide and in the sheep, histamine release is positive but of less significance.