A polyneuropathy affecting a large number of workers was recently observed at a plant producing plastic-coated and color-printed fabrics. Epidemiological data suggested strongly that methyl N-butyl ketone (MBK) was responsible for the outbreak. This hypothesis is now supported by the development of a peripheral neuropathy in chickens, rats, and cats exposed to MBK at atmospheric concentrations of 200 to 600 parts per million, 24 hours per day, 7 days per week. Although the animals were exposed continuously and the affected workers were exposed intermittently, the averages of the total number of hours of exposure for development of the peripheral neutropathy in the animals and workers were remarkably close.
The role of a cholinergic muscarinic inhibitory mechanism in sympathetic neurotransmission was investigated in isolated rabbit and guinea pig hearts with intact sympathetic nerves. The effect of varying frequencies of stimulation (2.5, 5 and 10 Hz) on the concentration of noradrenaline (NA) and dopamine-beta-hydroxylase (DBH) released into the perfusate was investigated. Stimulation in the presence of atropine sulfate (3.4 micrometer) resulted in an augmented outflow of NA at all three frequencies while DBH outflow was significantly incrreased only at 5 and 10 Hz. d-Tubocurarine (2.0 micrometer) attenuated the augmenting effect of atropine on NA release at all frequencies of stimulation whereas it negated the significant effect of atropine on DBH release. Nerve stimulation in the presence of acetylcholine (0.55 micrometer) resulted in a significant decrease in the concentrations of NA and DBH in the perfusate. It is suggested that atropine augments NA outflow in part by blocking an "intrinsic" muscarinic inhibitory mechanism. Acetylcholine's inhibitory effect on NA release is reflected in a similar decrease in DBH release and, therefore, may function in vivo via an effect on exocytosis at the adrenergic nerve ending.
The pressor response to acetylcholine in the atropinized dog resulted from an increase in cardiac output. The pressor response was attributed solely to the release of adrenaline from the adrenal medulla. After giving compound P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea) to these dogs, acetylcholine lowered blood pressure, owing to a decrease in total peripheral resistance in the absence of an increase in cardiac output. P-286 presumably blocked the liberation of adrenaline from the adrenal glands by acetylcholine. The blood vessels contributing to the fall in peripheral resistance were not in the intestines. The fall in blood pressure was not blocked by dichloroisoprenaline and it was still present in dogs treated with reserpine. It is suggested that the fall in blood pressure was due to stimulation of ganglion cells subserving vasodilatation.The pressor action of an intravenous injection of acetylcholine into the atropinized dog is reversed after the release of catechol amines from the adrenal medulla has been blocked by N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea, P-286 (Gardier, Abreu, Richards & Herrlich, 1960). The mechanism suggested by Shaw, Keogh & MacCallum (1948) and Shaw & MacCallum (1949) to explain the reversal, by various drugs, of the pressor response to acetylcholine after atropine is that acetylcholine stimulates sympathetic ganglion cells subserving vasodilator functions, the effect of which is revealed in the absence of pressor activity. In our opinion insufficient evidence has been available to substantiate this hypothesis.The studies reported here are concerned with the mechanism of the vasodepressor response to acetylcholine after administration of P-286 into the atropinized dog; in addition evidence is given that the pressor response to acetylcholine results from specific stimulation of the adrenal medulla.
METHODSAdult mongrel dogs, of either sex, were maintained in stage III, plane 3 of general anaesthesia with sodium pentobarbitone (30 mg/kg, intravenously); small supplementary doses (2.5 to 5 mg/kg) were administered when necessary. The usual dose of atropine sulphate was 1 mg/kg,
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