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In anaesthetized dogs at room temperatures of 28-33 degrees C, the cerebral ventricles were perfused with artificial CSF from the left lateral ventricular to the aqueductal cannulae. The animals' temperatures were recorded from the rectum. Addition of Ca(++) in excess to the artificial CSF perfusing the ventricles produced hyperthermia and addition of Na+ in excess produced hypothermia. Perfusion with medium deficient in Ca(++) and containing sodium edetate produced hypothermia. The temperature effects of Na(+) or Ca(++) in excess were mutually antagonistic.

Treatment with phenoxybenzamine and dichloroisoprenaline prevented the rise of blood pressure, contraction of the nictitating membrane and increase in cardiac contractile force produced by intravenous injections of bretylium and guanethidine in anaesthetized or spinal cats. Treatment with cocaine, imipramine or reserpine reduced the sensitivity to bretylium and guanethidine of the spinal cat. In the spinal cat treated with reserpine, sensitivity to the drugs could be restored by an infusion of noradrenaline. Chlorpromazine also blocked the pressor and nictitating membrane responses to bretylium and guanethidine. The drug effects were unaltered 1 hr after bilateral adrenalectomy. During the intravenous infusion of noradrenaline into spinal cats the pressor responses to bretylium and guanethidine were increased, whilst those to adrenaline and to noradrenaline were decreased. Guanethidine (3 to 5 mg/kg) injected intravenously into the cat caused a sudden relaxation of the rat isolated stomach-strip bathed in blood. In seven similar experiments bretylium (3 to 5 mg/kg) relaxed the strip only once; in the other six experiments there was either no effect (four experiments) or an increase in the tone of the strip (two experiments). It is concluded that the initial adrenergic effects of bretylium and guanethidine are mediated, at least in part, through a release of catechol amines from stores in the effector organ.

The uptake of dehydroemetine by adrenergic neurones was studied indirectly by testing the ability of various procedures to prevent or reverse adrenergic neurone blockade in the periarterially stimulated rabbit isolated ileum. Adrenergic neurone blockade was prevented but not reversed by equilibration with dehydroemetine at low temperature (0 degrees C), in the absence of sodium or in the presence of tetrodotoxin. Noradrenaline, cocaine, potassium deprivation and potassium excess did not modify the adrenergic neurone blocking action of dehydroemetine.

1. Insulin antibodies were induced in young guinea-pigs of both sexes weighing 300-400 g and housed in a room maintained at 28 degrees C+/-2 degrees C, by subcutaneous injection of 2 ml of freshly prepared insulin antigen emulsion between the shoulders once every month.2. To estimate the titre of serum antibody the serum was incubated with a known concentration of insulin for 90 min at 37 degrees C and the insulin not bound to antibody was estimated by the rat hemidiaphragm method.3. No significant (P>0.5) development of insulin antibody could be detected in the serum samples collected 1 month after the first and 15 days after the second monthly injections in groups of ten male guinea-pigs and six female guinea-pigs. However, the titre of insulin antibody in the serum of these groups of guinea-pigs 15 days after the third monthly injection of insulin antigen emulsion was significantly (P<0.01) raised. There was no further increase in the titre of insulin antibody in the sera 15 days after the fourth and fifth monthly injections of insulin antigen emulsion. Thus the peak titre was reached 15 days after the third monthly injection of the antigen.4. Two groups of ten male guinea-pigs each received testosterone propionate or diethylstilboestrol daily for 1 week after each monthly injection of insulin antigen emulsion. Two other groups of six female guinea-pigs each received testosterone propionate or diethylstilboestrol in a similar manner. One more group of ten female guinea-pigs received both sex hormones for 1 week after each monthly injection of insulin antigen emulsion. Testosterone facilitated the induction of insulin antibody in the serum of males but did not affect the antibody titre in the female guinea-pigs. Diethylstilboestrol facilitated the induction of insulin antibody in the serum of groups of either sex, the peak titre being attained after the second monthly injection of insulin antigen emulsion. The response of the females which received both sex hormones was similar to that of females which received diethylstilboestrol alone.5. Fifteen days after the third monthly injection of insulin antigen emulsion a group of ten guinea-pigs received hydrocortisone subcutaneously each day for 1 month. The serum antibody titre was estimated at the end of the drug treatment, and was significantly (P<0.01) reduced.6. Fifteen days after the third monthly injection of insulin antigen emulsion three different groups of five-six guinea-pigs each received tolbutamide, chlorpropamide or phenformin orally every day for a month. Antibody titres of the serum were estimated at the end of this period; there was no significant (P>0.05) reduction in groups receiving chlorpropamide or phenformin, but the serum antibody titre of the group receiving tolbutamide was significantly (P<0.01) raised.7. Fifteen days after the third monthly injection of insulin antigen emulsion different groups of five-six guinea-pigs received one of the following: 5-bromouracil, 5-fluorouracil, 6-mercaptopurine, methotrexate, 6-azauridine, busulphan, chlorambucil, cyclophosphamide, actinomycin-D or mytomycin-C intraperitoneally each day for 5 days. The serum antibody titre of all the groups of guinea-pigs was significantly (P<0.01) reduced. On the other hand the serum antibody titre of a control group of six guinea-pigs receiving normal saline intraperitoneally each day for 5 days was not significantly (P>0.5) affected.

Fifteen of twenty-one perfused human umbilical artery preparations constricted in response to tyramine. These responses were unaffected by atropine, mepyramine or bromolysergic acid diethylamide but were blocked by phentolamine or dihydroergotamine. Cocaine augmented the constriction responses to tyramine or noradrenaline but not those to adrenaline, acetylcholine or 5-hydroxytryptamine. Infusion of noradrenaline restored the responses of preparations which had become tachyphylactic to tyramine.

Enhancement of both excitatory and inhibitory responses to adrenaline, noradrenaline and isoprenaline was demonstrated with bretylium both in vivo and in vitro. Excitatory responses studied included rise of blood pressure and contraction of the nictitating membrane in cats and the contraction of aortic strip in rabbits; the inhibitory responses studied were fall of cat blood pressure and relaxation of rat uterus and rabbit tracheal chain. Possible mechanisms of potentiation of the effects of catechol amines by bretylium are discussed. A sensitization of the peripheral effector cells is suggested as a likely mechanism of potentiation.

Bretylium and guanethidine produced a block of neuromuscular transmission in the rat phrenic nerve diaphragm and cat sciatic gastrocnemius preparations, but had a potentiating effect on acetylcholine-induced contracture of the frog rectus. On the sciatic gastrocnemius preparation of the cat the compounds had a twofold action, consisting of an initial transient, and a delayed but more sustained, block of neuromuscular transmission. Bretylium and guanethidine had no immediate effect on the response of the muscle to direct stimulation, though a weak delayed depressant effect was observed. Intravenous injection of these compounds produced a flaccid paralysis in pigeons. Possible mechanisms of the neuromuscular blocking action of bretylium and guanethidine are discussed. Inhibition of acetylcholine release from motor nerve endings resulting from local anaesthesia by these compounds is suggested as a possible mechanism of their neuromuscular blocking action.

1. The uptake of guanethidine by adrenergic neurones has been studied indirectly by testing the ability of various procedures to prevent or reverse adrenergic neurone blockade in the periarterially stimulated isolated ileum preparation.2. Adrenergic neurone blockade was prevented but not reversed by equilibration with guanethidine (3.3 x 10(-6)M) at low temperatures (10 degrees C), in the absence of sodium or in the presence of tetrodotoxin (0.3 x 10(-6)M) or noradrenaline (1.2 x 10(-3)M).3. Calcium (5 x 10(-2)M) both prevented and, to some extent, reversed the adrenergic neurone blocking action of guanethidine.4. Equilibration with guanethidine in the presence of mersalyl (0.6 x 10(-7)M) or in the absence of potassium or calcium could neither prevent nor reverse adrenergic neurone blockade.