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Influence of chronic treatment of rats with and calcium channel blockers (CCBs) and isoprenaline (ISP) on responses to noradrenaline (NA) was investigated on electrically--driven isolated right ventricle preparations. The ventricles were obtained from animals treated with chronic ISP or CCBs alone and chronic nifedipine, verapamil, diltiazem or nimodipine plus chronic ISP. A decreased response to NA as evidenced by an increase in EC50 for contraction which was observed in chronic ISP- treated preparations may be due to development of desensitisation (down-regulation) of beta-adrenoceptors. In chronic CCB-treated preparations there was a significant decrease in the EC50 of NA and decreased contractile response suggesting an increase in the beta-adrenoceptors and decreased availability of calcium, respectively. In chronic CCBs + ISP treated preparations further decreases in the EC50 values were observed suggesting that the voltage gated L-type Ca2+ channels may be affected directly or indirectly by change in beta-adrenoceptor activity. By the above results a proposed mechanism of interrelationship of beta-adrenoceptors with voltage gated L-type calcium channels in cardiac muscle is supported.

1 The cerebral ventricles of dogs under intravenous pentobarbitone sodium anaesthesia, were perfused with artificial cerebro-spinal fluid (CSF) at a rate of 0.4-0.5 ml/min from the ventricular to the aqueductal cannulae. The effluent was collected from the aqueductal cannula in 20 min samples. The animals' temperatures were recorded from the rectum.2 gamma-Aminobutyric acid (GABA) 0.1-5 mg when injected into the ventricles produced variable temperature effects. Doses of 0.1 and 0.5 mg always produced hyperthermia and 1 and 5 mg doses sometimes produced hyperthermia and sometimes hypothermia.3 Intraventricular perfusion with 2-bromolysergic acid diethylamide (BOL) and hyoscine did not block hyperthermia. Tests on the rat isolated stomach strip or the guinea-pig isolated superfused ileum for the possible release, respectively, of 5-hydroxytryptamine or acetylcholine by GABA were negative.4 When tested for the presence of prostaglandin E(PGE)-like substances on the isolated rat stomach strip, both the control effluent and the GABA effluent showed activity, the latter being much more potent. There was a temporal correlation between this effect and hyperthermia. Intraventricularly administered sodium salicylate converted the GABA-induced hyperthermia to hypothermia and blocked the release of PGE-like substances.5 Hypothermia induced by GABA alone or in the presence of sodium salicylate was associated with the release of noradrenaline into the effluent.6 Intraventricular administration of GABA in reserpinized dogs produced hyperthermia and not hypothermia. Similar results were obtained with phentolamine perfusion in normal dogs.7 Perfusion with calcium-free solution blocked both the noradrenaline-releasing and hypothermic actions of GABA.8 It is concluded that hyperthermia associated with intraventricular injections of GABA is due to the release of PGE-like substance and hypothermia is due to the release of noradrenaline.

Albino rats of either sex received chronic ethinyl oestradiol (EO) treatment (1.5 mg kg-1 daily, i.m.) for 3 weeks. Untreated control rats received arachis oil vehicle alone. Chronic EO treatment resulted in elevation of blood pressure in both sexes. Female rats exhibited significantly greater elevation in blood pressure than males. In chronic EO-treated rats pressor responses to low doses (0.5 micrograms kg-1) of noradrenaline were significantly increased, while those to angiotensin II, acetylcholine and isoprenaline were unaltered. Chronic EO treatment also sensitized the vascular bed of the rats' hindquarters to noradrenaline. EO-induced hypertension was associated with significant increase in dopamine-beta-hydroxylase activity of adrenal glands. Complete bilateral adrenalectomy or chemical sympathectomy prevented the development of EO-induced hypertension. It is suggested that chronic treatment of rats with EO induces and maintains hypertension. The peripheral sympathetic system plays an important role in this phenomenon.

1 Stimulation of periarterial nerves to the ileum of 1 to 12 day old rabbits with supramaximal voltages and frequencies of 1, 2, 5, 10 and 20 Hz with square wave pulses of 2--5 ms duration for 30--40 s produced responses that were initially contractor. In the course of the first week, the responses changed from motor to inhibitory, the change occurring first at the highest rates of stimulation. By the 7th day of life, almost all responses were inhibitory. 2 The motor responses were potentiated by physostigmine and blocked by hyoscine suggesting that they were mediated by acetylcholine. 3 In preparations from rabbits older than 3 days, motor responses could be converted to inhibitory ones by prior exposure to noradrenaline (NA, 1 microgram/ml) for 20 min. This procedure also significantly increased the responses which were already inhibitory. 4 The ability of the ileum to take up NA increased with age. This uptake was blocked by cocaine. 5 The following explanations are possible: (a) changeover from cholinergic to adrenergic transmission in sympathetic fibres; (b) existence of 'parasympathetic' splanchnic nerves or a permanent cholinergic 'sympathetic' component of splanchnic nerves and (c) temporal delay in the development of adrenergic nerves (compared with cholinergic nerves) in the intestine.

The uptake of exogenously added noradrenaline (NA) (0.5-2.5 mug/ml) by the human umbilical artery was linear with time up to 10 minutes. The uptake was saturable and could be described by the Michaelis-Menten equation. The uptake was cocaine-resistant, normetanephrine-sensitive, was considerably inhibited in the cold and was partially inhibited by Na+- deficiency. Of NA accumulated in the artery 31% could be washed out by NA-free medium. It is concluded that the mechanism of uptake of NA by the human umbilical artery is similar to the uptake2 mechanism.

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.

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.

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.

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.

Bretylium and guanethidine blocked the pressor effect of physostigmine and potentiated the responses to adrenaline and noradrenaline on the blood pressure of the rat. Morphine and atropine in small doses blocked the pressor effect of physostigmine without interfering with the actions of adrenaline and noradrenaline. Chlorpromazine in small doses (0.5 to 2.5 mg/kg) blocked the pressor effect of physostigmine and potentiated the responses to noradrenaline whilst those to adrenaline remained unaltered. 3,6-Di(3-diethylaminopropoxy)pyridazine di(methiodide) (Win 4981) blocked the pressor effect of physostigmine and, in its early stages, this block was partially reversed by choline chloride. N-Diethylaminoethyl-N-isopentyl-N'N'-diisopropylurea (P-286), in a dose that reduced the effect of dimethylphenylpiperazinium, had no effect on the pressor response to physostigmine or on the responses to adrenaline and noradrenaline. Hexamethonium, even in large doses (100 mg/kg), only blocked partially the effect of physostigmine while mecamylamine produced a complete block; the responses to adrenaline and noradrenaline were potentiated in both instances.

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.

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.

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.

In spinal rats physostigmine failed to produce a pressor response even after treatment of the animals with hexamethonium, whereas noradrenaline, McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride) and AHR602 (3-acetoxy-1-benzyl-1-methylpyrrolidinium bromide) all produced large pressor effects. In rats anaesthetized with urethane, hexamethonium completely abolished the pressor effect of dimethylphenylpiperazinium but only partially blocked the pressor response to physostigmine; pressor effects of noradrenaline, McN-A-343 and AHR602 were potentiated. Combined treatment with hexamethonium and atropine and with hexamethonium and cocaine, however, completely abolished the pressor effect of physostigmine; simultaneously the pressor effects of McN-A-343 and AHR602 as well as of dimethylphenylpiperazinium were also blocked. P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea) produced an early and a late block of the pressor effect of physostigmine; the initial block was due to an adrenergic blocking action while the late block was probably due to a dual action of the drug in abolishing the effects of both the nicotinic and non-nicotinic ganglion stimulants. Pressor responses to physostigmine, McN-A-343, AHR602 and dimethylphenylpiperazinium were abolished immediately after ganglion-blocking doses of nicotine. It is suggested that an unusual ganglionic pathway participates in the mediation of the pressor response to physostigmine in the rat, especially when the established ganglionic pathways are blocked.

Antagonism by chlorpromazine of the responses of the rabbit aortic strip and the rat seminal vesicle to adrenaline and noradrenaline fulfils the conditions of competitive antagonism. Chlorpromazine was a remarkably potent antagonist (pA(2) approximately 14) of adrenaline and noradrenaline. In the cat anaesthetized with chloralose small doses (1.8 to 4.5 mg/kg) of chlorpromazine greatly reduced or reversed the pressor effect of adrenaline but the pressor effect of noradrenaline was unaffected. A larger dose (9 mg/kg) of chlorpromazine slightly reduced the pressor effect of noradrenaline but caused a spectacular reversal of the pressor effect of adrenaline. This difference was not observed in rabbits and in cats treated with dichloroisoprenaline. Chlorpromazine potentiated the depressor effect of isoprenaline. On the basis of these findings it is concluded that in the cat chlorpromazine in small doses (1.8 to 4.5 mg/kg) has no real adrenergic blocking action and that the selective block of adrenaline pressor effects by these doses is due to a potentiation of adrenergic vasodilatation. Large doses (7.2 to 28.8 mg/kg) of chlorpromazine reduced the pressor effect of noradrenaline; reciprocal analysis showed that this inhibition is competitive.

1. The ability of alpha-methyl amino-acids and their corresponding amines to restore the sympathomimetic actions of tyramine, and the uptake of the amino-acids and the amines, were studied in isolated tissue preparations obtained from reserpine pretreated animals.2. Tyramine relaxed isolated rat ileum preparations from non-reserpinized rats but not from reserpine treated animals. alpha-Methyldopa, alpha-methylnoradrenaline and lower concentrations of metaraminol restored the responses of reserpinized preparations. alpha-Methyldopamine, alpha-methyl-m-tyrosine, alpha-methyl-p-tyrosine and higher concentrations of metaraminol did not do so. The restoring effect of alpha-methyldopa was blocked by disulphiram. alpha-Methyl-p-tyrosine or alpha-methyl-m-tyrosine blocked the restoring action of alpha-methyldopa but not of alpha-methylnoradrenaline. Cocaine blocked the restoration of responses to tyramine by alpha-methylnoradrenaline but not by alpha-methyldopa. alpha-Methyldopa and alpha-methylnoradrenaline failed to restore responses to tyramine in the presence of sodium-free Tyrode solution.3. Tyramine increased the perfusion pressure in isolated rabbit ear preparations obtained from non-reserpinized animals but was very much less active in preparations obtained from reserpine treated animals. alpha-Methyldopa, alpha-methyl-m-tyrosine, alpha-methylnoradrenaline, alpha-methyl-p-tyrosine and metaraminol restored the effects of tyramine. alpha-Methyldopamine did not do so. The restoring effect of alpha-methyldopa and alpha-methyl-m-tyrosine was blocked by disulfiram. alpha-Methyl-p-tyrosine blocked the restoring effect of alpha-methyl-m-tyrosine.4. Tyramine produced positive inotropic effects in isolated rabbit heart preparations. This was either reduced or absent in preparations obtained from reserpine pretreated animals. alpha-Methyldopa, alpha-methylnoradrenaline, alpha-methyl-m-tyrosine and metaraminol restored the responses to tyramine. alpha-Methyldopamine and alpha-methyl-p-tyrosine did not do so.

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.